GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P00742	P08709	2	binding	up-regulates activity	0.541	TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively.	SIGNOR-263545
P08709	P00742	2	cleavage	up-regulates activity	0.541	The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa.	SIGNOR-263523
P15172	Q6STE5	2	binding	up-regulates activity	0.538	We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes.	SIGNOR-238289
Q6STE5	P15172	2	binding	up-regulates	0.538	This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion	SIGNOR-136130
P23458	P52333	2	phosphorylation	up-regulates	0.536	Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.	SIGNOR-152917
P60484	P12931	2	phosphorylation	down-regulates	0.536	Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols.	SIGNOR-103721
P52333	P23458	2	phosphorylation	up-regulates	0.536	Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.	SIGNOR-152914
P12931	P60484	2	dephosphorylation	down-regulates activity	0.536	Antisense- or shRNA mediated downregulation of PTEN induced SRC Tyr416 phosphorylation, SRC activation, and ultimately elevated TZMB resistance, whereas induction of PTEN phosphatase activity directly dephosphorylated SRC Tyr416 residue and so abolished SRC activity .\|These observations indicate that the loss of PTEN phosphatase activity induces SRC activation and so implicates SRC in shaping de novo TZMB resistance in PTEN deficient cells .	SIGNOR-277009
O60674	P15509	2	binding	up-regulates activity	0.533	JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.	SIGNOR-249502
P15509	O60674	2	phosphorylation	up-regulates activity	0.533	JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.	SIGNOR-249503
Q9UKV5	P06744	2	binding	up-regulates	0.53	Pgi is a housekeeping gene encoding phosphoglucose isomerase (pgi) a glycolytic enzyme that also functions as a cytokine (autocrine motility factor (amf)/neuroleukin/maturation factor) upon secretion from the cell and binding to its 78 kda seven-transmembrane domain receptor (gp78/amf-r)	SIGNOR-97270
Q14457	Q92995	2	deubiquitination	up-regulates quantity by stabilization	0.53	Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E)	SIGNOR-260295
P06744	Q9UKV5	2	polyubiquitination	down-regulates quantity by destabilization	0.53	Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF.	SIGNOR-272177
Q92995	Q14457	2	deubiquitination	up-regulates quantity by stabilization	0.53	We found that endogenous Beclin1 can interact with USP13 and the interaction was reduced in the presence of spautin-1 (Figure 5C). Interestingly, the DUB activities were significantly increased when USP13 and USP10 coincubated together or with Beclin1 or all 3 proteins together, suggesting the DUB activity can be significantly enhanced when USP13 interacts with its substrate Beclin1 or USP10.	SIGNOR-260296
P22681	P06213	2	phosphorylation	up-regulates activity	0.528	Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation.	SIGNOR-251304
P06213	P22681	2	ubiquitination	down-regulates	0.528	Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor	SIGNOR-109688
P29350	P12931	2	phosphorylation	up-regulates	0.527	Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells.	SIGNOR-120492
P09619	P00519	2	phosphorylation	down-regulates activity	0.527	C-Abl phosphorylates three tyrosine residues on PDGFR-β (Y686, Y934, Y970) \| These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis.	SIGNOR-260931
P00519	P09619	2	phosphorylation	up-regulates activity	0.527	Here, we show that PDGFR-beta-phosphorylation of Abl kinases has functional consequences as PDGFR-beta phosphorylates Abl kinases on Y245 and Y412, sites known to be required for activation of Abl kinases.	SIGNOR-278319
P12931	P29350	2	dephosphorylation	up-regulates activity	0.527	Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B	SIGNOR-248472
O43526	O43525	2	binding	up-regulates activity	0.515	The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current.	SIGNOR-268832
O43525	O43526	2	binding	up-regulates activity	0.515	The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current.	SIGNOR-268833
Q13362	P28482	2	phosphorylation	down-regulates	0.513	Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.	SIGNOR-144313
P28482	Q13362	2	binding	down-regulates	0.513	B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk	SIGNOR-144325
Q14457	Q14694	2	deubiquitination	up-regulates quantity by stabilization	0.509	Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E)	SIGNOR-260299
Q14694	Q14457	2	deubiquitination	up-regulates quantity by stabilization	0.509	Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities.	SIGNOR-260298
P10721	Q9ULZ2	2	binding	up-regulates activity	0.507	STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.	SIGNOR-261822
Q9ULZ2	P10721	2	phosphorylation	up-regulates activity	0.507	STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.	SIGNOR-261820
P38398	P31749	2	phosphorylation	up-regulates	0.506	Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation	SIGNOR-154312
P31749	P38398	2	ubiquitination	down-regulates quantity by destabilization	0.506	The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation	SIGNOR-252435
O75385	P54646	2	phosphorylation	up-regulates	0.505	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-186637
P54646	O75385	2	phosphorylation	down-regulates	0.505	Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit.	SIGNOR-173050
O75626	Q02548	2	transcriptional regulation	down-regulates quantity	0.502	Overexpression of BSAP reduced Blimp-1 expression in CH12.LX.A2 clones but not in MPC11 clones. In addition, overexpression of BSAP in CH12.LX.A2 cells suppressed spontaneous appearance of cells with high Syndecan-1 expression and high amounts of intracytosolic as well as secreted Ig synthesi	SIGNOR-269085
Q02548	O75626	2	transcriptional regulation	down-regulates quantity	0.502	Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner.	SIGNOR-269089
Q99801	P10275	2	transcriptional regulation	up-regulates quantity by expression	0.502	Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events.	SIGNOR-251546
P10275	Q99801	2	transcriptional regulation	down-regulates quantity by repression	0.502	Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events.	SIGNOR-251547
Q06187	Q08881	2	phosphorylation	down-regulates activity	0.497	Btk-SH3 mutant Y223A was not phosphorylated by Itk. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.\|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role	SIGNOR-251333
Q08881	Q06187	2	phosphorylation	up-regulates	0.497	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanismthe major phosphorylation sites were identified as conserved tyrosines, for itk y180	SIGNOR-98036
P42680	Q06187	2	phosphorylation	up-regulates	0.496	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated	SIGNOR-98086
Q06187	P42680	2	phosphorylation	down-regulates activity	0.496	Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the SH3 domain via a transphosphorylation mechanism, which for Bruton's tyrosine kinase (Btk) affects tyrosine 223.\|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role	SIGNOR-246652
P01023	P14780	2	cleavage	down-regulates quantity by destabilization	0.492	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.\|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261740
P14780	P01023	2	binding	down-regulates activity	0.492	Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity\| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261801
P28360	P50458	2	binding	down-regulates activity	0.477	Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity	SIGNOR-241327
P50458	P28360	2	binding	down-regulates activity	0.477	Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity	SIGNOR-241330
Q16539	P43403	2	phosphorylation	up-regulates activity	0.476	Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323.	SIGNOR-276030
P43403	Q16539	2	phosphorylation	down-regulates activity	0.476	We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex.	SIGNOR-277384
Q96LT7	P62820	2	binding	up-regulates activity	0.474	Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.	SIGNOR-261282
Q13363	O60315	2	binding	up-regulates activity	0.474	The two members of the ZEB family of zinc finger factors (ZEB-1/deltaEF1 and ZEB-2/SIP1) regulate TGFbeta/BMP signaling in opposite ways: ZEB-1/deltaEF1 synergizes with Smad-mediated transcriptional activation, while ZEB-2/SIP1 represses it. Here we report that these antagonistic effects by the ZEB proteins arise from the differential recruitment of transcriptional coactivators (p300 and P/CAF) and corepressors (CtBP) to the Smads. Thus, while ZEB-1/deltaEF1 binds to p300 and promotes the formation of a p300-Smad transcriptional complex, ZEB-2/SIP1 acts as a repressor by recruiting CtBP.	SIGNOR-268953
O60315	Q13363	2	binding	up-regulates activity	0.474	Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP	SIGNOR-225484
P62820	Q96LT7	2	binding	up-regulates activity	0.474	C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation	SIGNOR-261297
P24385	Q92769	2	binding	up-regulates	0.469	Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.	SIGNOR-134062
Q92769	P24385	2	binding	up-regulates	0.469	Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.	SIGNOR-134053
P06241	P17612	2	phosphorylation	up-regulates	0.459	The serine 21 (s21) residue of fyn is a protein kinase a (pka) recognition site within an rxxs motif of the amino terminal sh4 domain of fyn. In addition, s21 is critical for fyn kinase-linked cellular signaling. Mutation of s21a blocks pka phosphorylation of fyn and alters its tyrosine kinase activity.	SIGNOR-167147
Q9UN86	Q13283	2	binding	up-regulates activity	0.459	Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli.	SIGNOR-260862
Q13283	Q9UN86	2	binding	up-regulates activity	0.459	Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli.	SIGNOR-260863
P17612	P06241	2	phosphorylation	up-regulates activity	0.459	We found that the Src family kinase Fyn phosphorylates the catalytic subunit of PKA (PKA-C) at Y69, thereby increasing PKA kinase activity.	SIGNOR-277410
P31749	Q01860	2	transcriptional regulation	down-regulates quantity by repression	0.457	Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription.	SIGNOR-252635
Q01860	P31749	2	phosphorylation	up-regulates quantity by stabilization	0.457	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-252545
Q5S007	Q14155	2	binding	up-regulates	0.456	Arhgef7 is interacting with lrrk2 in vitro and in vivo. Gtpase activity of full-length lrrk2 increases in the presence of recombinant arhgef7. Arhgef7 might act as a guanine nucleotide exchange factor for lrrk2	SIGNOR-169217
O15146	O96014	2	binding	up-regulates	0.456	Musk has an extracellular region with homology to the frizzled crd,binding of which by wnt11 stimulates a pcp-like pathway during neuromuscolar development. Here, we show that in vivo, wnt11r and wnt4a initiate musk translocation from muscle membranes to recycling endosomes we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase	SIGNOR-199641
Q14155	Q5S007	2	phosphorylation	up-regulates	0.456	Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence	SIGNOR-169221
O96014	O15146	2	binding	up-regulates	0.456	Like ror, musk has an extracellular region with homolgogy to the frizzled crd, binding of which by wnt11 stimulates a pcp-like pathway during neuromuscular development	SIGNOR-199518
P24941	P22674	2	binding	up-regulates activity	0.453	Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2\|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O	SIGNOR-275616
P22674	P24941	2	phosphorylation	up-regulates activity	0.453	Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2\|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O\|CKD2 phosphorylates the 81st serine residue of cyclin O	SIGNOR-275615
Q9ULJ6	P46531	2	binding	up-regulates activity	0.452	The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions	SIGNOR-263937
P46531	Q9ULJ6	2	binding	up-regulates activity	0.452	The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions	SIGNOR-263936
P49757	Q00987	2	ubiquitination	down-regulates	0.444	These data strongly suggest thatmdm2functions as the ubiquitin ligase toward hnumb and that it induces its degradation in intact cells.	SIGNOR-99497
Q00987	P49757	2	binding	down-regulates	0.444	Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53	SIGNOR-168454
Q00987	P32121	2	binding	up-regulates quantity by stabilization	0.434	Our current results demonstrated that the binding of Mdm2 to beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination.	SIGNOR-272592
P32121	Q00987	2	ubiquitination	down-regulates quantity	0.434	Indeed, the ubiquitination of \u03b2-arrestin2 by Mdm2 H457S was severely reduced in comparison to Mdm2 wt ( xref ).\|Loss of Mdm2 E3 ligase activity causes dominant nuclear localization of beta-arrestin2.	SIGNOR-278760
P10827	P10276	2	binding	up-regulates	0.432	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-133231
P10276	P10827	2	binding	up-regulates	0.432	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-133240
P67775	P12931	2	phosphorylation	down-regulates	0.43	We found that ?-Syn gene overexpression in sk-n-sh cells and primary neurons led to pp2a/c phosphorylation at y307, a known target of src kinase, and consequent phosphatase inhibition.	SIGNOR-202192
P12931	P67775	2	dephosphorylation	down-regulates activity	0.43	We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC	SIGNOR-247970
P00533	P30530	2	phosphorylation	up-regulates activity	0.43	AXL trans-actives EGFR in a ligand independent manner and induces phosphorylation of EGFR on tyrosine 1173.\|In our models AXL seems to induce a re-wiring of the EGFR signaling towards the PLCgamma-PKC axis by receptor phosphorylation at tyrosine 1173.	SIGNOR-279141
P30530	P00533	2	phosphorylation	up-regulates activity	0.43	In this study, we have identified for the first time a direct interaction between EGFR and Axl RTKs, with EGF and EGFR induced activation of Axl as a novel signalling pathway to invasion in cancer cells.\|The activation of Axl was shown to occur through direct phosphorylation by EGFR of Axl tyrosine 779, one of the key residues within Axl that serves as a multi-substrate docking site for further downstream signalling.	SIGNOR-279734
Q12933	P61088	2	ubiquitination	up-regulates activity	0.428	Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38.	SIGNOR-121274
P61088	Q12933	2	binding	up-regulates activity	0.428	Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades.	SIGNOR-179479
P14921	Q99684	2	binding	down-regulates activity	0.426	Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. 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.	SIGNOR-254201
Q99684	P14921	2	binding	down-regulates activity	0.426	Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. 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.	SIGNOR-254202
P53350	P78527	2	phosphorylation	up-regulates activity	0.425	DNA-PKcs Promotes Plk1 Activation.\|Further analysis revealed that DNA-PKcs could directly phosphorylate the C-terminal PBD domain of Plk1 (lane 8).	SIGNOR-279562
P78527	P53350	2	phosphorylation	up-regulates activity	0.425	Moreover, PLK1 phosphorylates DNA-PKcs directly on Ser 3205 invitro, suggesting that DNA-PKcs Ser 3205 is a direct target of PLK1 in mitosis.	SIGNOR-278188
P27361	Q13362	2	binding	down-regulates	0.42	B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk	SIGNOR-144328
Q13362	P27361	2	phosphorylation	down-regulates	0.42	Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.	SIGNOR-144317
P13631	P10827	2	binding	up-regulates	0.419	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.	SIGNOR-133246
P10827	P13631	2	binding	up-regulates	0.419	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-133237
P10827	P10826	2	binding	up-regulates	0.416	We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-133234
P10826	P10827	2	binding	up-regulates	0.416	Ee report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs	SIGNOR-133243
O75592	P01106	2	transcriptional regulation	down-regulates quantity by repression	0.415	We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop.	SIGNOR-267145
P01106	O75592	2	ubiquitination	down-regulates quantity by destabilization	0.415	We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop.	SIGNOR-267147
P06733	P01106	2	transcriptional regulation	up-regulates quantity	0.411	C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.	SIGNOR-259989
P01106	P06733	2	transcriptional regulation	down-regulates quantity by repression	0.411	This result suggests that MBP-1 in vivo acts as a sequence-specific repressor.	SIGNOR-261594
O75843	P46934	2	monoubiquitination	up-regulates activity	0.401	Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination.	SIGNOR-272634
P46934	O75843	2	binding	up-regulates activity	0.401	Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination.	SIGNOR-272636
P00519	P16333	2	binding	down-regulates activity	0.4	We also show that overexpression of nck could repress the phosphorylation of cbl by abl in vivo. Studies with nck mutants suggested that the nck sh2 domain is responsible for inhibiting the activity of abl toward both cbl and nck itself, most likely by competing with the abl sh2 for tyrosine-phosphorylated binding sites	SIGNOR-109672
P16333	P00519	2	phosphorylation	up-regulates	0.4	Activated c-abl reduces the amplitude of mitogen-activated protein kinases (erk1/2, jnks and p38) activation in a dose-dependent manner by a negative feedback mechanism. By analysis of the adaptor proteins nck1 and grb2 mutants we further show that the negative loop on p38 is mediated by c-abl phosphorylation at tyrosine 105 of the adaptor protein nck1	SIGNOR-196043
P28360	Q07687	2	binding	down-regulates activity	0.399	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240918
Q07687	P28360	2	binding	down-regulates activity	0.399	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240929
P06241	P10586	2	dephosphorylation	down-regulates	0.396	Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule.	SIGNOR-96768
P10586	P06241	2	phosphorylation	up-regulates activity	0.396	LAR PTPase domain 2 was tyrosine phosphorylated by Fyn tyrosine kinase. we confirmed that LAR dephosphorylated the phosphorylated tyrosine residues of Lck and Fyn, and tyrosine residue(s) in LAR PTPase D2 was phosphorylated by Fyn to supply Fyn SH2 binding site.	SIGNOR-251180

P00742

P08709

2

binding

up-regulates activity

0.541

TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively.

SIGNOR-263545

P08709

P00742

2

cleavage

up-regulates activity

0.541

The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa.

SIGNOR-263523

P15172

Q6STE5

2

binding

up-regulates activity

0.538

We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes.

SIGNOR-238289

Q6STE5

P15172

2

binding

up-regulates

0.538

This suggests a novel mechanism by which myod interacts with the promoter indirectly via pbx-1 and recruits chromatin-remodeling enzymes, which then facilitate the binding of myod and other regulators. Demonstration of physical interactions between brg1 and myod and brg1 and pbx support this conclusion

SIGNOR-136130

P23458

P52333

2

phosphorylation

up-regulates

0.536

Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.

SIGNOR-152917

P60484

P12931

2

phosphorylation

down-regulates

0.536

Activated src reduces the ability of pten to dephosphorylate phosphatidylinositols in micelles and promotes akt translocation to cellular plasma membranes but does not alter pten activity toward water-soluble phosphatidylinositols.

SIGNOR-103721

P52333

P23458

2

phosphorylation

up-regulates

0.536

Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.

SIGNOR-152914

P12931

P60484

2

dephosphorylation

down-regulates activity

0.536

Antisense- or shRNA mediated downregulation of PTEN induced SRC Tyr416 phosphorylation, SRC activation, and ultimately elevated TZMB resistance, whereas induction of PTEN phosphatase activity directly dephosphorylated SRC Tyr416 residue and so abolished SRC activity .|These observations indicate that the loss of PTEN phosphatase activity induces SRC activation and so implicates SRC in shaping de novo TZMB resistance in PTEN deficient cells .

SIGNOR-277009

O60674

P15509

2

binding

up-regulates activity

0.533

JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.

SIGNOR-249502

P15509

O60674

2

phosphorylation

up-regulates activity

0.533

JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.

SIGNOR-249503

Q9UKV5

P06744

2

binding

up-regulates

0.53

Pgi is a housekeeping gene encoding phosphoglucose isomerase (pgi) a glycolytic enzyme that also functions as a cytokine (autocrine motility factor (amf)/neuroleukin/maturation factor) upon secretion from the cell and binding to its 78 kda seven-transmembrane domain receptor (gp78/amf-r)

SIGNOR-97270

Q14457

Q92995

2

deubiquitination

up-regulates quantity by stabilization

0.53

Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E)

SIGNOR-260295

P06744

Q9UKV5

2

polyubiquitination

down-regulates quantity by destabilization

0.53

Gp78 is a ubiquitin ligase that plays a vital role in endoplasmic reticulum (ER)-associated degradation (ERAD). Here we report that autocrine motility factor (AMF), also known as phosphoglucose isomerase (PGI), is a novel substrate of gp78. We show that polyubiquitylation of AMF requires cooperative interaction between gp78 and the ubiquitin ligase TRIM25 (tripartite motif-containing protein 25). While TRIM25 mediates the initial round of ubiquitylation, gp78 catalyzes polyubiquitylation of AMF.

SIGNOR-272177

Q92995

Q14457

2

deubiquitination

up-regulates quantity by stabilization

0.53

We found that endogenous Beclin1 can interact with USP13 and the interaction was reduced in the presence of spautin-1 (Figure 5C). Interestingly, the DUB activities were significantly increased when USP13 and USP10 coincubated together or with Beclin1 or all 3 proteins together, suggesting the DUB activity can be significantly enhanced when USP13 interacts with its substrate Beclin1 or USP10.

SIGNOR-260296

P22681

P06213

2

phosphorylation

up-regulates activity

0.528

Insulin receptor phosphorylates Cbl on tyrosines 371, 700, and 774 in the presence of APS. This phosphorylation event is required for the recruitment of Crk to the CAP/Cbl complex and for the subsequent activation of GLUT4 translocation.

SIGNOR-251304

P06213

P22681

2

ubiquitination

down-regulates

0.528

Aps couples c-cbl to theinsulinreceptor, resulting in ubiquitination of theinsulinreceptor

SIGNOR-109688

P29350

P12931

2

phosphorylation

up-regulates

0.527

Recombinant shp-1 had elevated activity subsequent to phosphorylation by src in vitro, and shp-1 variants with mutated phosphorylation sites in the c terminus, shp-1 y538f, and shp-1 y538f,y566f were less active toward src-generated phosphoproteins in intact cells.

SIGNOR-120492

P09619

P00519

2

phosphorylation

down-regulates activity

0.527

C-Abl phosphorylates three tyrosine residues on PDGFR-β (Y686, Y934, Y970) | These data are exciting as they indicate that abl kinases not only are activated by pdgfr and promote pdgfr-mediated proliferation and migration,but also act in an intricate negative feedback loop to turn-off pdgfr-mediated chemotaxis.

SIGNOR-260931

P00519

P09619

2

phosphorylation

up-regulates activity

0.527

Here, we show that PDGFR-beta-phosphorylation of Abl kinases has functional consequences as PDGFR-beta phosphorylates Abl kinases on Y245 and Y412, sites known to be required for activation of Abl kinases.

SIGNOR-278319

P12931

P29350

2

dephosphorylation

up-regulates activity

0.527

Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B

SIGNOR-248472

O43526

O43525

2

binding

up-regulates activity

0.515

The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current.

SIGNOR-268832

O43525

O43526

2

binding

up-regulates activity

0.515

The M-current regulates the subthreshold electrical excitability of many neurons, determining their firing properties and responsiveness to synaptic input. To date, however, the genes that encode subunits of this important channel have not been identified. The biophysical properties, sensitivity to pharmacological blockade, and expression pattern of the KCNQ2 and KCNQ3 potassium channels were determined. It is concluded that both these subunits contribute to the native M-current.

SIGNOR-268833

Q13362

P28482

2

phosphorylation

down-regulates

0.513

Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.

SIGNOR-144313

P28482

Q13362

2

binding

down-regulates

0.513

B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk

SIGNOR-144325

Q14457

Q14694

2

deubiquitination

up-regulates quantity by stabilization

0.509

Similarly, the overexpression of USP13 reduced the levels of ubiquitinated Beclin1 which was inhibited by spautin-1 (Figure 4E)

SIGNOR-260299

Q14694

Q14457

2

deubiquitination

up-regulates quantity by stabilization

0.509

Interestingly, Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities.

SIGNOR-260298

P10721

Q9ULZ2

2

binding

up-regulates activity

0.507

STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.

SIGNOR-261822

Q9ULZ2

P10721

2

phosphorylation

up-regulates activity

0.507

STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.

SIGNOR-261820

P38398

P31749

2

phosphorylation

up-regulates

0.506

Phosphatidylinositol 3-kinase/akt signaling enhances nuclear localization and transcriptional activity of brca1. mutation of threonine 509 in brca1, the site of akt phosphorylation, to an alanine, attenuates the ability of heregulin to induce brca1 nuclear accumulation

SIGNOR-154312

P31749

P38398

2

ubiquitination

down-regulates quantity by destabilization

0.506

The BRCA1-BRCT domains bind to phosphorylated AKT (pAKT) and lead to its ubiquitination toward protein degradation

SIGNOR-252435

O75385

P54646

2

phosphorylation

up-regulates

0.505

In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.

SIGNOR-186637

P54646

O75385

2

phosphorylation

down-regulates

0.505

Here we report that ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity. Thus, we propose that ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of ampk by ulk1 represents a negative feedback circuit.

SIGNOR-173050

O75626

Q02548

2

transcriptional regulation

down-regulates quantity

0.502

Overexpression of BSAP reduced Blimp-1 expression in CH12.LX.A2 clones but not in MPC11 clones. In addition, overexpression of BSAP in CH12.LX.A2 cells suppressed spontaneous appearance of cells with high Syndecan-1 expression and high amounts of intracytosolic as well as secreted Ig synthesi

SIGNOR-269085

Q02548

O75626

2

transcriptional regulation

down-regulates quantity

0.502

Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner.

SIGNOR-269089

Q99801

P10275

2

transcriptional regulation

up-regulates quantity by expression

0.502

Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events.

SIGNOR-251546

P10275

Q99801

2

transcriptional regulation

down-regulates quantity by repression

0.502

Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events.

SIGNOR-251547

Q06187

Q08881

2

phosphorylation

down-regulates activity

0.497

Btk-SH3 mutant Y223A was not phosphorylated by Itk. Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role

SIGNOR-251333

Q08881

Q06187

2

phosphorylation

up-regulates

0.497

Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanismthe major phosphorylation sites were identified as conserved tyrosines, for itk y180

SIGNOR-98036

P42680

Q06187

2

phosphorylation

up-regulates

0.496

Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated

SIGNOR-98086

Q06187

P42680

2

phosphorylation

down-regulates activity

0.496

Tec family protein tyrosine kinases (TFKs) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the SH3 domain via a transphosphorylation mechanism, which for Bruton's tyrosine kinase (Btk) affects tyrosine 223.|In Btk, the SH3 domain mutation Y223F results in enhanced fibroblast transformation, implying that the SH3 domain may play a negative regulatory role

SIGNOR-246652

P01023

P14780

2

cleavage

down-regulates quantity by destabilization

0.492

The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.

SIGNOR-261740

P14780

P01023

2

binding

down-regulates activity

0.492

Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.

SIGNOR-261801

P28360

P50458

2

binding

down-regulates activity

0.477

Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity

SIGNOR-241327

P50458

P28360

2

binding

down-regulates activity

0.477

Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity

SIGNOR-241330

Q16539

P43403

2

phosphorylation

up-regulates activity

0.476

Lck, Fyn, and Zap70 activate p38 even in the absence of Tyr182 phosphorylation.p38 is a substrate for Fyn, Lck and Zap70.Thus, T cell Src family kinases and Zap70 activate p38 by phosphorylating Tyr323.

SIGNOR-276030

P43403

Q16539

2

phosphorylation

down-regulates activity

0.476

We have found that T cell p38 MAP kinase (MAPK), which is directly phosphorylated and activated by ZAP-70 downstream of the TCR, in turn phosphorylates Thr-293 in the interdomain B region of ZAP-70. These results identify a tight negative feedback loop in which ZAP-70-activated p38 reciprocally phosphorylates ZAP-70 and destabilizes the signaling complex.

SIGNOR-277384

Q96LT7

P62820

2

binding

up-regulates activity

0.474

Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.

SIGNOR-261282

Q13363

O60315

2

binding

up-regulates activity

0.474

The two members of the ZEB family of zinc finger factors (ZEB-1/deltaEF1 and ZEB-2/SIP1) regulate TGFbeta/BMP signaling in opposite ways: ZEB-1/deltaEF1 synergizes with Smad-mediated transcriptional activation, while ZEB-2/SIP1 represses it. Here we report that these antagonistic effects by the ZEB proteins arise from the differential recruitment of transcriptional coactivators (p300 and P/CAF) and corepressors (CtBP) to the Smads. Thus, while ZEB-1/deltaEF1 binds to p300 and promotes the formation of a p300-Smad transcriptional complex, ZEB-2/SIP1 acts as a repressor by recruiting CtBP.

SIGNOR-268953

O60315

Q13363

2

binding

up-regulates activity

0.474

Polycomb protein Pc2 acts as an SUMO E3 ligase for SIP1. SIP1 is an active transcription repressor for many transcription factors and target genes. SIP1 Sumoylation Disrupts the Recruitment of the Corepressor CtBP

SIGNOR-225484

P62820

Q96LT7

2

binding

up-regulates activity

0.474

C9orf72 acts as an effector of Rab1a that recruits active Rab1a to theULK1 complex to promote translocation of the ULK1 complex to thephagophore during autophagy initiation

SIGNOR-261297

P24385

Q92769

2

binding

up-regulates

0.469

Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.

SIGNOR-134062

Q92769

P24385

2

binding

up-regulates

0.469

Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.

SIGNOR-134053

P06241

P17612

2

phosphorylation

up-regulates

0.459

The serine 21 (s21) residue of fyn is a protein kinase a (pka) recognition site within an rxxs motif of the amino terminal sh4 domain of fyn. In addition, s21 is critical for fyn kinase-linked cellular signaling. Mutation of s21a blocks pka phosphorylation of fyn and alters its tyrosine kinase activity.

SIGNOR-167147

Q9UN86

Q13283

2

binding

up-regulates activity

0.459

Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli.

SIGNOR-260862

Q13283

Q9UN86

2

binding

up-regulates activity

0.459

Ras-GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is a component of SGs that initiates the assembly of SGs by forming a multimer. In this study, we examined the role of G3BP2, a close relative of G3BP1, in SG formation. Although single knockdown of either G3BP1 or G3BP2 in 293T cells partially reduced the number of SG-positive cells induced by arsenite, the knockdowns of both genes significantly reduced the number. G3BP2 formed a homo-multimer and a hetero-multimer with G3BP1. Moreover, like G3BP1, the overexpression of G3BP2 induced SGs even without stress stimuli.

SIGNOR-260863

P17612

P06241

2

phosphorylation

up-regulates activity

0.459

We found that the Src family kinase Fyn phosphorylates the catalytic subunit of PKA (PKA-C) at Y69, thereby increasing PKA kinase activity.

SIGNOR-277410

P31749

Q01860

2

transcriptional regulation

down-regulates quantity by repression

0.457

Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription.

SIGNOR-252635

Q01860

P31749

2

phosphorylation

up-regulates quantity by stabilization

0.457

Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.

SIGNOR-252545

Q5S007

Q14155

2

binding

up-regulates

0.456

Arhgef7 is interacting with lrrk2 in vitro and in vivo. Gtpase activity of full-length lrrk2 increases in the presence of recombinant arhgef7. Arhgef7 might act as a guanine nucleotide exchange factor for lrrk2

SIGNOR-169217

O15146

O96014

2

binding

up-regulates

0.456

Musk has an extracellular region with homology to the frizzled crd,binding of which by wnt11 stimulates a pcp-like pathway during neuromuscolar development. Here, we show that in vivo, wnt11r and wnt4a initiate musk translocation from muscle membranes to recycling endosomes we provide evidence that wnt9a and wnt11 bind directly to the extracellular domain of musk, to induce musk dimerization and subsequent tyrosine phosphorylation of the kinase

SIGNOR-199641

Q14155

Q5S007

2

phosphorylation

up-regulates

0.456

Arhgef7 is interacting with lrrk2 in vitro and in vivo. Lrrk2 phosphorylates arhgef7 in vitro.Two Threonine residues, t107 and t143, within the arhgef7 n-terminus were identified with high confidence

SIGNOR-169221

O96014

O15146

2

binding

up-regulates

0.456

Like ror, musk has an extracellular region with homolgogy to the frizzled crd, binding of which by wnt11 stimulates a pcp-like pathway during neuromuscular development

SIGNOR-199518

P24941

P22674

2

binding

up-regulates activity

0.453

Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O

SIGNOR-275616

P22674

P24941

2

phosphorylation

up-regulates activity

0.453

Phosphorylation of cyclin O, a novel cyclin family protein containing a cyclin-like domain, is involved in the activation of cyclin-dependent kinase 2|This activity was reduced in cells overexpressing cyclin O, in which the 81st serine had been replaced with alanine (S81A). These results suggest that cyclin O is a novel cyclin family protein that regulates CDK2 kinase activity, which is mediated by the phosphorylation of the 81st serine residue of cyclin O|CKD2 phosphorylates the 81st serine residue of cyclin O

SIGNOR-275615

Q9ULJ6

P46531

2

binding

up-regulates activity

0.452

The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions

SIGNOR-263937

P46531

Q9ULJ6

2

binding

up-regulates activity

0.452

The N-terminal domain (NTD) is critical for Zmiz1 to function as a Notch collaborator. Zmiz1 and Notch1 cooperatively recruit each other to chromatin through the TPR domain. The N-terminal domain (NTD) of Zmiz1 is important for enhancing Notch reporter activity and contains tetratricopeptide repeats (TPR) that mediate protein-protein interactions

SIGNOR-263936

P49757

Q00987

2

ubiquitination

down-regulates

0.444

These data strongly suggest thatmdm2functions as the ubiquitin ligase toward hnumb and that it induces its degradation in intact cells.

SIGNOR-99497

Q00987

P49757

2

binding

down-regulates

0.444

Numb interacts with mdm2, and inhibits its ubiquitin-ligase function on tp53 (which in itself is inhibitory for tp53), thus numb activates (b) tp53

SIGNOR-168454

Q00987

P32121

2

binding

up-regulates quantity by stabilization

0.434

Our current results demonstrated that the binding of Mdm2 to beta-arrestin 2 was significantly enhanced by stimulation of GPCRs. Activation of GPCRs led to formation of a ternary complex of Mdm2, beta-arrestin 2, and GPCRs and thus recruited Mdm2 to GPCRs at plasma membrane. Moreover, the binding of beta-arrestin 2 to Mdm2 suppressed the self-ubiquitination of Mdm2 and consequently reduced the Mdm2-mediated p53 degradation and ubiquitination.

SIGNOR-272592

P32121

Q00987

2

ubiquitination

down-regulates quantity

0.434

Indeed, the ubiquitination of \u03b2-arrestin2 by Mdm2 H457S was severely reduced in comparison to Mdm2 wt ( xref ).|Loss of Mdm2 E3 ligase activity causes dominant nuclear localization of beta-arrestin2.

SIGNOR-278760

P10827

P10276

2

binding

up-regulates

0.432

We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.

SIGNOR-133231

P10276

P10827

2

binding

up-regulates

0.432

We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.

SIGNOR-133240

P67775

P12931

2

phosphorylation

down-regulates

0.43

We found that ?-Syn gene overexpression in sk-n-sh cells and primary neurons led to pp2a/c phosphorylation at y307, a known target of src kinase, and consequent phosphatase inhibition.

SIGNOR-202192

P12931

P67775

2

dephosphorylation

down-regulates activity

0.43

We show that PR55gamma binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC

SIGNOR-247970

P00533

P30530

2

phosphorylation

up-regulates activity

0.43

AXL trans-actives EGFR in a ligand independent manner and induces phosphorylation of EGFR on tyrosine 1173.|In our models AXL seems to induce a re-wiring of the EGFR signaling towards the PLCgamma-PKC axis by receptor phosphorylation at tyrosine 1173.

SIGNOR-279141

P30530

P00533

2

phosphorylation

up-regulates activity

0.43

In this study, we have identified for the first time a direct interaction between EGFR and Axl RTKs, with EGF and EGFR induced activation of Axl as a novel signalling pathway to invasion in cancer cells.|The activation of Axl was shown to occur through direct phosphorylation by EGFR of Axl tyrosine 779, one of the key residues within Axl that serves as a multi-substrate docking site for further downstream signalling.

SIGNOR-279734

Q12933

P61088

2

ubiquitination

up-regulates activity

0.428

Intact ring and zinc finger domains are required for tnfalfa-induced traf2 ubiquitination, which is also dependent on ubc13. Traf2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of jnk. Ubc13 expression by rnai resulted in tnfalfa-induced traf2 translocation and impaired activation of jnk but not of ikk or p38.

SIGNOR-121274

P61088

Q12933

2

binding

up-regulates activity

0.428

Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades.

SIGNOR-179479

P14921

Q99684

2

binding

down-regulates activity

0.426

Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. 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.

SIGNOR-254201

Q99684

P14921

2

binding

down-regulates activity

0.426

Co-immunoprecipitation analyses and glutathione-S-transferase pull-down assays revealed that ETS1 bound directly to GFI1 via its Ets domain, and GFI1 bound to ETS1 via its zinc-finger domain. 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.

SIGNOR-254202

P53350

P78527

2

phosphorylation

up-regulates activity

0.425

DNA-PKcs Promotes Plk1 Activation.|Further analysis revealed that DNA-PKcs could directly phosphorylate the C-terminal PBD domain of Plk1 (lane 8).

SIGNOR-279562

P78527

P53350

2

phosphorylation

up-regulates activity

0.425

Moreover, PLK1 phosphorylates DNA-PKcs directly on Ser 3205 invitro, suggesting that DNA-PKcs Ser 3205 is a direct target of PLK1 in mitosis.

SIGNOR-278188

P27361

Q13362

2

binding

down-regulates

0.42

B56-containing pp2a dephosphorylate erk and their activity is controlled by the early gene iex-1 and erk

SIGNOR-144328

Q13362

P27361

2

phosphorylation

down-regulates

0.42

Iex-1 binds to b56 subunits and perk independently, enhances b56 phosphorylation by erk at a conserved ser/pro site in this complex and triggers dissociation from the catalytic subunit.

SIGNOR-144317

P13631

P10827

2

binding

up-regulates

0.419

We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs.

SIGNOR-133246

P10827

P13631

2

binding

up-regulates

0.419

We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs

SIGNOR-133237

P10827

P10826

2

binding

up-regulates

0.416

We report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs

SIGNOR-133234

P10826

P10827

2

binding

up-regulates

0.416

Ee report that the retinoic acid receptors (rars), a distinct class of nuclear receptors, are also efficient heterodimer partners for trs

SIGNOR-133243

O75592

P01106

2

transcriptional regulation

down-regulates quantity by repression

0.415

We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop.

SIGNOR-267145

P01106

O75592

2

ubiquitination

down-regulates quantity by destabilization

0.415

We identified several E3 ligases as strong candidates responsible for AR and MYC protein loss as HECTD4, MYCBP2, and TRIM49. HECTD4 and MYCBP2 target AR and MYC for degradation while TRIM49 appears to promote AR and MYC stability. We have shown that these E3 ligases in turn are directly regulated by MYC. MYC in turn represses the expression of ubiquitin ligases, HECTD4 and MYCBP2 that promote AR and MYC protein degradation, further suppressing MYC and AR in a feed forward loop.

SIGNOR-267147

P06733

P01106

2

transcriptional regulation

up-regulates quantity

0.411

C-Myc directly transactivates genes encoding GLUT1, phosphofructokinase, and enolase and increases glucose uptake in Rat1 fibroblasts. Nuclear run-on studies confirmed that the GLUT1 transcriptional rate is elevated by c-Myc. Our findings suggest that overexpression of the c-Myc oncoprotein deregulates glycolysis through the activation of several components of the glucose metabolic pathway.

SIGNOR-259989

P01106

P06733

2

transcriptional regulation

down-regulates quantity by repression

0.411

This result suggests that MBP-1 in vivo acts as a sequence-specific repressor.

SIGNOR-261594

O75843

P46934

2

monoubiquitination

up-regulates activity

0.401

Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination.

SIGNOR-272634

P46934

O75843

2

binding

up-regulates activity

0.401

Gamma2-Adaptin is a putative member of the clathrin adaptor protein family with unknown physiological function. We previously reported that gamma2-adaptin acts as a ubiquitin receptor by virtue of its ubiquitin-interacting motif. Here we demonstrate that this motif mediates a specific physical interaction with the ubiquitin ligase Nedd4 and promotes ubiquitination of gamma2-adaptin. These antibodies clearly recognized the 96 kDa form, thus demonstrating that a fraction of γ2-adaptin is modified by monoubiquitination (Fig. 1C). Thus, binding of γ2-adaptin to Nedd4 is not necessary for its membrane association.Accordingly, one possible function of γ2-adaptin may be to act as an adaptor for Nedd4, recruiting it to membrane compartments for subsequent ubiquitination.

SIGNOR-272636

P00519

P16333

2

binding

down-regulates activity

0.4

We also show that overexpression of nck could repress the phosphorylation of cbl by abl in vivo. Studies with nck mutants suggested that the nck sh2 domain is responsible for inhibiting the activity of abl toward both cbl and nck itself, most likely by competing with the abl sh2 for tyrosine-phosphorylated binding sites

SIGNOR-109672

P16333

P00519

2

phosphorylation

up-regulates

0.4

Activated c-abl reduces the amplitude of mitogen-activated protein kinases (erk1/2, jnks and p38) activation in a dose-dependent manner by a negative feedback mechanism. By analysis of the adaptor proteins nck1 and grb2 mutants we further show that the negative loop on p38 is mediated by c-abl phosphorylation at tyrosine 105 of the adaptor protein nck1

SIGNOR-196043

P28360

Q07687

2

binding

down-regulates activity

0.399

We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.

SIGNOR-240918

Q07687

P28360

2

binding

down-regulates activity

0.399

We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.

SIGNOR-240929

P06241

P10586

2

dephosphorylation

down-regulates

0.396

Regulation of lck and fyn tyrosine kinase activities by transmembrane protein tyrosine phosphatase leukocyte common antigen-related molecule.

SIGNOR-96768

P10586

P06241

2

phosphorylation

up-regulates activity

0.396

LAR PTPase domain 2 was tyrosine phosphorylated by Fyn tyrosine kinase. we confirmed that LAR dephosphorylated the phosphorylated tyrosine residues of Lck and Fyn, and tyrosine residue(s) in LAR PTPase D2 was phosphorylated by Fyn to supply Fyn SH2 binding site.

SIGNOR-251180