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
Q9Y490	P05107	1	binding	up-regulates activity	0.719	Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.	SIGNOR-257618
P14735	P01308	1	cleavage	down-regulates quantity by destabilization	0.719	IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds	SIGNOR-260986
P55210	P09874	1	cleavage	down-regulates	0.719	Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis.	SIGNOR-83703
P48730	P56645	1	phosphorylation	down-regulates quantity by destabilization	0.719	We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway.	SIGNOR-267998
P27361	Q15349	1	phosphorylation	up-regulates	0.719	Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms	SIGNOR-44949
Q9BXM7	Q8IXI1	1	phosphorylation	down-regulates quantity by destabilization	0.719	PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C).	SIGNOR-272727
Q04206	P05412	1	binding	up-regulates	0.719	Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment	SIGNOR-160330
Q92538	P84077	1	guanine nucleotide exchange factor	up-regulates activity	0.719	GBF1 Stimulates Production of Arf-GTP In Vivo	SIGNOR-277400
P08069	P27986	1	binding	up-regulates	0.718	Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively)	SIGNOR-179386
P24941	P10244	1	phosphorylation	up-regulates activity	0.718	Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. \| Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. \| These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity.	SIGNOR-250735
P27361	Q15418	1	phosphorylation	up-regulates activity	0.718	Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-102648
Q9UHD2	Q9BRV8	1	phosphorylation	down-regulates quantity	0.718	Mechanism of endogenous regulation of the type I interferon response by suppressor of I\u03baB kinase epsilon (SIKE), a novel substrate of TANK-binding kinase 1 (TBK1).\|TBK1 phosphorylation of IRF3 and SIKE displayed negative cooperativity.	SIGNOR-280152
Q6Q788	P06858	1	binding	up-regulates activity	0.718	Apo A5 binds to and enhances the activity of lipoprotein lipase (LPL) enzyme	SIGNOR-251845
P62820	Q08379	1	relocalization	up-regulates activity	0.718	Here, we demonstrate that the cis ‐Golgi tethering protein GM130, complexed with GRASP65 and other proteins, forms a novel Rab1 effector complex that interacts with activated Rab1‐GTP in a p115‐independent manner and is required for coat protein II vesicle targeting/fusion with the cis ‐Golgi	SIGNOR-261285
Q12933	Q13233	1	binding	up-regulates	0.718	Traf2, ubc13, and ikkgamma were required for complex assembly and activation of mekk1 and mapk cascades.	SIGNOR-179476
O95398	P61224	1	guanine nucleotide exchange factor	up-regulates activity	0.718	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263957
P01127	P16234	1	binding	up-regulates activity	0.718	Pdgf-b activates both pdgfr-alpha and pdgfr-beta	SIGNOR-107397
P14921	P01100	1	transcriptional regulation	up-regulates quantity	0.718	Furthermore, the possible involvement of an Ets protein in the control of c-fos has interesting implications for proto-oncogene cooperation in cellular growth control.	SIGNOR-256495
O75582	Q04206	1	phosphorylation	up-regulates	0.718	Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276.	SIGNOR-99210
Q96N96	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.718	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260576
P00519	P46937	1	phosphorylation	up-regulates	0.718	In this study, we show that c-abl directly phosphorylates yap1 at position y357 in response to dna damage. Tyrosine-phosphorylated yap1 is a more stable protein that displays higher affinity to p73 and selectively coactivates p73 proapoptotic target genes.	SIGNOR-160860
P28482	O43524	1	phosphorylation	down-regulates quantity by destabilization	0.717	Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation.	SIGNOR-160415
P27361	P01100	1	phosphorylation	up-regulates activity	0.717	In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.	SIGNOR-118023
Q8TE77	P23528	1	dephosphorylation	up-regulates activity	0.717	Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.\|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).	SIGNOR-248759
Q9Y5U4	Q12770	1	binding	down-regulates activity	0.717	insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi.	SIGNOR-256209
Q96BN8	P0CG48	1	cleavage	up-regulates quantity	0.717	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270820
P28482	Q15349	1	phosphorylation	up-regulates	0.717	Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-161515
P27361	Q14790	1	phosphorylation	down-regulates	0.717	We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity	SIGNOR-203480
O14757	Q9HB96	1	phosphorylation	up-regulates	0.716	Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway.	SIGNOR-153023
P53350	P13693	1	phosphorylation	down-regulates	0.716	Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase	SIGNOR-91348
Q96BD5	O60341	1	binding	down-regulates activity	0.716	BHC80 Inhibits LSD1 Demethylase Activity In Vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity.	SIGNOR-264505
Q9Y570	P62714	1	demethylation	down-regulates activity	0.716	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits \|Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans.	SIGNOR-265750
P27361	P49407	1	phosphorylation	down-regulates	0.716	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-67634
P28482	O43521	1	phosphorylation	down-regulates quantity by destabilization	0.716	In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel	SIGNOR-129874
P24394	P23458	1	binding	up-regulates	0.716	IL-4Rα, γc, and IL-13Rα1 all contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectively. Il-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells.	SIGNOR-100774
P28482	P17676	1	phosphorylation	up-regulates	0.716	Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction.	SIGNOR-187798
P00519	Q00987	1	phosphorylation	down-regulates activity	0.716	C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2.	SIGNOR-90512
P98174	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.716	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260551
P46937	O15350	1	binding	up-regulates	0.716	Yap also interacts with p73, a p53 family pro-apoptotic transcription factor, to induce expression of genes such as bax, puma and pml.	SIGNOR-175934
P06493	Q9BQQ3	1	phosphorylation	down-regulates activity	0.715	Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. Phosphorylation of Ser-277 is also dramatically increased during mitosis, however this is mediated by Cdk1 and not by ERK. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events.	SIGNOR-262840
Q8TD19	Q8TDX7	1	phosphorylation	up-regulates activity	0.715	Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity	SIGNOR-103030
P46940	P63000	1	binding	down-regulates activity	0.715	Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.	SIGNOR-261889
Q99748	P07949	1	binding	up-regulates	0.715	A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling	SIGNOR-49122
Q8WZA2	Q09428	1	binding	up-regulates quantity	0.715	The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε.	SIGNOR-278141
P23443	Q6R327	1	phosphorylation	down-regulates	0.715	Phosphorylation of rictor on thr1135 did not affect mtorc2 assembly, kinase activity, or cellular localization. However, cells expressing a rictor t1135a mutant were found to have increased mtorc2-dependent phosphorylation of akt	SIGNOR-161995
P01116	P42338	1	binding	up-regulates	0.714	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k.	SIGNOR-175207
P28482	Q07889	1	phosphorylation	down-regulates activity	0.714	In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1	SIGNOR-235929
P28702	P13631	2	binding	up-regulates	0.714	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16683
Q13115	P45983	1	dephosphorylation	down-regulates	0.714	Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2	SIGNOR-27756
P15260	O60674	2	binding	up-regulates	0.714	The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2	SIGNOR-135955
O60674	P15260	2	phosphorylation	up-regulates activity	0.714	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249490
Q16539	Q16644	1	phosphorylation	up-regulates activity	0.714	These results, taken together, suggest the importance of the docking interaction in the efficient phosphorylation and activation of 3pk by p38.	SIGNOR-235451
Q13873	Q04771	1	binding	up-regulates	0.714	Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.	SIGNOR-33434
P20809	P40189	1	binding	up-regulates	0.714	Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-4	SIGNOR-48033
P22301	Q08334	1	binding	up-regulates	0.714	The il-10r2 chain is ubiquitously expressed, whereas the il-10 activity is restricted mainly to cells of hematopoietic origin (35, 36). This raised the question of why the second chain of the il-10 receptor complex is widely expressed when its function was required only in limited cellular subsets. One hypothesis is that the il-10r2 chain is shared by receptors for ligands other than il-10	SIGNOR-83191
Q96KN7	Q92834	1	binding	down-regulates activity	0.714	The RPGR H98Q and F130C mutants exhibit compromised interaction with RPGRIP1, suggesting that RPGR–RPGRIP1 interaction may be an important determinant of RPGR activity. 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.	SIGNOR-253031
P17252	Q13393	1	phosphorylation	up-regulates	0.714	Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells.	SIGNOR-69938
Q9Y4K3	Q8N5C8	1	binding	up-regulates activity	0.714	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205461
Q9Y2X7	P62330	1	guanine nucleotide exchange factor	up-regulates activity	0.714	Activated RAC1 interacts with GIT1, a GAP protein of ARF6, and causes the inactivation of ARF6 [78]. As ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane, the inactivation of ARF6 by RAC1 reduces the recycling of macropinosomes.	SIGNOR-277784
P07948	P14317	1	phosphorylation	up-regulates activity	0.714	Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252	SIGNOR-251401
Q86XI6	P13807	1	binding	up-regulates	0.714	In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)	SIGNOR-271734
Q99558	O14920	1	phosphorylation	up-regulates	0.714	Activation of the transcription factor nf-kappab by inflammatory cytokines involves the successive action of nf-kappab-inducing kinase (nik) and two ikappab kinases, ikk-alpha and ikk-beta. Here we show that nik preferentially phosphorylates ikk-alpha over ikk-beta	SIGNOR-55949
Q9UBE8	P10242	1	phosphorylation	down-regulates activity	0.714	Furthermore, the downregulation of c-Myb by NLK overexpression could be inhibited in cells that had been treated with the 26S proteasome inhibitor MG132 but not in those treated with DMSO ( ).\|HIPK2 and NLK directly bind to c-Myb, and NLK phosphorylates c-Myb at multiple sites, resulting in its ubiquitination and proteasome-dependent degradation [32].	SIGNOR-280049
Q16667	P24941	1	dephosphorylation	down-regulates activity	0.714	The CDK-interacting protein phosphatase KAP dephosphorylates phosphoThr-160 (pThr-160) of the CDK2 activation segment, the site of regulatory phosphorylation that is essential for kinase activity.	SIGNOR-248724
Q9NR31	O94855	1	binding	up-regulates quantity	0.714	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.	SIGNOR-265301
P13631	P28702	2	binding	up-regulates	0.714	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16662
O75385	Q8NEB9	1	phosphorylation	up-regulates activity	0.713	In the nucleation step of autophagy, The ULK1 complex phosphorylates and activates the Beclin-1-VPS34 complex.	SIGNOR-279670
P33981	Q13257	1	phosphorylation	up-regulates activity	0.713	Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.\|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2.	SIGNOR-252036
Q13315	P12956	1	phosphorylation	up-regulates activity	0.713	Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks.	SIGNOR-274020
P19838	Q04206	1	binding	up-regulates activity	0.713	Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna	SIGNOR-55378
Q07890	P01116	1	guanine nucleotide exchange factor	up-regulates	0.713	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-175265
Q9Y616	Q9NWZ3	1	binding	down-regulates	0.713	Irak3 exerts negative regulatory effects through preventing (i) the dissociation of irak1 and irak4 from myd88 irak3 negatively regulates irak signalling through suppression of irak4 and irak1 activation	SIGNOR-205434
P56524	Q06413	1	binding	down-regulates	0.713	We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.	SIGNOR-76234
P20382	Q99705	1	binding	up-regulates	0.713	Here we show that the 353-amino-acid human orphan g-protein-coupled receptor slc-1 expressed in hek293 cells binds mch with sub-nanomolar affinity, and is stimulated by mch to mobilize intracellular ca2+ and reduce forskolin-elevated cyclic amp levels.	SIGNOR-69517
Q96QV1	Q14623	1	binding	down-regulates activity	0.713	Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal.	SIGNOR-65075
P42345	Q9H063	1	phosphorylation	down-regulates	0.712	The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly.	SIGNOR-165795
P84022	Q13485	1	binding	up-regulates activity	0.712	TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus.	SIGNOR-235168
P01106	Q9Y6K1	1	binding	up-regulates activity	0.712	Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the speciﬁc methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the speciﬁcity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc.	SIGNOR-255806
Q9H8V3	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.712	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260550
P49841	P05412	1	phosphorylation	down-regulates activity	0.712	The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance	SIGNOR-236717
O15169	O15105	1	binding	down-regulates	0.712	Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia.	SIGNOR-145851
O96014	O75084	1	binding	up-regulates activity	0.712	Consistent with this, xfz7 biochemically and functionally interacts with xwnt11	SIGNOR-78406
Q13501	Q14145	1	ubiquitination	down-regulates quantity by destabilization	0.712	When autophagy is impaired, accumulated SQSTM1 interacts with KEAP1, leading to the proteasomal degradation of KEAP1. This interaction sequesters KEAP1 away from NFE2L2, preventing the ubiquitination and degradation of NFE2L2. Consequently, NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins.	SIGNOR-279849
Q13164	Q02078	1	phosphorylation	up-regulates	0.711	We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.	SIGNOR-236579
P40818	P00533	2	deubiquitination	up-regulates quantity by stabilization	0.711	Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells.	SIGNOR-259103
P06493	Q96FF9	1	phosphorylation	down-regulates activity	0.711	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.	SIGNOR-276118
P22681	P06239	1	polyubiquitination	down-regulates quantity by destabilization	0.711	Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain.	SIGNOR-272614
P45984	Q12968	1	relocalization	down-regulates	0.711	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin.	SIGNOR-103360
P02751	P31431	1	binding	up-regulates activity	0.711	Sdc4 is a high affinity receptor for fibronectin (FN) […] Therefore, we conclude that Sdc4 binds FN on activated satellite cells.	SIGNOR-255846
O43318	P45985	1	phosphorylation	up-regulates activity	0.711	Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway.	SIGNOR-50618
Q8NEV9	Q6UWB1	1	binding	up-regulates	0.711	Wsx-1 and glycoprotein 130 constitute a signal-transducing receptor for il-27.	SIGNOR-121799
P35968	P29353	1	relocalization	up-regulates activity	0.711	In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.	SIGNOR-261949
Q9UKW4	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.711	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260584
P00533	P40818	2	phosphorylation	up-regulates activity	0.711	EGFR activates USP8 by phosphorylating Tyr-717 and Tyr-810.\|Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr 717 and Tyr 810 in RPE1 cells.	SIGNOR-279037
Q05513	Q8TEW0	1	phosphorylation	up-regulates	0.711	These results imply that serine 827 in the apkc binding site of par-3 is a target of apkc and that the regulated interaction between a protein kinase, apkc, and its substrate, par-3, plays an essential role in the establishment of cell polarity	SIGNOR-94523
P12544	Q01105	1	cleavage	down-regulates	0.711	Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity.	SIGNOR-110462
P34925	Q9H461	1	binding	up-regulates	0.711	Interaction between ryk and fz has been reported, suggesting that the two proteins may form a multi-receptor complex signalling through the canonical pathway	SIGNOR-150010
Q8IZJ0	Q8IU57	1	binding	up-regulates	0.71	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96206
P10147	P32246	1	binding	up-regulates activity	0.71	The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.	SIGNOR-255114
O95398	P62834	1	guanine nucleotide exchange factor	up-regulates activity	0.71	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263956

Q9Y490

P05107

1

binding

up-regulates activity

0.719

Over the past 10 years, the binding of talin to the cytoplasmic tail of integrin-β subunits has been established to have a key role in integrin activation. Binding of the phosphotyrosinebinding (PTB)-domain-like subdomain of the protein 4.1, ezrin, radixin, moesin (FERM) domain of talin to the conserved WxxxNP(I/L)Y motif of the β-integrin tail permits additional weaker interactions between talin and the membrane-proximal region of the tail that trigger integrin activation, probably through the disruption of inhibitory interactions between α- and β-subunit cytoplasmic tails.

SIGNOR-257618

P14735

P01308

1

cleavage

down-regulates quantity by destabilization

0.719

IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds

SIGNOR-260986

P55210

P09874

1

cleavage

down-regulates

0.719

Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis.

SIGNOR-83703

P48730

P56645

1

phosphorylation

down-regulates quantity by destabilization

0.719

We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKIepsilon and CKIdelta. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway.

SIGNOR-267998

P27361

Q15349

1

phosphorylation

up-regulates

0.719

Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms

SIGNOR-44949

Q9BXM7

Q8IXI1

1

phosphorylation

down-regulates quantity by destabilization

0.719

PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C).

SIGNOR-272727

Q04206

P05412

1

binding

up-regulates

0.719

Chromatin immunoprecipitation (chip) analysis confirmed the serum-induced recruitment of jund to the promoter in vivo and showed that the presence of jund was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of jund recruitment

SIGNOR-160330

Q92538

P84077

1

guanine nucleotide exchange factor

up-regulates activity

0.719

GBF1 Stimulates Production of Arf-GTP In Vivo

SIGNOR-277400

P08069

P27986

1

binding

up-regulates

0.718

Igf-1 activated both the pi3k and the extracellular signal-regulated kinase [?] (erk [?]) Pathways as evidenced by phosphorylation of either akt or erk1 [?]/2 (respectively)

SIGNOR-179386

P24941

P10244

1

phosphorylation

up-regulates activity

0.718

Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity.

SIGNOR-250735

P27361

Q15418

1

phosphorylation

up-regulates activity

0.718

Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.

SIGNOR-102648

Q9UHD2

Q9BRV8

1

phosphorylation

down-regulates quantity

0.718

Mechanism of endogenous regulation of the type I interferon response by suppressor of I\u03baB kinase epsilon (SIKE), a novel substrate of TANK-binding kinase 1 (TBK1).|TBK1 phosphorylation of IRF3 and SIKE displayed negative cooperativity.

SIGNOR-280152

Q6Q788

P06858

1

binding

up-regulates activity

0.718

Apo A5 binds to and enhances the activity of lipoprotein lipase (LPL) enzyme

SIGNOR-251845

P62820

Q08379

1

relocalization

up-regulates activity

0.718

Here, we demonstrate that the cis ‐Golgi tethering protein GM130, complexed with GRASP65 and other proteins, forms a novel Rab1 effector complex that interacts with activated Rab1‐GTP in a p115‐independent manner and is required for coat protein II vesicle targeting/fusion with the cis ‐Golgi

SIGNOR-261285

Q12933

Q13233

1

binding

up-regulates

0.718

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

SIGNOR-179476

O95398

P61224

1

guanine nucleotide exchange factor

up-regulates activity

0.718

Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.

SIGNOR-263957

P01127

P16234

1

binding

up-regulates activity

0.718

Pdgf-b activates both pdgfr-alpha and pdgfr-beta

SIGNOR-107397

P14921

P01100

1

transcriptional regulation

up-regulates quantity

0.718

Furthermore, the possible involvement of an Ets protein in the control of c-fos has interesting implications for proto-oncogene cooperation in cellular growth control.

SIGNOR-256495

O75582

Q04206

1

phosphorylation

up-regulates

0.718

Transcriptional activation of the nf-kappab p65 subunit by mitogen- and stress-activated protein kinase-1 (msk1)mutational analysis of p65 revealed ser276 as a target for phosphorylation and transactivation in response to tnf. Moreover, we identified msk1 as a nuclear kinase for p65, since msk1 associates with p65 in a stimulus-dependent way and phosphorylates p65 at ser276.

SIGNOR-99210

Q96N96

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.718

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260576

P00519

P46937

1

phosphorylation

up-regulates

0.718

In this study, we show that c-abl directly phosphorylates yap1 at position y357 in response to dna damage. Tyrosine-phosphorylated yap1 is a more stable protein that displays higher affinity to p73 and selectively coactivates p73 proapoptotic target genes.

SIGNOR-160860

P28482

O43524

1

phosphorylation

down-regulates quantity by destabilization

0.717

Here, we show that erk downregulates forkhead box o 3a (foxo3a) by directly interacting with and phosphorylating foxo3a at ser 294, ser 344 and ser 425, which consequently promotes cell proliferation and tumorigenesisMDM2 is required for ERk-mediated FOXO3a degradation.

SIGNOR-160415

P27361

P01100

1

phosphorylation

up-regulates activity

0.717

In a previous study we have observed that exposure of nih 3t3 cells to pdgf or serum leads to c-fos phosphorylation by erk on specific residues, thr232, thr325, thr331, and ser374, within the cooh-terminal c-fos tad we have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity.

SIGNOR-118023

Q8TE77

P23528

1

dephosphorylation

up-regulates activity

0.717

Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).

SIGNOR-248759

Q9Y5U4

Q12770

1

binding

down-regulates activity

0.717

insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi.

SIGNOR-256209

Q96BN8

P0CG48

1

cleavage

up-regulates quantity

0.717

Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.

SIGNOR-270820

P28482

Q15349

1

phosphorylation

up-regulates

0.717

Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.

SIGNOR-161515

P27361

Q14790

1

phosphorylation

down-regulates

0.717

We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity

SIGNOR-203480

O14757

Q9HB96

1

phosphorylation

up-regulates

0.716

Chk1 directly phosphorylates the fance subunit of the fa core complex on two conserved sites (threonine 346 and serine 374). chk1-mediated phosphorylation of fance is required for the fanconi anemia/brca pathway.

SIGNOR-153023

P53350

P13693

1

phosphorylation

down-regulates

0.716

Plk phosphorylates tctp on two serine residues. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of tctp and promotes the increase in microtubule dynamics that occurs after metaphase

SIGNOR-91348

Q96BD5

O60341

1

binding

down-regulates activity

0.716

BHC80 Inhibits LSD1 Demethylase Activity In Vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity.

SIGNOR-264505

Q9Y570

P62714

1

demethylation

down-regulates activity

0.716

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans.

SIGNOR-265750

P27361

P49407

1

phosphorylation

down-regulates

0.716

Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation

SIGNOR-67634

P28482

O43521

1

phosphorylation

down-regulates quantity by destabilization

0.716

In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel

SIGNOR-129874

P24394

P23458

1

binding

up-regulates

0.716

IL-4Rα, γc, and IL-13Rα1 all contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectively. Il-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells.

SIGNOR-100774

P28482

P17676

1

phosphorylation

up-regulates

0.716

Phosphorylation of cebpb at thr(235) peaked at 16 hours in il-1beta-stimulated cells. The mek inhibitor u0126 inhibited this phosphorylation and reduced mmp-1 gene induction.

SIGNOR-187798

P00519

Q00987

1

phosphorylation

down-regulates activity

0.716

C-abl binds and phosphorylates mdm2 in vivo and in vitro;phosphorylation of mdm2 by c-abl impairs the inhibition of p53 by mdm2.

SIGNOR-90512

P98174

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.716

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260551

P46937

O15350

1

binding

up-regulates

0.716

Yap also interacts with p73, a p53 family pro-apoptotic transcription factor, to induce expression of genes such as bax, puma and pml.

SIGNOR-175934

P06493

Q9BQQ3

1

phosphorylation

down-regulates activity

0.715

Here we show that GRASP65 is phosphorylated on serine 277 in interphase cells, and this is strongly enhanced in response to the addition of serum or epidermal growth factor. This is directly mediated by ERK suggesting that GRASP65 has some role in growth factor signal transduction. Phosphorylation of Ser-277 is also dramatically increased during mitosis, however this is mediated by Cdk1 and not by ERK. These results argue against Ser-277 phosphorylation alone causing the dissolution of GRASP65 oligomers and cisternal unstacking, although it may make a significant contribution to these events.

SIGNOR-262840

Q8TD19

Q8TDX7

1

phosphorylation

up-regulates activity

0.715

Nercc1 catalyzes the phosphorylation of nek6 (ser206) and the equivalent site on nek7 (ser195), resulting in a 20-25-fold activation of nek6/7 kinase activity

SIGNOR-103030

P46940

P63000

1

binding

down-regulates activity

0.715

Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.

SIGNOR-261889

Q99748

P07949

1

binding

up-regulates

0.715

A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling

SIGNOR-49122

Q8WZA2

Q09428

1

binding

up-regulates quantity

0.715

The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε.

SIGNOR-278141

P23443

Q6R327

1

phosphorylation

down-regulates

0.715

Phosphorylation of rictor on thr1135 did not affect mtorc2 assembly, kinase activity, or cellular localization. However, cells expressing a rictor t1135a mutant were found to have increased mtorc2-dependent phosphorylation of akt

SIGNOR-161995

P01116

P42338

1

binding

up-regulates

0.714

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k.

SIGNOR-175207

P28482

Q07889

1

phosphorylation

down-regulates activity

0.714

In this report, we describe the identification of five map kinase sites (s-1137, s-1167, s-1178, s-1193, and s-1197) on hsos1Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1

SIGNOR-235929

P28702

P13631

2

binding

up-regulates

0.714

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.

SIGNOR-16683

Q13115

P45983

1

dephosphorylation

down-regulates

0.714

Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2

SIGNOR-27756

P15260

O60674

2

binding

up-regulates

0.714

The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2

SIGNOR-135955

O60674

P15260

2

phosphorylation

up-regulates activity

0.714

In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation

SIGNOR-249490

Q16539

Q16644

1

phosphorylation

up-regulates activity

0.714

These results, taken together, suggest the importance of the docking interaction in the efficient phosphorylation and activation of 3pk by p38.

SIGNOR-235451

Q13873

Q04771

1

binding

up-regulates

0.714

Bmpr-ii is a transmembrane serine/threonine kinase that binds bmp-2 and bmp-7 in association with multiple type i receptors, including bmpr-ia/brk1, bmpr-ib, and actr-i, which is also an activin type i receptor.

SIGNOR-33434

P20809

P40189

1

binding

up-regulates

0.714

Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-4

SIGNOR-48033

P22301

Q08334

1

binding

up-regulates

0.714

The il-10r2 chain is ubiquitously expressed, whereas the il-10 activity is restricted mainly to cells of hematopoietic origin (35, 36). This raised the question of why the second chain of the il-10 receptor complex is widely expressed when its function was required only in limited cellular subsets. One hypothesis is that the il-10r2 chain is shared by receptors for ligands other than il-10

SIGNOR-83191

Q96KN7

Q92834

1

binding

down-regulates activity

0.714

The RPGR H98Q and F130C mutants exhibit compromised interaction with RPGRIP1, suggesting that RPGR–RPGRIP1 interaction may be an important determinant of RPGR activity. 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.

SIGNOR-253031

P17252

Q13393

1

phosphorylation

up-regulates

0.714

Serine 2, threonine 147, and serine 561 were identified as phosphorylation sites of pld1 by pkcalpha in the cells.

SIGNOR-69938

Q9Y4K3

Q8N5C8

1

binding

up-regulates activity

0.714

The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.

SIGNOR-205461

Q9Y2X7

P62330

1

guanine nucleotide exchange factor

up-regulates activity

0.714

Activated RAC1 interacts with GIT1, a GAP protein of ARF6, and causes the inactivation of ARF6 [78]. As ARF6 plays a role in the promotion of the recycling of macropinosomes to the plasma membrane, the inactivation of ARF6 by RAC1 reduces the recycling of macropinosomes.

SIGNOR-277784

P07948

P14317

1

phosphorylation

up-regulates activity

0.714

Lyn and Syk synergistically phosphorylate HS1, and that Tyr-378 and Tyr-397 of HS1 are the critical residues for its BCR-induced phosphorylation. tyrosine phosphorylation of HS1 is required for BCR-induced apoptosis and nuclear translocation of HS1 may be a prerequisite for B cell apoptosis. PMID: 9104825 PMCID: PMC2196252

SIGNOR-251401

Q86XI6

P13807

1

binding

up-regulates

0.714

In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)

SIGNOR-271734

Q99558

O14920

1

phosphorylation

up-regulates

0.714

Activation of the transcription factor nf-kappab by inflammatory cytokines involves the successive action of nf-kappab-inducing kinase (nik) and two ikappab kinases, ikk-alpha and ikk-beta. Here we show that nik preferentially phosphorylates ikk-alpha over ikk-beta

SIGNOR-55949

Q9UBE8

P10242

1

phosphorylation

down-regulates activity

0.714

Furthermore, the downregulation of c-Myb by NLK overexpression could be inhibited in cells that had been treated with the 26S proteasome inhibitor MG132 but not in those treated with DMSO ( ).|HIPK2 and NLK directly bind to c-Myb, and NLK phosphorylates c-Myb at multiple sites, resulting in its ubiquitination and proteasome-dependent degradation [32].

SIGNOR-280049

Q16667

P24941

1

dephosphorylation

down-regulates activity

0.714

The CDK-interacting protein phosphatase KAP dephosphorylates phosphoThr-160 (pThr-160) of the CDK2 activation segment, the site of regulatory phosphorylation that is essential for kinase activity.

SIGNOR-248724

Q9NR31

O94855

1

binding

up-regulates quantity

0.714

Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.

SIGNOR-265301

P13631

P28702

2

binding

up-regulates

0.714

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.

SIGNOR-16662

O75385

Q8NEB9

1

phosphorylation

up-regulates activity

0.713

In the nucleation step of autophagy, The ULK1 complex phosphorylates and activates the Beclin-1-VPS34 complex.

SIGNOR-279670

P33981

Q13257

1

phosphorylation

up-regulates activity

0.713

Mps1 is an upstream component of the spindle assembly checkpoint, which, in human cells, is required for checkpoint activation in response to spindle damage but not apparently during an unperturbed mitosis. Mps1 also recruits Mad1 and Mad2 to kinetochores.|Thus, in human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2.

SIGNOR-252036

Q13315

P12956

1

phosphorylation

up-regulates activity

0.713

Ku70 phosphorylation occurs within minutes of genotoxic stress and involves DNA-PKcs and/or ATM kinase activities.By using specific vectors enabling the simultaneous shRNA-mediated inhibition of endogenous Ku70 and the expression of exogenous Ku70 resistant to shRNA (i.e. S27-S33-Ku70 and A27-A33-Ku70 expressing cells), we showed that phospho-Ku70 contributes to faster but error-prone DNA repair resulting in higher levels of chromosomal breaks.

SIGNOR-274020

P19838

Q04206

1

binding

up-regulates activity

0.713

Here we report the crystal structure at 2.9 a resolution of the p50/p65 heterodimer bound to the kappab dna

SIGNOR-55378

Q07890

P01116

1

guanine nucleotide exchange factor

up-regulates

0.713

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.

SIGNOR-175265

Q9Y616

Q9NWZ3

1

binding

down-regulates

0.713

Irak3 exerts negative regulatory effects through preventing (i) the dissociation of irak1 and irak4 from myd88 irak3 negatively regulates irak signalling through suppression of irak4 and irak1 activation

SIGNOR-205434

P56524

Q06413

1

binding

down-regulates

0.713

We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.

SIGNOR-76234

P20382

Q99705

1

binding

up-regulates

0.713

Here we show that the 353-amino-acid human orphan g-protein-coupled receptor slc-1 expressed in hek293 cells binds mch with sub-nanomolar affinity, and is stimulated by mch to mobilize intracellular ca2+ and reduce forskolin-elevated cyclic amp levels.

SIGNOR-69517

Q96QV1

Q14623

1

binding

down-regulates activity

0.713

Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal.

SIGNOR-65075

P42345

Q9H063

1

phosphorylation

down-regulates

0.712

The protein is phosphorylated mainly on residues s60, s68, and s75, and this inhibits its pol iii repression function. The responsible kinase is mtorc1, which phosphorylates maf1 directly.

SIGNOR-165795

P84022

Q13485

1

binding

up-regulates activity

0.712

TGF-² treatment initiates a kinase cascade that results in the phosphorylation of Smad3, followed by its heteromerization with Smad4 and subsequent translocation into the nucleus.

SIGNOR-235168

P01106

Q9Y6K1

1

binding

up-regulates activity

0.712

Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the speciﬁc methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the speciﬁcity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc.

SIGNOR-255806

Q9H8V3

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.712

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260550

P49841

P05412

1

phosphorylation

down-regulates activity

0.712

The c-jun and c-myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation similar to c-myc, we report here that phosphorylation of c-jun by gsk3 creates a high-affinity binding site for the e3 ligase fbw7, which targets c-jun for polyubiquitination and proteasomal degradation.Phosphorylation of Thr-239 and Ser-243 is required for Fbw7-mediated c-Jun disappearance

SIGNOR-236717

O15169

O15105

1

binding

down-regulates

0.712

Here, we show that axin activates tgf-beta signaling by forming a multimeric complex consisting of smad7 and ubiquitin e3 ligase arkadia.

SIGNOR-145851

O96014

O75084

1

binding

up-regulates activity

0.712

Consistent with this, xfz7 biochemically and functionally interacts with xwnt11

SIGNOR-78406

Q13501

Q14145

1

ubiquitination

down-regulates quantity by destabilization

0.712

When autophagy is impaired, accumulated SQSTM1 interacts with KEAP1, leading to the proteasomal degradation of KEAP1. This interaction sequesters KEAP1 away from NFE2L2, preventing the ubiquitination and degradation of NFE2L2. Consequently, NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins.

SIGNOR-279849

Q13164

Q02078

1

phosphorylation

up-regulates

0.711

We have previously shown that bmk1 regulates c-jun gene expression through direct phosphorylation and activation of transcription factor mef2c.Here, we demonstrate that, in addition to mef2c, bmk1 phosphorylates and activates mef2a and mef2d but not mef2b.The sites phosphorylated by activated bmk1 were mapped to ser-355, thr-312, and thr-319 of mef2a and ser-179 of mef2d both in vitro and in vivo.

SIGNOR-236579

P40818

P00533

2

deubiquitination

up-regulates quantity by stabilization

0.711

Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells.

SIGNOR-259103

P06493

Q96FF9

1

phosphorylation

down-regulates activity

0.711

Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.

SIGNOR-276118

P22681

P06239

1

polyubiquitination

down-regulates quantity by destabilization

0.711

Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain.

SIGNOR-272614

P45984

Q12968

1

relocalization

down-regulates

0.711

Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin.

SIGNOR-103360

P02751

P31431

1

binding

up-regulates activity

0.711

Sdc4 is a high affinity receptor for fibronectin (FN) […] Therefore, we conclude that Sdc4 binds FN on activated satellite cells.

SIGNOR-255846

O43318

P45985

1

phosphorylation

up-regulates activity

0.711

Mitogen-activated protein kinase kinase 4 (mkk4)/stress-activated protein kinase/extracellular signal-regulated kinase (sek1), a dual-specificity kinase that phosphorylates and activates jnk, synergized with tak1 in activating jnk.Taken together, these results identify TAK1 as a regulator in the HPK1 --> TAK1 --> MKK4/SEK1 --> JNK kinase cascade and indicate the involvement of JNK in the TGF-beta signaling pathway.

SIGNOR-50618

Q8NEV9

Q6UWB1

1

binding

up-regulates

0.711

Wsx-1 and glycoprotein 130 constitute a signal-transducing receptor for il-27.

SIGNOR-121799

P35968

P29353

1

relocalization

up-regulates activity

0.711

In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.

SIGNOR-261949

Q9UKW4

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.711

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260584

P00533

P40818

2

phosphorylation

up-regulates activity

0.711

EGFR activates USP8 by phosphorylating Tyr-717 and Tyr-810.|Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr 717 and Tyr 810 in RPE1 cells.

SIGNOR-279037

Q05513

Q8TEW0

1

phosphorylation

up-regulates

0.711

These results imply that serine 827 in the apkc binding site of par-3 is a target of apkc and that the regulated interaction between a protein kinase, apkc, and its substrate, par-3, plays an essential role in the establishment of cell polarity

SIGNOR-94523

P12544

Q01105

1

cleavage

down-regulates

0.711

Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity.

SIGNOR-110462

P34925

Q9H461

1

binding

up-regulates

0.711

Interaction between ryk and fz has been reported, suggesting that the two proteins may form a multi-receptor complex signalling through the canonical pathway

SIGNOR-150010

Q8IZJ0

Q8IU57

1

binding

up-regulates

0.71

Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.

SIGNOR-96206

P10147

P32246

1

binding

up-regulates activity

0.71

The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.

SIGNOR-255114

O95398

P62834

1

guanine nucleotide exchange factor

up-regulates activity

0.71

Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.

SIGNOR-263956