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
P61962	Q13627	1	binding	up-regulates activity	0.71	Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions.	SIGNOR-260630
Q9P2J3	Q96GD4	1	binding	up-regulates activity	0.71	Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis.	SIGNOR-271658
P06213	P29353	1	binding	up-regulates	0.71	The npxy motif around 960-tyr residue of the insulin receptor binds to the n-terminal ptb domain of shc.	SIGNOR-84251
P13232	P31785	1	binding	up-regulates	0.71	The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, il-15, il-2, il21	SIGNOR-108864
Q9NRD0	P62330	1	binding	down-regulates quantity by destabilization	0.71	Fbx8 Is a Component of the SCF Complex and Mediates Ubiquitination of Arf6. We first examined whether Fbx8 makes a complex with Cul1, through its binding to Skp1. We expressed GST-tagged Fbx8 together with FLAG-tagged Skp1 and Myc-tagged Cul1 in Cos-7 cells and found that Myc-Cul1 is coprecipitated with GST-Fbx8 in the presence of FLAG-Skp1 (Figure 1A).	SIGNOR-271764
Q92585	Q99466	1	binding	up-regulates	0.71	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4	SIGNOR-84916
O43791	P10070	1	ubiquitination	down-regulates quantity	0.71	RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins	SIGNOR-268860
O75888	O14836	1	binding	up-regulates	0.71	Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys.	SIGNOR-81308
P24522	P06493	1	binding	down-regulates	0.71	Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex	SIGNOR-68221
Q9UQL6	Q14814	1	binding	down-regulates	0.71	The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.	SIGNOR-84029
Q969H4	P04049	1	binding	up-regulates	0.71	Here we demonstrate that the connector enhancer of ksr1, cnk1, mediates src-dependent tyrosine phosphorylation and activation of raf-1. Cnk1 binds preactivated raf-1 and activated src and forms a trimeric complex.	SIGNOR-135674
P45983	P05067	1	phosphorylation	up-regulates	0.71	Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1	SIGNOR-117852
Q9HAU4	P36897	1	polyubiquitination	down-regulates quantity by destabilization	0.71	Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.	SIGNOR-272938
P27037	Q15796	1	phosphorylation	up-regulates activity	0.71	In ACVR2A/B dKO parental cells, only ACVR2A , but not ACVR2A , could rescue both pSMAD2 and pSMAD1/5 (Fig\u00a04B).\|In marked contrast, in ACVR2A/B dKO HOM1 cells, ACVR2A restored SMAD1/5 phosphorylation, but not SMAD2 phosphorylation (Fig\u00a04C).	SIGNOR-279786
Q14289	O43294	1	phosphorylation	up-regulates activity	0.71	Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5.	SIGNOR-262876
P16333	Q13153	1	binding	up-regulates activity	0.709	Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors.	SIGNOR-236512
Q9ULJ6	P10275	1	binding	up-regulates activity	0.709	Our results demonstrate that hZimp10 is a novel AR interacting protein that augments AR-mediated transcription. Moreover, hZimp10 co-localized with AR and SUMO-1 at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo.	SIGNOR-263935
Q9UHD2	Q13501	1	phosphorylation	up-regulates	0.709	Tbk-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on ser-403, a residue essential for its role in autophagic clearance.	SIGNOR-191944
Q9NR31	P53992	1	binding	up-regulates quantity	0.709	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-265302
P35222	P48431	1	binding	up-regulates activity	0.709	The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes.	SIGNOR-242087
Q13115	P27361	1	dephosphorylation	down-regulates activity	0.709	Dephosphorylation and Inactivation of ERKs\|ERK1 phosphorylated on either threonine (ERK1Y204F) or tyrosine alone (ERK1T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1 mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1T202A more efficiently than ERK1Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK	SIGNOR-248716
Q9P2F6	P61586	1	gtpase-activating protein	down-regulates activity	0.709	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-260472
O43464	P98170	1	binding	down-regulates	0.709	Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo.	SIGNOR-110834
Q12982	P60953	1	binding	up-regulates activity	0.709	Cdo-bnip-2-cdc42 complex stimulates cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation.	SIGNOR-179861
P40763	O14543	1	transcriptional regulation	up-regulates quantity by expression	0.709	We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells	SIGNOR-253583
P04628	P34925	1	binding	up-regulates	0.709	Mammalian ryk is a wnt coreceptor required for stimulation of neurite outgrowth	SIGNOR-129577
O95407	O95150	1	binding	down-regulates	0.709	Tl1a, is a ligand for dr3 and decoy receptor tr6/dcr3. Tr6-fc protein antagonizes nf-kappab activation and apoptosis induced by tl1a	SIGNOR-116256
P10071	Q13635	1	transcriptional regulation	up-regulates quantity by expression	0.709	GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin	SIGNOR-188884
O95393	P37023	1	binding	up-regulates	0.709	Taken together, our results sug- gest that bmp9 and bmp10 are two spe- cific alk1 ligands that may physiologi- cally trigger the effects of alk1 on angiogenesis	SIGNOR-150201
Q16566	P16220	1	phosphorylation	up-regulates activity	0.708	Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. All these kinases target CREB on S133 to activate CREB.	SIGNOR-102722
Q9HCE7	Q15797	1	ubiquitination	down-regulates	0.708	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps	SIGNOR-195660
O00238	O15198	1	phosphorylation	up-regulates activity	0.708	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255264
P21860	P42336	1	binding	up-regulates	0.708	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146861
Q9Y243	O43524	1	phosphorylation	down-regulates quantity by destabilization	0.708	AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.	SIGNOR-249644
P04090	Q8WXD0	1	binding	up-regulates	0.708	Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway.	SIGNOR-114585
O75376	P37231	1	transcriptional regulation	down-regulates quantity by repression	0.708	In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.	SIGNOR-253507
P20333	Q12933	1	binding	up-regulates activity	0.708	Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly.	SIGNOR-34645
Q12923	P98172	1	dephosphorylation	up-regulates activity	0.708	Loss of PTPN13 function increases EFNB1 phosphorylation, enhances EFNB1 's interaction with ERBB1 and correlates with potentiated ERK1/2 activation.\|Moreover, acquisition of PTPN13 loss-of-function mutations or its decreased expression (due to HPV infection or epigenetic silencing) may further enhance ERBB1 and EFNB1 mediated signals.	SIGNOR-277002
P23458	P35568	1	phosphorylation	up-regulates activity	0.708	Janus kinase-dependent activation of insulin receptor substrate 1	SIGNOR-251343
O15524	P52333	1	binding	down-regulates activity	0.708	SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR).	SIGNOR-238642
Q13153	Q14247	1	phosphorylation	up-regulates	0.707	Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis.	SIGNOR-169690
O75581	O14640	2	binding	up-regulates activity	0.707	The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.	SIGNOR-262526
Q13464	P61587	1	phosphorylation	up-regulates	0.707	We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability.	SIGNOR-134703
P41221	Q9NPG1	1	binding	up-regulates activity	0.707	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141434
Q9UJM3	P04626	1	binding	down-regulates activity	0.707	The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2	SIGNOR-252077
Q7KZI7	P10636-2	1	phosphorylation	down-regulates activity	0.707	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.	SIGNOR-275437
P27361	P01106	1	phosphorylation	up-regulates activity	0.707	ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation	SIGNOR-236250
O14640	O75581	2	binding	up-regulates activity	0.707	The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization.	SIGNOR-156072
Q7KZI7	P10636	1	phosphorylation	down-regulates activity	0.707	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.	SIGNOR-275436
O76050	P78504	1	ubiquitination	down-regulates quantity by destabilization	0.707	We find that NEDD4 targets an RNA-binding protein, NANOS2, in spermatogonia to destabilize it, leading to cell differentiation.\|Jagged1 is also regulated by the E3 ligase Neuralized-like1 (Neurl1), which induces the monoubiquitination of membrane tethered Jagged1 in the C-terminal region.	SIGNOR-278772
Q06124	Q16620	1	dephosphorylation	down-regulates activity	0.707	Conversely, PTPN11 knockdown lead to increased Y 515 phosphorylation of TrkB compared to the scramble control in the neuronal cells.\|This study established that TrkB activation as demonstrated by receptor phosphorylation at Tyr 515 in the SH-SY5Y cells is negatively regulated by PTPN11 actions.	SIGNOR-277123
Q13309	P24864	1	binding	down-regulates quantity by destabilization	0.707	Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3.	SIGNOR-272566
P27361	P35568	1	phosphorylation	down-regulates activity	0.707	Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation.	SIGNOR-123177
O14981	P20226	1	binding	up-regulates activity	0.707	We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP.	SIGNOR-263919
P01344	P06213	1	binding	up-regulates	0.707	Therefore, these results provide genetic evidence that the growth-promoting function of igf-ii during mouse embryogenesis is mediated in part by signaling through the insulin receptor.	SIGNOR-50719
O14944	Q15303	1	binding	up-regulates	0.706	For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4.	SIGNOR-191788
P08581	P40763	1	phosphorylation	up-regulates activity	0.706	It has been reported that c-Met can activate STAT3 at the endosome and phosphorylated STAT3 induced by c-Met is colocalized with EEA1, an early endosome marker.	SIGNOR-280041
P09237	P10451	1	cleavage	up-regulates activity	0.706	In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA.	SIGNOR-253321
Q9UQL6	Q02078	1	binding	down-regulates	0.706	The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.	SIGNOR-84023
P36894	O15198	1	phosphorylation	up-regulates activity	0.706	To ascertain whether overexpression of BMPr1A can initiate adipocyte lineage commitment in the absence of its BMP ligand, constitutively active (CA)-BMPr1A and CA-BMPr1B were expressed in C3H10T1/2 stem cells using a mouse stem cell virus (MSCV) retroviral system. […]Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway.	SIGNOR-255772
Q9H4B4	P04637	1	phosphorylation	up-regulates activity	0.706	Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3.	SIGNOR-109239
P45984	P35568	1	phosphorylation	down-regulates	0.706	Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632	SIGNOR-118877
Q05397	P62993	1	binding	up-regulates activity	0.706	Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade.	SIGNOR-257733
Q9Y2R2	P43403	1	dephosphorylation	down-regulates	0.706	Native ptpn22 dephosphorylated lck and zap70 at their activating tyrosine residues tyr-394 and tyr-493, respectively, but not at the regulatory tyrosines tyr-505 (lck) or tyr-319 (zap70).	SIGNOR-144345
P27361	P42229	1	phosphorylation	up-regulates	0.706	Serine 780 is the only substrate in full-length stat5a for active erk	SIGNOR-66247
P28482	O75030	1	phosphorylation	down-regulates	0.705	The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation.	SIGNOR-75030
Q9H2K2	O15169	1	ADP-ribosylation	down-regulates quantity by destabilization	0.705	Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin.	SIGNOR-263378
Q9P1A6	P78352	1	binding	up-regulates activity	0.705	SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.	SIGNOR-264210
Q9Y6W6	P45983	1	dephosphorylation	down-regulates	0.705	Mkp-5 directly dephosphorylates sapk/jnk and p38 in vitromkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk	SIGNOR-68986
Q13315	Q14683	1	phosphorylation	up-regulates activity	0.705	Atm phosphorylates Smc1 on serines 957 and 966 in vitro and in vivo, and expression of an Smc1 protein mutated at these phosphorylation sites abrogates the ionizing irradiation-induced S phase cell cycle checkpoint	SIGNOR-255589
P30304	P11802	1	dephosphorylation	up-regulates activity	0.705	Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs.	SIGNOR-267568
O15530	Q16513	1	phosphorylation	up-regulates	0.705	It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)	SIGNOR-76710
P53350	Q96FF9	1	phosphorylation	down-regulates activity	0.705	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-276122
P35222	Q09472	1	binding	up-regulates	0.705	Ctnnb1 forms a ternary complex with lef1 and ep300 that is disrupted by ctnnbip1 binding	SIGNOR-76987
P53350	Q08050	1	phosphorylation	up-regulates	0.705	It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression	SIGNOR-187892
P45983	P08047	1	phosphorylation	up-regulates	0.705	In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed.	SIGNOR-184194
Q12864	P35222	1	binding	up-regulates activity	0.705	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265856
Q13164	Q14814	1	phosphorylation	up-regulates	0.705	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-236041
P12931	Q13480	1	phosphorylation	up-regulates	0.704	Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis	SIGNOR-236314
P19784	P60484	1	phosphorylation	down-regulates activity	0.704	We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).	SIGNOR-251025
P08238	P10275	1	binding	up-regulates activity	0.704	The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes.	SIGNOR-251535
P48454	O95644	1	relocalization	up-regulates	0.704	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-179796
Q96FW1	P61088	1	binding	down-regulates	0.704	The deubiquitinating enzyme otub1 suppresses rnf168 dependent ubiquitination by direct the e2 ligase ubc13	SIGNOR-175050
Q99956	P27361	1	binding	down-regulates	0.704	Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein.	SIGNOR-176589
O75385	Q8N122	1	phosphorylation	down-regulates activity	0.704	ULK1 phosphorylates RPTOR at S792, S855, and S859.\|When active, ULK1 inhibits MTOR complex 1 through phosphorylation of RPTOR, which has the effect of limiting RPTOR-mediated recruitment of MTOR substrates to MTOR complex 1 [ ].	SIGNOR-278461
Q969G9	Q92997	1	binding	down-regulates	0.704	Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation	SIGNOR-167984
P31749	P21453	1	phosphorylation	up-regulates activity	0.704	Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis	SIGNOR-252467
P06493	P30260	1	phosphorylation	up-regulates	0.704	Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation	SIGNOR-119873
P27361	P03372	1	phosphorylation	up-regulates	0.704	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity	SIGNOR-156864
P27361	P04637	1	phosphorylation	up-regulates	0.704	Mutant p53 is constitutively phosphorylated at serine 15 in uv-induced mouse skin tumors: involvement of erk1/2 map kinase.	SIGNOR-100270
Q8IV63	P51452	1	binding	up-regulates activity	0.704	Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding	SIGNOR-275546
O43791	P10071	1	ubiquitination	down-regulates quantity	0.704	RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins	SIGNOR-268861
P78536	P01375	1	cleavage	up-regulates quantity	0.704	We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified.	SIGNOR-46754
Q13467	O14641	1	binding	up-regulates activity	0.704	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.	SIGNOR-258960
P30304	Q00534	1	dephosphorylation	up-regulates activity	0.704	Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs.	SIGNOR-267569
Q9ULV1	O75197	1	binding	up-regulates activity	0.704	Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain.	SIGNOR-258967
P15260	P23458	2	binding	up-regulates	0.703	Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively	SIGNOR-150194
Q13163	Q13164	2	phosphorylation	up-regulates	0.703	Mek5 is the mapk kinase that phosphorylates and activates erk5 in response to growth factors, oxidative stress, and hyperosmotic conditions.	SIGNOR-104631
Q13164	Q13163	2	phosphorylation	up-regulates	0.703	Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)	SIGNOR-99127
Q04771	Q15797	1	phosphorylation	up-regulates activity	0.703	ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif	SIGNOR-251439

P61962

Q13627

1

binding

up-regulates activity

0.71

Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions.

SIGNOR-260630

Q9P2J3

Q96GD4

1

binding

up-regulates activity

0.71

Aurora B Interacts with the Cul3 Complex during Mitosis and Is Ubiquitylated in a Cul3-Dependent Manner In Vivo and In Vitro. our results suggest that Cul3/KLHL9/KLHL13 activity is required to remove the chromosomal passenger protein Aurora B from mitotic chromosomes, and that Aurora B is ubiquitylated in vivo and in vitro in a KLHL9/13-dependent manner. We conclude that the Cul3/KLHL9/KLHL13 E3 ligase is an important cell-cycle regulator which, in addition to the anaphase-promoting complex (APC), coordinates mitotic progression and completion of cytokinesis.

SIGNOR-271658

P06213

P29353

1

binding

up-regulates

0.71

The npxy motif around 960-tyr residue of the insulin receptor binds to the n-terminal ptb domain of shc.

SIGNOR-84251

P13232

P31785

1

binding

up-regulates

0.71

The common gamma-chain (gamma(c)) is an indispensable subunit of the functional receptor complexes for il-4, il-7, il-9, il-15, il-2, il21

SIGNOR-108864

Q9NRD0

P62330

1

binding

down-regulates quantity by destabilization

0.71

Fbx8 Is a Component of the SCF Complex and Mediates Ubiquitination of Arf6. We first examined whether Fbx8 makes a complex with Cul1, through its binding to Skp1. We expressed GST-tagged Fbx8 together with FLAG-tagged Skp1 and Myc-tagged Cul1 in Cos-7 cells and found that Myc-Cul1 is coprecipitated with GST-Fbx8 in the presence of FLAG-Skp1 (Figure 1A).

SIGNOR-271764

Q92585

Q99466

1

binding

up-regulates

0.71

Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes4

SIGNOR-84916

O43791

P10070

1

ubiquitination

down-regulates quantity

0.71

RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins

SIGNOR-268860

O75888

O14836

1

binding

up-regulates

0.71

Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys.

SIGNOR-81308

P24522

P06493

1

binding

down-regulates

0.71

Gadd45 has now been found to directly inhibit the activity of cdc2/cyclin b1 complex

SIGNOR-68221

Q9UQL6

Q14814

1

binding

down-regulates

0.71

The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.

SIGNOR-84029

Q969H4

P04049

1

binding

up-regulates

0.71

Here we demonstrate that the connector enhancer of ksr1, cnk1, mediates src-dependent tyrosine phosphorylation and activation of raf-1. Cnk1 binds preactivated raf-1 and activated src and forms a trimeric complex.

SIGNOR-135674

P45983

P05067

1

phosphorylation

up-regulates

0.71

Phosphorylation of amyloid precursor protein at threonine 668 is essential for its copper-responsive trafficking in sh-sy5y neuroblastoma cells. We found that the threonine 668 within the abetapp intracellular domain (aid or elsewhere aicd) is indeed phosphorylated by jnk1

SIGNOR-117852

Q9HAU4

P36897

1

polyubiquitination

down-regulates quantity by destabilization

0.71

Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.

SIGNOR-272938

P27037

Q15796

1

phosphorylation

up-regulates activity

0.71

In ACVR2A/B dKO parental cells, only ACVR2A , but not ACVR2A , could rescue both pSMAD2 and pSMAD1/5 (Fig\u00a04B).|In marked contrast, in ACVR2A/B dKO HOM1 cells, ACVR2A restored SMAD1/5 phosphorylation, but not SMAD2 phosphorylation (Fig\u00a04C).

SIGNOR-279786

Q14289

O43294

1

phosphorylation

up-regulates activity

0.71

Hic-5 is a CAKbeta-binding protein localized at focal adhesions. Here we show that overexpression of CAKbeta or Fyn, but not FAK, enhanced the tyrosine phosphorylation of coexpressed Hic-5 in COS-7 cells. The Y60F mutant of Hic-5 was not phosphorylated, and Hic-5 phosphorylated on tyrosine 60 was bound specifically to the SH2 domain of Csk. Specific phosphorylation of Hic-5 by CAKbeta and Fyn may activate a signaling pathway mediated by Hic-5.

SIGNOR-262876

P16333

Q13153

1

binding

up-regulates activity

0.709

Both nck and grb4 proteins could associate with receptor tyrosine kinases and the sh3-binding proteins pak, sos1, and prk2, and they synergized with v-abl and sos to induce gene expression via the transcription factor elk-1. Association of nck with pak1 may serve to link this important regulatory kinase to cell activation by growth factor receptors.

SIGNOR-236512

Q9ULJ6

P10275

1

binding

up-regulates activity

0.709

Our results demonstrate that hZimp10 is a novel AR interacting protein that augments AR-mediated transcription. Moreover, hZimp10 co-localized with AR and SUMO-1 at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo.

SIGNOR-263935

Q9UHD2

Q13501

1

phosphorylation

up-regulates

0.709

Tbk-1 coordinated assembly and function of the autophagic machinery and phosphorylated the autophagic adaptor p62 (sequestosome 1) on ser-403, a residue essential for its role in autophagic clearance.

SIGNOR-191944

Q9NR31

P53992

1

binding

up-regulates quantity

0.709

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-265302

P35222

P48431

1

binding

up-regulates activity

0.709

The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes.

SIGNOR-242087

Q13115

P27361

1

dephosphorylation

down-regulates activity

0.709

Dephosphorylation and Inactivation of ERKs|ERK1 phosphorylated on either threonine (ERK1*Y204F) or tyrosine alone (ERK1*T202A) was utilized as a substrate for HVH2. Threonine 202 and tyrosine 204 in ERK1 (53) correspond to threonine 183 and tyrosine 185 in ERK2 which are the activation-phosphorylation sites by MEK(14, 15, 16). ERK1*, a kinase-deficient mutant, was phosphorylated on both threonine and tyrosine by MEK2 (Fig. 3B). ERK1*T202A, having threonine 202 substituted by an alanine, was phosphorylated only on tyrosine while ERK1*Y204F, having tyrosine 204 substituted by a phenylalanine, was phosphorylated only on threonine (Fig. 3B). GST-HVH2 dephosphorylated all three ERK1* mutants (Fig. 3A), suggesting that double phosphorylations of adjacent threonine and tyrosine were not a prerequisite for HVH2 recognition. However, HVH2 dephosphorylated ERK1* and ERK1*T202A more efficiently than ERK1*Y204F (Fig. 3A), indicating that HVH2 preferred phosphotyrosine over phosphothreonine. Interestingly, MEK also phosphorylated tyrosine residues more efficiently than threonine residues of ERK

SIGNOR-248716

Q9P2F6

P61586

1

gtpase-activating protein

down-regulates activity

0.709

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-260472

O43464

P98170

1

binding

down-regulates

0.709

Here we report that a serine protease called htra2/omi is released from mitochondria and inhibits the function of xiap by direct binding in a similar way to diablo.

SIGNOR-110834

Q12982

P60953

1

binding

up-regulates activity

0.709

Cdo-bnip-2-cdc42 complex stimulates cdc42 activation which in turn promotes p38 alpha/beta activity and cell differentiation.

SIGNOR-179861

P40763

O14543

1

transcriptional regulation

up-regulates quantity by expression

0.709

We also found that the wild type SOCS-3 promoter construct has significantly greater activity in non-small-cell lung cancer cell lines than in normal cells in accordance with STAT3 disregulation in these cells

SIGNOR-253583

P04628

P34925

1

binding

up-regulates

0.709

Mammalian ryk is a wnt coreceptor required for stimulation of neurite outgrowth

SIGNOR-129577

O95407

O95150

1

binding

down-regulates

0.709

Tl1a, is a ligand for dr3 and decoy receptor tr6/dcr3. Tr6-fc protein antagonizes nf-kappab activation and apoptosis induced by tl1a

SIGNOR-116256

P10071

Q13635

1

transcriptional regulation

up-regulates quantity by expression

0.709

GLI activators bind to GACCACCCA motif to regulate transcription of GLI1, PTCH1, PTCH2, HHIP1, MYCN, CCND1, CCND2, BCL2, CFLAR, FOXF1, FOXL1, PRDM1 (BLIMP1), JAG2, GREM1, and Follistatin

SIGNOR-188884

O95393

P37023

1

binding

up-regulates

0.709

Taken together, our results sug- gest that bmp9 and bmp10 are two spe- cific alk1 ligands that may physiologi- cally trigger the effects of alk1 on angiogenesis

SIGNOR-150201

Q16566

P16220

1

phosphorylation

up-regulates activity

0.708

Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. All these kinases target CREB on S133 to activate CREB.

SIGNOR-102722

Q9HCE7

Q15797

1

ubiquitination

down-regulates

0.708

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps

SIGNOR-195660

O00238

O15198

1

phosphorylation

up-regulates activity

0.708

Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.

SIGNOR-255264

P21860

P42336

1

binding

up-regulates

0.708

Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.

SIGNOR-146861

Q9Y243

O43524

1

phosphorylation

down-regulates quantity by destabilization

0.708

AKT phosphorylates FOXO3a at three conserved sites (Thr32, Ser253 and Ser315), therefore creating binding sites for the 14-3-3 chaperone proteins and leading to the active export of FOXO3a to the cytoplasm where it is targeted for proteasomal degradation.

SIGNOR-249644

P04090

Q8WXD0

1

binding

up-regulates

0.708

Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway.

SIGNOR-114585

O75376

P37231

1

transcriptional regulation

down-regulates quantity by repression

0.708

In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.

SIGNOR-253507

P20333

Q12933

1

binding

up-regulates activity

0.708

Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly.

SIGNOR-34645

Q12923

P98172

1

dephosphorylation

up-regulates activity

0.708

Loss of PTPN13 function increases EFNB1 phosphorylation, enhances EFNB1 's interaction with ERBB1 and correlates with potentiated ERK1/2 activation.|Moreover, acquisition of PTPN13 loss-of-function mutations or its decreased expression (due to HPV infection or epigenetic silencing) may further enhance ERBB1 and EFNB1 mediated signals.

SIGNOR-277002

P23458

P35568

1

phosphorylation

up-regulates activity

0.708

Janus kinase-dependent activation of insulin receptor substrate 1

SIGNOR-251343

O15524

P52333

1

binding

down-regulates activity

0.708

SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR).

SIGNOR-238642

Q13153

Q14247

1

phosphorylation

up-regulates

0.707

Strikingly, we find that pak1 phosphorylation of cortactin on serine residues 405 and 418 increases its association with n-wasp. Thus, pak1, by controlling the interaction between cortactin and n-wasp, could regulate the polymerization of actin during clathrin-independent endocytosis.

SIGNOR-169690

O75581

O14640

2

binding

up-regulates activity

0.707

The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.

SIGNOR-262526

Q13464

P61587

1

phosphorylation

up-regulates

0.707

We show that rock phosphorylates endogenous rhoe at serine 11 upon cell stimulation with platelet-derived growth factor. Phosphorylation has no effect on rhoe binding to rock i, but instead increases rhoe protein stability.

SIGNOR-134703

P41221

Q9NPG1

1

binding

up-regulates activity

0.707

Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.

SIGNOR-141434

Q9UJM3

P04626

1

binding

down-regulates activity

0.707

The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2

SIGNOR-252077

Q7KZI7

P10636-2

1

phosphorylation

down-regulates activity

0.707

We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.

SIGNOR-275437

P27361

P01106

1

phosphorylation

up-regulates activity

0.707

ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation

SIGNOR-236250

O14640

O75581

2

binding

up-regulates activity

0.707

The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization.

SIGNOR-156072

Q7KZI7

P10636

1

phosphorylation

down-regulates activity

0.707

We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.

SIGNOR-275436

O76050

P78504

1

ubiquitination

down-regulates quantity by destabilization

0.707

We find that NEDD4 targets an RNA-binding protein, NANOS2, in spermatogonia to destabilize it, leading to cell differentiation.|Jagged1 is also regulated by the E3 ligase Neuralized-like1 (Neurl1), which induces the monoubiquitination of membrane tethered Jagged1 in the C-terminal region.

SIGNOR-278772

Q06124

Q16620

1

dephosphorylation

down-regulates activity

0.707

Conversely, PTPN11 knockdown lead to increased Y 515 phosphorylation of TrkB compared to the scramble control in the neuronal cells.|This study established that TrkB activation as demonstrated by receptor phosphorylation at Tyr 515 in the SH-SY5Y cells is negatively regulated by PTPN11 actions.

SIGNOR-277123

Q13309

P24864

1

binding

down-regulates quantity by destabilization

0.707

Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3.

SIGNOR-272566

P27361

P35568

1

phosphorylation

down-regulates activity

0.707

Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation.

SIGNOR-123177

O14981

P20226

1

binding

up-regulates activity

0.707

We present evidence that the NC2alpha subunit interacts with BTAF1. Addition of NC2alpha or the NC2 complex can stimulate the ability of BTAF1 to interact with TBP.

SIGNOR-263919

P01344

P06213

1

binding

up-regulates

0.707

Therefore, these results provide genetic evidence that the growth-promoting function of igf-ii during mouse embryogenesis is mediated in part by signaling through the insulin receptor.

SIGNOR-50719

O14944

Q15303

1

binding

up-regulates

0.706

For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4.

SIGNOR-191788

P08581

P40763

1

phosphorylation

up-regulates activity

0.706

It has been reported that c-Met can activate STAT3 at the endosome and phosphorylated STAT3 induced by c-Met is colocalized with EEA1, an early endosome marker.

SIGNOR-280041

P09237

P10451

1

cleavage

up-regulates activity

0.706

In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA.

SIGNOR-253321

Q9UQL6

Q02078

1

binding

down-regulates

0.706

The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.

SIGNOR-84023

P36894

O15198

1

phosphorylation

up-regulates activity

0.706

To ascertain whether overexpression of BMPr1A can initiate adipocyte lineage commitment in the absence of its BMP ligand, constitutively active (CA)-BMPr1A and CA-BMPr1B were expressed in C3H10T1/2 stem cells using a mouse stem cell virus (MSCV) retroviral system. […]Thus, their overexpression provoked a substantial rise in the phosphorylation of Smad1/5/8 and p38 MAPK, known downstream phosphorylated intermediates in the BMP signaling pathway.

SIGNOR-255772

Q9H4B4

P04637

1

phosphorylation

up-regulates activity

0.706

Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3.

SIGNOR-109239

P45984

P35568

1

phosphorylation

down-regulates

0.706

Map kinases and mtor mediate insulin-induced phosphorylation ofinsulinreceptor substrate-1 on serine residues 307, 612 and 632

SIGNOR-118877

Q05397

P62993

1

binding

up-regulates activity

0.706

Src-mediated phosphorylation of FAK at Tyr925 creates an SH2 binding site for the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which leads to the activation of Ras and the extracellular signal-regulated kinase-2 (ERK2) cascade.

SIGNOR-257733

Q9Y2R2

P43403

1

dephosphorylation

down-regulates

0.706

Native ptpn22 dephosphorylated lck and zap70 at their activating tyrosine residues tyr-394 and tyr-493, respectively, but not at the regulatory tyrosines tyr-505 (lck) or tyr-319 (zap70).

SIGNOR-144345

P27361

P42229

1

phosphorylation

up-regulates

0.706

Serine 780 is the only substrate in full-length stat5a for active erk

SIGNOR-66247

P28482

O75030

1

phosphorylation

down-regulates

0.705

The current study reveals that c-kit signaling triggers two phosphorylation events on mi, which up-regulate transactivation potential yet simultaneously target mi for ubiquitin-dependent proteolysis. The specific activation/degradation signals derive from mapk/erk targeting of serine 73the results suggested that s1p reduced melanin synthesis via s1p(3) receptor-mediated erk and rsk-1 activation, and subsequent mitf dual phosphorylation and degradation.

SIGNOR-75030

Q9H2K2

O15169

1

ADP-ribosylation

down-regulates quantity by destabilization

0.705

Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin.

SIGNOR-263378

Q9P1A6

P78352

1

binding

up-regulates activity

0.705

SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.

SIGNOR-264210

Q9Y6W6

P45983

1

dephosphorylation

down-regulates

0.705

Mkp-5 directly dephosphorylates sapk/jnk and p38 in vitromkp-5 binds to p38 and sapk/jnk, but not to mapk/erk, and inactivates p38 and sapk/jnk

SIGNOR-68986

Q13315

Q14683

1

phosphorylation

up-regulates activity

0.705

Atm phosphorylates Smc1 on serines 957 and 966 in vitro and in vivo, and expression of an Smc1 protein mutated at these phosphorylation sites abrogates the ionizing irradiation-induced S phase cell cycle checkpoint

SIGNOR-255589

P30304

P11802

1

dephosphorylation

up-regulates activity

0.705

Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs.

SIGNOR-267568

O15530

Q16513

1

phosphorylation

up-regulates

0.705

It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)

SIGNOR-76710

P53350

Q96FF9

1

phosphorylation

down-regulates activity

0.705

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-276122

P35222

Q09472

1

binding

up-regulates

0.705

Ctnnb1 forms a ternary complex with lef1 and ep300 that is disrupted by ctnnbip1 binding

SIGNOR-76987

P53350

Q08050

1

phosphorylation

up-regulates

0.705

It has been reported that plk1 could directly phosphorylate foxm1 at ser-715 and ser-724 for full activation and proper mitotic progression

SIGNOR-187892

P45983

P08047

1

phosphorylation

up-regulates

0.705

In addition, for mutation of the jnk-1 phosphorylated residues of sp1, namely, sp1(t278/739a) and sp1(t278/739d), the effect of ga on sp1 stability was reversed.

SIGNOR-184194

Q12864

P35222

1

binding

up-regulates activity

0.705

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265856

Q13164

Q14814

1

phosphorylation

up-regulates

0.705

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-236041

P12931

Q13480

1

phosphorylation

up-regulates

0.704

Using both mutagenesis and mass spectrometry approaches, y242, y259, y317, y373 and y627 of gab1 were identified to be phosphorylated by c-src a gab1 mutant with substitutions of the src phosphorylation sites failed to promote hgf-induced dna synthesis

SIGNOR-236314

P19784

P60484

1

phosphorylation

down-regulates activity

0.704

We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).

SIGNOR-251025

P08238

P10275

1

binding

up-regulates activity

0.704

The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes.

SIGNOR-251535

P48454

O95644

1

relocalization

up-regulates

0.704

The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.

SIGNOR-179796

Q96FW1

P61088

1

binding

down-regulates

0.704

The deubiquitinating enzyme otub1 suppresses rnf168 dependent ubiquitination by direct the e2 ligase ubc13

SIGNOR-175050

Q99956

P27361

1

binding

down-regulates

0.704

Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein.

SIGNOR-176589

O75385

Q8N122

1

phosphorylation

down-regulates activity

0.704

ULK1 phosphorylates RPTOR at S792, S855, and S859.|When active, ULK1 inhibits MTOR complex 1 through phosphorylation of RPTOR, which has the effect of limiting RPTOR-mediated recruitment of MTOR substrates to MTOR complex 1 [ ].

SIGNOR-278461

Q969G9

Q92997

1

binding

down-regulates

0.704

Naked (nkd)1 and nkd2 are mammalian homologs of drosophila naked cuticle, which negatively regulates canonical wnt signaling by binding dishevelled. various reports using cell culture assays indicate that nkd-mediated wnt antagonism involves dvl degradation

SIGNOR-167984

P31749

P21453

1

phosphorylation

up-regulates activity

0.704

Activated akt binds to edg-1 and phosphorylates the third intracellular loop at the t(236) residue. Transactivation of edg-1 by akt is not required for g(i)-dependent signaling but is indispensable for rac activation, cortical actin assembly, and chemotaxis

SIGNOR-252467

P06493

P30260

1

phosphorylation

up-regulates

0.704

Apc activation is thought to depend on apc phosphorylation and cdc20 binding. We have identified 43 phospho_sites on apc of which at least 34 are mitosis specific. Of these, 32 sites are clustered in parts of apc1 and the tetratricopeptide repeat (tpr) subunits cdc27, cdc16, cdc23 and apc7. In vitro, at least 15 of the mitotic phospho_sites can be generated by cyclin_dependent kinase 1 (cdk1), and 3 by polo_like kinase 1 (plk1). Apc phosphorylation by cdk1, but not by plk1, is sufficient for increased cdc20 binding and apc activation

SIGNOR-119873

P27361

P03372

1

phosphorylation

up-regulates

0.704

In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.Phosphorylation at serines 104 and 106 by erk1/2 mapk is important for estrogen receptor-alpha activity

SIGNOR-156864

P27361

P04637

1

phosphorylation

up-regulates

0.704

Mutant p53 is constitutively phosphorylated at serine 15 in uv-induced mouse skin tumors: involvement of erk1/2 map kinase.

SIGNOR-100270

Q8IV63

P51452

1

binding

up-regulates activity

0.704

Vaccinia-related kinase 3 (VRK3), a member of the VRK family, is widely expressed in human tissues and increases VHR phosphatase activity through a direct binding

SIGNOR-275546

O43791

P10071

1

ubiquitination

down-regulates quantity

0.704

RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins

SIGNOR-268861

P78536

P01375

1

cleavage

up-regulates quantity

0.704

We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified.

SIGNOR-46754

Q13467

O14641

1

binding

up-regulates activity

0.704

Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.

SIGNOR-258960

P30304

Q00534

1

dephosphorylation

up-regulates activity

0.704

Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs.

SIGNOR-267569

Q9ULV1

O75197

1

binding

up-regulates activity

0.704

Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain.

SIGNOR-258967

P15260

P23458

2

binding

up-regulates

0.703

Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively

SIGNOR-150194

Q13163

Q13164

2

phosphorylation

up-regulates

0.703

Mek5 is the mapk kinase that phosphorylates and activates erk5 in response to growth factors, oxidative stress, and hyperosmotic conditions.

SIGNOR-104631

Q13164

Q13163

2

phosphorylation

up-regulates

0.703

Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)

SIGNOR-99127

Q04771

Q15797

1

phosphorylation

up-regulates activity

0.703

ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif

SIGNOR-251439