GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 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
P54578	P61073	1	deubiquitination	up-regulates quantity by stabilization	0.448	The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor\|We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation	SIGNOR-265057
Q8NEZ5	O43474	1	ubiquitination	down-regulates quantity by destabilization	0.365	F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression	SIGNOR-273444
P08754	Q9UBY5	2	binding	up-regulates activity	0.461	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257025
P60953	O75044	0	gtpase-activating protein	down-regulates activity	0.604	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-260517
P11309	P68431	1	phosphorylation	down-regulates activity	0.2	Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation.	SIGNOR-156946
Q14247	Q14689	0	acetylation	up-regulates activity	0.2	DIP2A binds to cortactin and modulates cortactin acetylation. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin.	SIGNOR-266589
Q8IZL8	P11802	0	phosphorylation	up-regulates	0.351	Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function.	SIGNOR-167770
P46108	P42684	0	phosphorylation	down-regulates	0.695	Abl2 kinase activity toward crk leads to increased phosphorylation of crk, inhibiting this cytoskeletal regulator by promoting intramolecular over intermolecular associations.	SIGNOR-136958
P55085	P00734	2	binding	up-regulates	0.611	Other major aspects of par-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of par-2.	SIGNOR-108183
Q99459	O96017	0	phosphorylation	down-regulates activity	0.304	Remarkably, however, the activation of the DDC triggers a Rad53-dependent phosphorylation of Cdc5 that inhibits the polo-like kinase, thus favoring Cdh1 activity and subsequently also restraining spindle elongation and anaphase progression [34,54] (Figure 1).	SIGNOR-279694
P54821	Q9Y5Q3	2	binding	down-regulates activity	0.306	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221899
P03372	Q15788	2	binding	up-regulates	0.845	Steroid receptor co-activator (src1) is one of a number of transcriptional co-activators that are capable of potentiating the activity of nuclear receptors including the oestrogen receptor (er).	SIGNOR-54442
P51843	Q96EP0	0	monoubiquitination	up-regulates quantity by stabilization	0.437	RNF31 promotes monoubiquitination of DAX-1 in an RBR domain-dependent manner. In conclusion, our results suggest that the major DAX-1 modification observed in different experimental settings is likely to be monoubiquitination at one or more lysine residues (multiubiquitination) possibly located within the LBD of DAX-1. RNF31 stabilizes endogenous DAX-1.	SIGNOR-271786
Q53GT1	P53350	2	binding	down-regulates activity	0.446	Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors.	SIGNOR-272108
P45974	Q08050	1	deubiquitination	up-regulates quantity by stabilization	0.351	Wnt signaling activation inhibits FoxM1 phosphorylation by GSK3-Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP5, thereby deubiquitination and stabilization of FoxM1.	SIGNOR-277210
P53350	Q9UKT4	1	phosphorylation	down-regulates	0.783	We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity.	SIGNOR-142949
Q96FE5	P23515	2	binding	up-regulates	0.505	Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1...	SIGNOR-133640
P49841	P26358	1	phosphorylation	down-regulates quantity	0.272	We determined that in a human lung cell line, glycogen synthase kinase 3beta (GSK3beta) phosphorylated DNMT1 to recruit beta-transducin repeat-containing protein (betaTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3beta function and thereby attenuating DNMT1 degradation.	SIGNOR-279181
Q13094	P42681	0	phosphorylation	up-regulates	0.728	Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function	SIGNOR-44669
P01112	P04049	2	binding	up-regulates	0.935	We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src.	SIGNOR-235786
P07948	O15492	1	phosphorylation	up-regulates activity	0.346	Lyn kinase phosphorylated recombinant RGS16 in vitro. Induction of RGS16 tyrosine phosphorylation was associated with increased RGS16 protein levels and enhanced GAP activity in cell membranes.	SIGNOR-251410
P01009	P00734	2	binding	down-regulates activity	0.423	Alpha1PI, historically known as alpha1-antitrypsin, is a 51 kDa, 394 amino acid glycoprotein, synthesized in the liver, circulating at c. 1.3 mg mL-1 with a half-life of 4.5 days	SIGNOR-263524
Q13153	P21333	1	phosphorylation	up-regulates	0.789	In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152.	SIGNOR-92065
P57086	P28698	2	binding	up-regulates activity	0.365	Co-immunoprecipitation and yeast two-hybrid analyses demonstrate that MZF1B and RAZ1 associate in vitro via a SCAN box-dependent mechanism. The interaction between MZF1B and RAZ1 might be necessary for mediating MZF1B function	SIGNOR-221561
P0DP25	Q08209	2	binding	up-regulates	0.626	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266343
Q9Y5K5	O15105	2	binding	up-regulates	0.662	Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases.	SIGNOR-138879
P50876	P09874	1	ubiquitination	down-regulates quantity by destabilization	0.2	As RNF144A is a newly characterized E3 ubiquitin ligase , ], we next investigated whether RNF144A could promote PARP1 ubiquitination.\|RNF144A promotes the proteasomal degradation of PARP1.	SIGNOR-278776
Q8NEG5	P61077	2	binding	up-regulates activity	0.331	MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.	SIGNOR-271557
Q9UPN3	P49841	0	phosphorylation	down-regulates activity	0.435	We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.	SIGNOR-264428
Q9UHD2	P56962	1	phosphorylation	up-regulates activity	0.291	Stx17 is phosphorylated by TBK1 whereby phospho-Stx17 controls the formation of the ATG13+FIP200+ mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202.	SIGNOR-273812
P50148	Q9P212	2	binding	up-regulates	0.282	Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate manymolecules, including phospholipases, ion channels and lipid kinases.	SIGNOR-152609
P29597	P17181	1	phosphorylation	up-regulates activity	0.91	We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2.	SIGNOR-246934
P56817	Q00535	0	phosphorylation	up-regulates activity	0.44	BACE1 is phosphorylated by p25 and Cdk5 at Thr252.\|Our finding that p25/Cdk5 stimulates BACE1 activity supports that p25/Cdk5 may represent a promising target for the development of drugs to treat Alzheimer's disease.	SIGNOR-278249
Q9Y2T1	P53350	0	phosphorylation	up-regulates activity	0.486	Plk1 phosphorylates axin2 at Ser311.	SIGNOR-277180
Q01844	P05771	0	phosphorylation	down-regulates activity	0.275	Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation.	SIGNOR-52854
P10071	Q6PHR2	0	phosphorylation	up-regulates activity	0.561	We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro	SIGNOR-260799
Q9Y566	Q86YM7	2	binding	up-regulates activity	0.744	It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD	SIGNOR-264243
Q13489	Q86VP3	1	polyubiquitination	down-regulates quantity by destabilization	0.286	Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay.	SIGNOR-272852
Q9NZJ5	Q13217	2	binding	down-regulates activity	0.616	The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK	SIGNOR-246201
Q13976	Q01970	1	phosphorylation	down-regulates activity	0.539	PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG.	SIGNOR-249077
Q9BWT7	Q04759	1	relocalization	up-regulates activity	0.435	TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation	SIGNOR-272471
Q9Y2R2	P20963	1	dephosphorylation	down-regulates activity	0.447	In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. 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). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.	SIGNOR-248837
Q86VW2	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.835	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-260544
P0DMV8	P22413	1	post transcriptional regulation	up-regulates quantity	0.2	We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation.	SIGNOR-252197
P09874	P00533	0	phosphorylation	up-regulates activity	0.394	EGFR and MET heterodimer interacts with and phosphorylates PARP1.	SIGNOR-279169
Q86Y01	Q96J02	0	ubiquitination	down-regulates	0.7	Itch/aip4 mediates deltex degradation through the formation of k29-linked polyubiquitin chains.	SIGNOR-150002
P29474	Q02156	0	phosphorylation	down-regulates activity	0.331	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251632
Q5VWK5	O60674	2	binding	up-regulates	0.701	Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12.	SIGNOR-87808
P27361	Q13950	1	phosphorylation	up-regulates	0.565	In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation.	SIGNOR-188347
P02649	P10636	2	binding	up-regulates activity	0.567	Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.\|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3.	SIGNOR-262588
P17612	O75899	1	phosphorylation	down-regulates activity	0.2	Here we show that the functional coupling of GABA(B)R1/GABA(B)R2 receptors to inwardly rectifying K(+) channels rapidly desensitizes. This effect is alleviated after direct phosphorylation of a single serine residue (Ser892) in the cytoplasmic tail of GABA(B)R2 by cyclic AMP (cAMP)-dependent protein kinase (PKA).	SIGNOR-263150
P39687	P06400	2	binding	down-regulates activity	0.2	We further demonstrate that pp32-Rb interaction inhibits the apoptotic activity of pp32 and stimulates proliferation.	SIGNOR-259083
P41594	P05129	0	phosphorylation	up-regulates activity	0.415	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249289
Q9NXR1	P17612	0	phosphorylation	up-regulates	0.4	Here, we demonstrate that disc1 and pde4 modulate nde1 phosphorylation by camp-dependent protein kinase a (pka) and identify a novel pka substrate site on nde1 at threonine-131 (t131).Since phosphorylated t131 is detectable at multiple subcellular locations (centrosome, nucleus, postsynaptic density, proximal axon), there is potential for disc1/pde4 to influence several important brain processes that critically depend on the nde1/ndel1/lis1 comple	SIGNOR-174410
Q14204	Q9GZM8	2	binding	up-regulates activity	0.72	LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex	SIGNOR-252159
Q9Y243	O15119	1	phosphorylation	up-regulates activity	0.354	We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion.	SIGNOR-223534
P17252	P16144	1	phosphorylation	down-regulates	0.531	Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures	SIGNOR-124494
Q12888	O15297	0	dephosphorylation	down-regulates activity	0.392	In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1.	SIGNOR-277046
Q9GZQ6	P63096	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256708
Q9UQM7	Q13224	1	phosphorylation	up-regulates activity	0.7	By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons.	SIGNOR-250630
Q15391	P19086	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257118
Q9UDY8	Q9NYJ8	2	binding	up-regulates	0.606	Tab2/tak1 associate with ubiquitinated malt1 upon t-cell stimulation.	SIGNOR-158551
Q13416	P24941	0	phosphorylation	up-regulates	0.756	We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.	SIGNOR-116364
Q5VWQ8	Q9HCE7	0	ubiquitination	down-regulates quantity by destabilization	0.262	DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1	SIGNOR-254776
Q8N695	P17676	0	transcriptional regulation	up-regulates quantity by expression	0.2	Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription.	SIGNOR-254054
P12931	Q9Y613	1	phosphorylation	up-regulates activity	0.306	Our results show that only Src can efficiently phosphorylate FHOD1 at Y99 to enable the downstream activation by ROCK.	SIGNOR-276612
O14920	Q15653	1	phosphorylation	down-regulates	0.765	We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation	SIGNOR-52932
P06213	P18031	2	phosphorylation	up-regulates activity	0.788	Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex\| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B	SIGNOR-249370
P28482	Q9BYT3	0	phosphorylation	up-regulates activity	0.273	In vitro kinase assay results indicated that STK33 can phosphorylate ERK2.\|STK33 phosphorylated ERK2 and increased the activity of ERK2 and promote the tumorigenesis of colorectal cancer HCT15 cells.	SIGNOR-279351
P43405	O14986	1	phosphorylation	down-regulates activity	0.2	We identified spleen tyrosine kinase (Syk), which is activated by oxidants, as a candidate PIP5Kbeta kinase in this pathway, and mapped the oxidant-sensitive tyrosine phosphorylation site to residue 105. The PIP5KbetaY105E phosphomimetic is catalytically inactive and cytosolic, whereas the Y105F non-phosphorylatable mutant has higher intrinsic lipid kinase activity and is much more membrane associated than wild type PIP5Kbeta.	SIGNOR-276227
Q05655	Q99808	1	phosphorylation	up-regulates activity	0.2	Phosphorylation of hENT1 by PKC has effects on both the function and subcellular trafficking of hENT1	SIGNOR-260888
O15355	Q13315	2	dephosphorylation	down-regulates activity	0.303	After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. \|ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage.\|DNA Damage Leads to ATM Dependent USP7S Dephosphorylation by PPM1G.	SIGNOR-277158
Q9Y496	P49407	2	binding	up-regulates	0.55	Kif3a is essential for shh-mediated signaling in mammalian systems (5), and we identified kif3a as a arr1 binding partner in a proteomics screen (18). To test whether arrs, smo, and kif3a might work in concert.	SIGNOR-178672
P11161	P17676	1	transcriptional regulation	up-regulates quantity by expression	0.534	Ectopic expression of krox20 can transactivate the c/ebpbeta promoter and increase c/ebpbeta gene expression in 3t3-l1 preadipocytes	SIGNOR-139292
P35240	P17252	0	phosphorylation	down-regulates activity	0.328	PKC\u03b1\nnormally phosphorylates and inactivates NF2.\|PKCalpha normally phosphorylates and inactivates NF2.	SIGNOR-280081
P36888	P29353	1	phosphorylation	up-regulates activity	0.446	Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313.	SIGNOR-251147
Q15788	P28482	0	phosphorylation	up-regulates	0.364	Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene.	SIGNOR-74880
Q6PEY2	Q14980	2	binding	up-regulates	0.248	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116738
Q9P0J1	P11362	0	phosphorylation	down-regulates activity	0.292	Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.	SIGNOR-276640
Q14145	Q13501	0	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
P68400	P17936	1	phosphorylation	up-regulates quantity by stabilization	0.338	The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro \| These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment.	SIGNOR-250903
P46531	P41240	2	binding	up-regulates	0.281	We found that the notch-1-furin interaction is regulated by the non-receptor tyrosine kinase, c-src. c-src and notch-1 are physically associated, and this association is responsible for notch-1 processing and activation	SIGNOR-196824
P61160	P18075	2	binding	up-regulates	0.289	The two ligands induce the formation of two ligand-receptor complexes, cbmp7 (blue) and ctgf-b (red), that share the type i receptor alk2	SIGNOR-144144
P24723	O15530	0	phosphorylation	up-regulates activity	0.316	Protein kinase C(eta) is phosphorylated by PDK1 in vitro, leading to kinase activation as similarly reported for protein kinase C(epsilon) activation by PDK1.	SIGNOR-280062
P20719	O15550	0	transcriptional regulation	up-regulates quantity by expression	0.27	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260023
Q86YJ5	P10586	1	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271536
P62714	P04637	1	dephosphorylation	up-regulates quantity by stabilization	0.437	A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55\| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis	SIGNOR-248583
Q8NFT8	P46531	2	binding	up-regulates	0.462	Dner binds to notch1 at cell-cell contacts and activates notch signaling in vitro.	SIGNOR-138346
P37231	O75688	0	dephosphorylation	up-regulates activity	0.372	Furthermore we show that PPM1B can directly dephosphorylate PPARgamma, both in intact cells and in vitro.\|In addition PPM1B increases PPARγ-mediated transcription via dephosphorylation of Ser(112).\|The serine/threonine phosphatase PPM1B (PP2Cbeta) selectively modulates PPARgamma activity.	SIGNOR-277073
P08476	Q13705	2	binding	up-regulates activity	0.787	Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.	SIGNOR-235142
P00734	P08709	1	null	up-regulates activity	0.301	Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind	SIGNOR-263529
P63096	P18825	2	binding	up-regulates activity	0.48	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256699
Q9Y297	P35222	1	ubiquitination	down-regulates	0.872	Here we show that fwd1 (the mouse homologue of slimb/betatrcp), an f-box/wd40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, axin, gsk-3beta and apc. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with fwd1. Fwd1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels.	SIGNOR-67374
Q05195	Q9UQE7	2	binding	down-regulates activity	0.296	We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.	SIGNOR-241278
P50148	P28223	2	binding	up-regulates activity	0.608	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257137
O95644	Q03405	1	transcriptional regulation	up-regulates quantity by expression	0.2	Inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays.	SIGNOR-253336
O15550	Q99607	1	transcriptional regulation	down-regulates quantity by repression	0.279	Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase	SIGNOR-260031
Q9UGM6	Q2TAL8	0	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269411
Q9UBK2	P37231	0	transcriptional regulation	up-regulates quantity by expression	0.903	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma\|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263984
P56524	P67775	0	dephosphorylation	up-regulates	0.35	Different signal-regulated serine/threonine kinases phosphorylate class ii histone deacetylases (hdacs) to promote nuclear export, cytosolic accumulation, and activation of gene transcriptionhere we show that hdac4 forms a complex with the pp2a holoenzyme c alpha, a alpha, b/pr55 alpha. In vitro and in vivo binding studies demonstrate that the n-terminus of hdac4 interacts with the catalytic subunit of pp2a. Hdac4 is dephosphorylated by pp2a	SIGNOR-159492

P54578

P61073

1

deubiquitination

up-regulates quantity by stabilization

0.448

The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor|We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation

SIGNOR-265057

Q8NEZ5

O43474

1

ubiquitination

down-regulates quantity by destabilization

0.365

F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression

SIGNOR-273444

P08754

Q9UBY5

2

binding

up-regulates activity

0.461

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257025

P60953

O75044

0

gtpase-activating protein

down-regulates activity

0.604

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-260517

P11309

P68431

1

phosphorylation

down-regulates activity

0.2

Pim1-dependent phosphorylation of histone h3 at serine 10 is required for myc-dependent transcriptional activation and oncogenic transformation.

SIGNOR-156946

Q14247

Q14689

0

acetylation

up-regulates activity

0.2

DIP2A binds to cortactin and modulates cortactin acetylation. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin.

SIGNOR-266589

Q8IZL8

P11802

0

phosphorylation

up-regulates

0.351

Using site-directed mutagenesis and in vitro kinase assays, we identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we identified pelp1 as a novel substrate of cdks and found that cdk phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function.

SIGNOR-167770

P46108

P42684

0

phosphorylation

down-regulates

0.695

Abl2 kinase activity toward crk leads to increased phosphorylation of crk, inhibiting this cytoskeletal regulator by promoting intramolecular over intermolecular associations.

SIGNOR-136958

P55085

P00734

2

binding

up-regulates

0.611

Other major aspects of par-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of par-2.

SIGNOR-108183

Q99459

O96017

0

phosphorylation

down-regulates activity

0.304

Remarkably, however, the activation of the DDC triggers a Rad53-dependent phosphorylation of Cdc5 that inhibits the polo-like kinase, thus favoring Cdh1 activity and subsequently also restraining spindle elongation and anaphase progression [34,54] (Figure 1).

SIGNOR-279694

P54821

Q9Y5Q3

2

binding

down-regulates activity

0.306

Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.

SIGNOR-221899

P03372

Q15788

2

binding

up-regulates

0.845

Steroid receptor co-activator (src1) is one of a number of transcriptional co-activators that are capable of potentiating the activity of nuclear receptors including the oestrogen receptor (er).

SIGNOR-54442

P51843

Q96EP0

0

monoubiquitination

up-regulates quantity by stabilization

0.437

RNF31 promotes monoubiquitination of DAX-1 in an RBR domain-dependent manner. In conclusion, our results suggest that the major DAX-1 modification observed in different experimental settings is likely to be monoubiquitination at one or more lysine residues (multiubiquitination) possibly located within the LBD of DAX-1. RNF31 stabilizes endogenous DAX-1.

SIGNOR-271786

Q53GT1

P53350

2

binding

down-regulates activity

0.446

Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors.

SIGNOR-272108

P45974

Q08050

1

deubiquitination

up-regulates quantity by stabilization

0.351

Wnt signaling activation inhibits FoxM1 phosphorylation by GSK3-Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP5, thereby deubiquitination and stabilization of FoxM1.

SIGNOR-277210

P53350

Q9UKT4

1

phosphorylation

down-regulates

0.783

We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity.

SIGNOR-142949

Q96FE5

P23515

2

binding

up-regulates

0.505

Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1...

SIGNOR-133640

P49841

P26358

1

phosphorylation

down-regulates quantity

0.272

We determined that in a human lung cell line, glycogen synthase kinase 3beta (GSK3beta) phosphorylated DNMT1 to recruit beta-transducin repeat-containing protein (betaTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3beta function and thereby attenuating DNMT1 degradation.

SIGNOR-279181

Q13094

P42681

0

phosphorylation

up-regulates

0.728

Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function

SIGNOR-44669

P01112

P04049

2

binding

up-regulates

0.935

We have examined whether the other two members of the Raf family, A-Raf and B-Raf, are regulated in a similar way to Raf-1. A-Raf behaves like Raf-1, being weakly activated by oncogenic Ras more strongly activated by oncogenic Src, and these signals synergize to give maximal activation. B-Raf by contrast is strongly activated by oncogenic Ras alone and is not activated by oncogenic Src.

SIGNOR-235786

P07948

O15492

1

phosphorylation

up-regulates activity

0.346

Lyn kinase phosphorylated recombinant RGS16 in vitro. Induction of RGS16 tyrosine phosphorylation was associated with increased RGS16 protein levels and enhanced GAP activity in cell membranes.

SIGNOR-251410

P01009

P00734

2

binding

down-regulates activity

0.423

Alpha1PI, historically known as alpha1-antitrypsin, is a 51 kDa, 394 amino acid glycoprotein, synthesized in the liver, circulating at c. 1.3 mg mL-1 with a half-life of 4.5 days

SIGNOR-263524

Q13153

P21333

1

phosphorylation

up-regulates

0.789

In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152.

SIGNOR-92065

P57086

P28698

2

binding

up-regulates activity

0.365

Co-immunoprecipitation and yeast two-hybrid analyses demonstrate that MZF1B and RAZ1 associate in vitro via a SCAN box-dependent mechanism. The interaction between MZF1B and RAZ1 might be necessary for mediating MZF1B function

SIGNOR-221561

P0DP25

Q08209

2

binding

up-regulates

0.626

Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.

SIGNOR-266343

Q9Y5K5

O15105

2

binding

up-regulates

0.662

Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases.

SIGNOR-138879

P50876

P09874

1

ubiquitination

down-regulates quantity by destabilization

0.2

As RNF144A is a newly characterized E3 ubiquitin ligase , ], we next investigated whether RNF144A could promote PARP1 ubiquitination.|RNF144A promotes the proteasomal degradation of PARP1.

SIGNOR-278776

Q8NEG5

P61077

2

binding

up-regulates activity

0.331

MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.

SIGNOR-271557

Q9UPN3

P49841

0

phosphorylation

down-regulates activity

0.435

We discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules.

SIGNOR-264428

Q9UHD2

P56962

1

phosphorylation

up-regulates activity

0.291

Stx17 is phosphorylated by TBK1 whereby phospho-Stx17 controls the formation of the ATG13+FIP200+ mammalian pre-autophagosomal structure (mPAS) in response to induction of autophagy. TBK1 phosphorylates Stx17 at S202.

SIGNOR-273812

P50148

Q9P212

2

binding

up-regulates

0.282

Typically galfas stimulates adenylyl cyclase and increases levels of cyclic amp (camp), whereas galfai inhibits adenylyl cyclase and lowers camp levels, and members of the galfaq family bind to and activate phospholipase c (plc), which cleaves phosphatidylinositol bisphosphate (pip2) into diacylglycerol and inositol triphosphate (ip3). The gbeta subunits and ggamma subunits function as a dimer to activate manymolecules, including phospholipases, ion channels and lipid kinases.

SIGNOR-152609

P29597

P17181

1

phosphorylation

up-regulates activity

0.91

We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2.

SIGNOR-246934

P56817

Q00535

0

phosphorylation

up-regulates activity

0.44

BACE1 is phosphorylated by p25 and Cdk5 at Thr252.|Our finding that p25/Cdk5 stimulates BACE1 activity supports that p25/Cdk5 may represent a promising target for the development of drugs to treat Alzheimer's disease.

SIGNOR-278249

Q9Y2T1

P53350

0

phosphorylation

up-regulates activity

0.486

Plk1 phosphorylates axin2 at Ser311.

SIGNOR-277180

Q01844

P05771

0

phosphorylation

down-regulates activity

0.275

Here we report thatews, a nuclearrna-bindingprooncoprotein, contains an iq domain, is phosphorylated byproteinkinase c, and interacts with calmodulin. Interestingly, pkc phosphorylation of ews inhibits its binding to rna homopolymers, and conversely,rna binding to ews interferes with pkc phosphorylation./ these data indicate that ews contains an iq domain with ser266 acting as the primary site for pkc phosphorylation.

SIGNOR-52854

P10071

Q6PHR2

0

phosphorylation

up-regulates activity

0.561

We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro

SIGNOR-260799

Q9Y566

Q86YM7

2

binding

up-regulates activity

0.744

It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD

SIGNOR-264243

Q13489

Q86VP3

1

polyubiquitination

down-regulates quantity by destabilization

0.286

Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay.

SIGNOR-272852

Q9NZJ5

Q13217

2

binding

down-regulates activity

0.616

The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK

SIGNOR-246201

Q13976

Q01970

1

phosphorylation

down-regulates activity

0.539

PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG.

SIGNOR-249077

Q9BWT7

Q04759

1

relocalization

up-regulates activity

0.435

TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation

SIGNOR-272471

Q9Y2R2

P20963

1

dephosphorylation

down-regulates activity

0.447

In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. 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). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.

SIGNOR-248837

Q86VW2

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.835

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-260544

P0DMV8

P22413

1

post transcriptional regulation

up-regulates quantity

0.2

We demonstrated the binding of heat shock protein 70 (HSP70) to ENPP1-3'UTR. Through this binding, HSP70 stabilizes ENPP1 mRNA and increases ENPP1 transcript and protein levels. This positive modulation of ENPP1 expression is paralleled by a reduced insulin-induced IR and IRS-1 phosphorylation.

SIGNOR-252197

P09874

P00533

0

phosphorylation

up-regulates activity

0.394

EGFR and MET heterodimer interacts with and phosphorylates PARP1.

SIGNOR-279169

Q86Y01

Q96J02

0

ubiquitination

down-regulates

0.7

Itch/aip4 mediates deltex degradation through the formation of k29-linked polyubiquitin chains.

SIGNOR-150002

P29474

Q02156

0

phosphorylation

down-regulates activity

0.331

The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites

SIGNOR-251632

Q5VWK5

O60674

2

binding

up-regulates

0.701

Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12.

SIGNOR-87808

P27361

Q13950

1

phosphorylation

up-regulates

0.565

In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation.

SIGNOR-188347

P02649

P10636

2

binding

up-regulates activity

0.567

Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3.

SIGNOR-262588

P17612

O75899

1

phosphorylation

down-regulates activity

0.2

Here we show that the functional coupling of GABA(B)R1/GABA(B)R2 receptors to inwardly rectifying K(+) channels rapidly desensitizes. This effect is alleviated after direct phosphorylation of a single serine residue (Ser892) in the cytoplasmic tail of GABA(B)R2 by cyclic AMP (cAMP)-dependent protein kinase (PKA).

SIGNOR-263150

P39687

P06400

2

binding

down-regulates activity

0.2

We further demonstrate that pp32-Rb interaction inhibits the apoptotic activity of pp32 and stimulates proliferation.

SIGNOR-259083

P41594

P05129

0

phosphorylation

up-regulates activity

0.415

Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.

SIGNOR-249289

Q9NXR1

P17612

0

phosphorylation

up-regulates

0.4

Here, we demonstrate that disc1 and pde4 modulate nde1 phosphorylation by camp-dependent protein kinase a (pka) and identify a novel pka substrate site on nde1 at threonine-131 (t131).Since phosphorylated t131 is detectable at multiple subcellular locations (centrosome, nucleus, postsynaptic density, proximal axon), there is potential for disc1/pde4 to influence several important brain processes that critically depend on the nde1/ndel1/lis1 comple

SIGNOR-174410

Q14204

Q9GZM8

2

binding

up-regulates activity

0.72

LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex

SIGNOR-252159

Q9Y243

O15119

1

phosphorylation

up-regulates activity

0.354

We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion.

SIGNOR-223534

P17252

P16144

1

phosphorylation

down-regulates

0.531

Egf stimulates a pkc-?-Dependent pathway that results in the phosphorylation of the ?4 Integrin subunit on serine residues and its redistribution to actin-rich structures together, these results highlight the importance of serine phosphorylation in regulating type ii hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of ?4, and argue for a key role for pkc-? In regulating these structures

SIGNOR-124494

Q12888

O15297

0

dephosphorylation

down-regulates activity

0.392

In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1.

SIGNOR-277046

Q9GZQ6

P63096

2

binding

up-regulates activity

0.25

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256708

Q9UQM7

Q13224

1

phosphorylation

up-regulates activity

0.7

By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons.

SIGNOR-250630

Q15391

P19086

2

binding

up-regulates activity

0.2

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257118

Q9UDY8

Q9NYJ8

2

binding

up-regulates

0.606

Tab2/tak1 associate with ubiquitinated malt1 upon t-cell stimulation.

SIGNOR-158551

Q13416

P24941

0

phosphorylation

up-regulates

0.756

We also found that horc2p is phosphorylated in vitro by cyclin a/cdk2, specifically at residues thr116 and thr226. These data combined strongly suggest that skp2 promotes horc1p turnover and that the n-terminal domain of horc1p, containing most of the phosphorylation sites and overlapping with one of the skp2-interacting domains, is a regulatory element for horc1p stability.

SIGNOR-116364

Q5VWQ8

Q9HCE7

0

ubiquitination

down-regulates quantity by destabilization

0.262

DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1

SIGNOR-254776

Q8N695

P17676

0

transcriptional regulation

up-regulates quantity by expression

0.2

Luciferase reporter assays of deletion mutants of SLC5A8 promoter demonstrated that a 295-bp region is essential for the basal promoter activity of the SLC5A8 gene. Further analysis indicated that the CCAAT boxes and GC boxes were involved in positive regulation of SLC5A8 promoter. Overexpression of two transcription factors, CCAAT/enhancer binding protein beta (C/EBPbeta) and specific transcription factor 1 (Sp1), upregulated the activities of the human SLC5A8 promoter and protein expression, suggesting that both C/EBPbeta and Sp1 transcription factors might have functions in SLC5A8 transcription.

SIGNOR-254054

P12931

Q9Y613

1

phosphorylation

up-regulates activity

0.306

Our results show that only Src can efficiently phosphorylate FHOD1 at Y99 to enable the downstream activation by ROCK.

SIGNOR-276612

O14920

Q15653

1

phosphorylation

down-regulates

0.765

We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation

SIGNOR-52932

P06213

P18031

2

phosphorylation

up-regulates activity

0.788

Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B

SIGNOR-249370

P28482

Q9BYT3

0

phosphorylation

up-regulates activity

0.273

In vitro kinase assay results indicated that STK33 can phosphorylate ERK2.|STK33 phosphorylated ERK2 and increased the activity of ERK2 and promote the tumorigenesis of colorectal cancer HCT15 cells.

SIGNOR-279351

P43405

O14986

1

phosphorylation

down-regulates activity

0.2

We identified spleen tyrosine kinase (Syk), which is activated by oxidants, as a candidate PIP5Kbeta kinase in this pathway, and mapped the oxidant-sensitive tyrosine phosphorylation site to residue 105. The PIP5KbetaY105E phosphomimetic is catalytically inactive and cytosolic, whereas the Y105F non-phosphorylatable mutant has higher intrinsic lipid kinase activity and is much more membrane associated than wild type PIP5Kbeta.

SIGNOR-276227

Q05655

Q99808

1

phosphorylation

up-regulates activity

0.2

Phosphorylation of hENT1 by PKC has effects on both the function and subcellular trafficking of hENT1

SIGNOR-260888

O15355

Q13315

2

dephosphorylation

down-regulates activity

0.303

After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. |ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage.|DNA Damage Leads to ATM Dependent USP7S Dephosphorylation by PPM1G.

SIGNOR-277158

Q9Y496

P49407

2

binding

up-regulates

0.55

Kif3a is essential for shh-mediated signaling in mammalian systems (5), and we identified kif3a as a arr1 binding partner in a proteomics screen (18). To test whether arrs, smo, and kif3a might work in concert.

SIGNOR-178672

P11161

P17676

1

transcriptional regulation

up-regulates quantity by expression

0.534

Ectopic expression of krox20 can transactivate the c/ebpbeta promoter and increase c/ebpbeta gene expression in 3t3-l1 preadipocytes

SIGNOR-139292

P35240

P17252

0

phosphorylation

down-regulates activity

0.328

PKC\u03b1\nnormally phosphorylates and inactivates NF2.|PKCalpha normally phosphorylates and inactivates NF2.

SIGNOR-280081

P36888

P29353

1

phosphorylation

up-regulates activity

0.446

Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313.

SIGNOR-251147

Q15788

P28482

0

phosphorylation

up-regulates

0.364

Furthermore, erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for src-1 regulation. Treatment of cells expressing src-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene.

SIGNOR-74880

Q6PEY2

Q14980

2

binding

up-regulates

0.248

Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.

SIGNOR-116738

Q9P0J1

P11362

0

phosphorylation

down-regulates activity

0.292

Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.

SIGNOR-276640

Q14145

Q13501

0

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

P68400

P17936

1

phosphorylation

up-regulates quantity by stabilization

0.338

The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment.

SIGNOR-250903

P46531

P41240

2

binding

up-regulates

0.281

We found that the notch-1-furin interaction is regulated by the non-receptor tyrosine kinase, c-src. c-src and notch-1 are physically associated, and this association is responsible for notch-1 processing and activation

SIGNOR-196824

P61160

P18075

2

binding

up-regulates

0.289

The two ligands induce the formation of two ligand-receptor complexes, cbmp7 (blue) and ctgf-b (red), that share the type i receptor alk2

SIGNOR-144144

P24723

O15530

0

phosphorylation

up-regulates activity

0.316

Protein kinase C(eta) is phosphorylated by PDK1 in vitro, leading to kinase activation as similarly reported for protein kinase C(epsilon) activation by PDK1.

SIGNOR-280062

P20719

O15550

0

transcriptional regulation

up-regulates quantity by expression

0.27

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260023

Q86YJ5

P10586

1

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.

SIGNOR-271536

P62714

P04637

1

dephosphorylation

up-regulates quantity by stabilization

0.437

A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55| In this study, we reported that the specific B regulatory subunits of PP2A B56gamma1 and B56gamma3 mediate dephosphorylation of p53 at Thr55. Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis

SIGNOR-248583

Q8NFT8

P46531

2

binding

up-regulates

0.462

Dner binds to notch1 at cell-cell contacts and activates notch signaling in vitro.

SIGNOR-138346

P37231

O75688

0

dephosphorylation

up-regulates activity

0.372

Furthermore we show that PPM1B can directly dephosphorylate PPARgamma, both in intact cells and in vitro.|In addition PPM1B increases PPARγ-mediated transcription via dephosphorylation of Ser(112).|The serine/threonine phosphatase PPM1B (PP2Cbeta) selectively modulates PPARgamma activity.

SIGNOR-277073

P08476

Q13705

2

binding

up-regulates activity

0.787

Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.

SIGNOR-235142

P00734

P08709

1

null

up-regulates activity

0.301

Thrombin also activates the cofactors FVIII (to FVIIIa) and FV (to FVa) and activates platelets such that they provide a procoagulant membrane surface to which these proteins then bind

SIGNOR-263529

P63096

P18825

2

binding

up-regulates activity

0.48

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256699

Q9Y297

P35222

1

ubiquitination

down-regulates

0.872

Here we show that fwd1 (the mouse homologue of slimb/betatrcp), an f-box/wd40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, axin, gsk-3beta and apc. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with fwd1. Fwd1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels.

SIGNOR-67374

Q05195

Q9UQE7

2

binding

down-regulates activity

0.296

We identified a novel ZIP-containing protein, Mmip1 (Mad member interacting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc. Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive eects of Mad proteins on c-myc functions.

SIGNOR-241278

P50148

P28223

2

binding

up-regulates activity

0.608

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257137

O95644

Q03405

1

transcriptional regulation

up-regulates quantity by expression

0.2

Inducible podocyte-specific expression of constitutively active NFATc1 increased podocyte uPAR expression by binding to the Plaur gene promoter (encoding uPAR) in chromatin immunoprecipitation assays.

SIGNOR-253336

O15550

Q99607

1

transcriptional regulation

down-regulates quantity by repression

0.279

Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase

SIGNOR-260031

Q9UGM6

Q2TAL8

0

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269411

Q9UBK2

P37231

0

transcriptional regulation

up-regulates quantity by expression

0.903

NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,

SIGNOR-263984

P56524

P67775

0

dephosphorylation

up-regulates

0.35

Different signal-regulated serine/threonine kinases phosphorylate class ii histone deacetylases (hdacs) to promote nuclear export, cytosolic accumulation, and activation of gene transcriptionhere we show that hdac4 forms a complex with the pp2a holoenzyme c alpha, a alpha, b/pr55 alpha. In vitro and in vivo binding studies demonstrate that the n-terminus of hdac4 interacts with the catalytic subunit of pp2a. Hdac4 is dephosphorylated by pp2a

SIGNOR-159492