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
Q01718	O00253	2	binding	down-regulates activity	0.441	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268696
P08069	P12931	0	phosphorylation	up-regulates activity	0.582	The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.	SIGNOR-247193
Q12772	Q7KZF4	1	transcriptional regulation	up-regulates quantity by expression	0.342	These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression.	SIGNOR-259136
Q96B36	P42345	0	phosphorylation	down-regulates activity	0.904	We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1.	SIGNOR-178128
P12931	P78536	1	phosphorylation	up-regulates activity	0.458	These data suggests that Src mediates TACE activation in mechanically stressed cardiomyocytes and this mechanism could be exploited for specific blockade of TNFalpha secretion and its detrimental effects in congestive heart failure.\|We found that the non receptor tyrosine kinase Src mediates TACE activation in mechanically stretched rat cardiomyocytes by phosphorylating the Tyr 702 residue within the intracellular tail of TACE.	SIGNOR-279115
Q16236	P48506	1	transcriptional regulation	up-regulates quantity by expression	0.47	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256277
Q15208	Q96RD6	1	phosphorylation	up-regulates activity	0.2	We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation.	SIGNOR-263032
Q9NPF5	P12931	0	phosphorylation	down-regulates activity	0.2	C-Src phosphorylates DMAP1 at Tyr246 and disrupts Bub3/DMAP1 complex formation.	SIGNOR-279431
Q13214	O75051	2	binding	up-regulates activity	0.652	We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.	SIGNOR-261812
P54646	O75385	2	phosphorylation	up-regulates	0.505	In a screen for conserved substrates of ampk, we identified ulk1 and ulk2, mammalian orthologs of the yeast protein kinase atg1, which is required for autophagy.	SIGNOR-186637
P04150	Q92831	1	relocalization	up-regulates activity	0.549	NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase	SIGNOR-269233
P40692	P04637	0	transcriptional regulation	up-regulates quantity	0.61	.... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron.	SIGNOR-257605
Q00987	O15297	0	dephosphorylation	up-regulates	0.681	Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation.	SIGNOR-158328
P68400	Q9UBF6	1	phosphorylation	up-regulates	0.457	Ckbbp1 is phosphorylated in vivo and threonine to alanine mutation at residue 10 abrogates the phosphorylation of ckbbp1 observed in vivo, indicating that ckii is a major kinase that is responsible for in vivo phosphorylation of ckbbp1. As compared with the wild-type ckbbp1 or ckbbp1t10e (in which threonine 10 is replaced by glutamate), overexpression of nonphosphorylatable ckbbp1 (ckbbp1t10a) results in accumulation of ikappabalpha and p27kip1.	SIGNOR-101187
Q13131	P08559	1	phosphorylation	up-regulates activity	0.2	AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex	SIGNOR-276837
P18075	P61160	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
Q92973	P35637	1	relocalization	up-regulates activity	0.642	The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1).	SIGNOR-262101
P10646	P98155	2	binding	up-regulates	0.257	Binding studies revealed that full-length tfpi, but not the truncated tfpi molecule, is recognized by the very low density lipoprotein receptor (vldl receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for tfpi	SIGNOR-106353
Q9H6Z9	P14618	1	hydroxylation	up-regulates activity	0.436	Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.	SIGNOR-267476
O43933	P50542	2	binding	up-regulates activity	0.548	Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. (Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner.	SIGNOR-253618
Q16539	Q9BY84	0	dephosphorylation	down-regulates	0.805	Mkp-7 binds to and inactivates p38 mapk and jnk/sapk, but not erk inhibited by dual specificity phosphatases, such as dusp1, dusp10, and dusp16(uniprot)	SIGNOR-108233
P55085	P19086	2	binding	up-regulates activity	0.334	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-257232
P09471	O15552	2	binding	up-regulates activity	0.307	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-257075
Q15910	Q14680	0	phosphorylation	up-regulates quantity by stabilization	0.329	We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination.	SIGNOR-277480
P06276	Q9H2X6	0	phosphorylation	down-regulates quantity	0.2	As shown in XREF_FIG, HIPK2 overexpression strongly reduced Myc-Che-1 levels, whereas it produced little effect on Che-1 T144A expression.\|Notably, we found that HIPK2 phosphorylates a specific residue of Che-1, which is required for its interaction with Pin1 and for its degradation through the proteasome pathway.	SIGNOR-279190
Q16539	Q15672	1	phosphorylation	up-regulates	0.269	Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro	SIGNOR-173409
P18848	P07814	1	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-269419
Q8WZ64	P60953	1	gtpase-activating protein	down-regulates activity	0.495	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-260455
P01106	Q15208	0	phosphorylation	down-regulates activity	0.282	Previously, we demonstrated that STK38 kinase mediates MYC phosphorylation.\|STK38-WT overexpression dramatically reduced MYC half-life (4-fold), compared to control un induced cells (XREF_FIG), while STK38-KD overexpression led to increased MYC half-life (1.7 fold), illustrating an involvement in MYC protein turnover regulation (XREF_FIG).	SIGNOR-280142
P17676	P27361	0	phosphorylation	up-regulates	0.668	Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes.	SIGNOR-184917
P68400	P11388	1	phosphorylation	down-regulates quantity by destabilization	0.595	This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361.	SIGNOR-276300
Q92519	Q9HCE7	0	ubiquitination	down-regulates quantity by destabilization	0.41	In this study, we found that TRIB2 was up-regulated and exhibited high stability in liver cancer cells compared with other cells. We performed a structure-function analysis of TRIB2 and identified a domain (amino acids 1-5) at the N terminus that interacted with the E3 ubiquitin ligase Smurf1 and was critical for protein stability. Deletion of this domain extended TRIB2 half-life time accompanied with a more significant malignant property compared with wild type TRIB2.	SIGNOR-275432
P16104	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265405
Q9UQ13	P28482	0	phosphorylation	down-regulates quantity by destabilization	0.322	Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation.	SIGNOR-277442
P15941	P00519	0	phosphorylation	up-regulates quantity by stabilization	0.455	The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site.	SIGNOR-260830
P00533	P04083	1	phosphorylation	up-regulates	0.508	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf	SIGNOR-202776
P63092	P32245	2	binding	up-regulates activity	0.521	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268707
P31749	Q13107	1	phosphorylation	up-regulates quantity by stabilization	0.465	AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability.	SIGNOR-273482
P63000	Q2M1Z3	0	gtpase-activating protein	down-regulates activity	0.566	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-260489
P63000	Q8IWW6	0	gtpase-activating protein	down-regulates activity	0.546	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-260469
O60260	P37840	1	ubiquitination	down-regulates quantity by destabilization	0.2	Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei\|2. Parkin-associated endothelin receptor-like receptor (Pael-R).	SIGNOR-249705
P00734	P12259	1	null	up-regulates activity	0.882	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-263530
O14964	Q7Z6J0	0	ubiquitination	down-regulates quantity	0.246	Importantly, ubiquitination of Hrs mediated by POSH caused the reduction of Hrs level via the ubiquitin-proteasome pathway.	SIGNOR-278575
P18146	Q14774	0	transcriptional regulation	down-regulates quantity by repression	0.262	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261621
O00459	P36897	2	binding	up-regulates	0.343	These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.	SIGNOR-227531
Q6ISU1	P06239	2	binding	up-regulates activity	0.333	However, non-canonical mechanisms of p38alfa activation have been also described. One is apparently specific to antigen receptor stimulated t-lymphocytes. This involves phosphorylation of p38alfa on tyr323 by the tcr-proximal tyrosine kinase zap70 and p56lck.	SIGNOR-166658
Q13546	P21580	0	ubiquitination	down-regulates quantity	0.655	The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation.	SIGNOR-259978
Q9ULU4	O43623	1	transcriptional regulation	down-regulates quantity by repression	0.2	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262038
Q05209	P12931	1	dephosphorylation	up-regulates activity	0.542	PTP-PEST increases dephosphorylation of Src at Y527 and activates it.\|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src).	SIGNOR-277086
Q04759	Q5JVS0	1	phosphorylation	down-regulates activity	0.303	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249256
Q05513	P08670	1	phosphorylation	up-regulates activity	0.2	Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells.	SIGNOR-277622
Q02224	Q16181	2	binding	up-regulates activity	0.2	These findings reveal a key role for the SEPT7-CENP-E interaction in the distribution of CENP-E to the kinetochore and achieving chromosome alignment. We propose that SEPT7 forms a link between kinetochore distribution of CENP-E and the mitotic spindle checkpoint.	SIGNOR-252040
P63092	Q99677	2	binding	up-regulates activity	0.385	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 ‚â• -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 ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256785
P15336	Q13153	0	phosphorylation	down-regulates activity	0.2	Overall, our results unequivocally confirmed that Pak1 physically interacts with ATF2 and phosphorylates ATF2 on the Ser62 residue, and this process secludes ATF2 in the cytoplasm.	SIGNOR-279377
P25116	P51813	0	phosphorylation	down-regulates activity	0.2	As shown in xref \u2013 xref , BMX overexpression increased PAR1-WT phosphorylation but had no effect on PAR1 Y 381 FY 383 F mutant, indicating that BMX phosphorylated PAR1 at Y 381 and Y 383 .\|Mechanically , BMX represses PAR1 signaling in ECs by promoting PAR1 phosphorylation and internalization .	SIGNOR-279593
Q13480	P18031	0	dephosphorylation	down-regulates activity	0.38	Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well.\|The results indicate that PTP1B completely dephosphorylated Gab1 and the mutant protein failed to dephosphorylate Gab1 (Figure\u00a0 xref C).	SIGNOR-276965
P42229	P05019	1	transcriptional regulation	up-regulates quantity by expression	0.433	Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α	SIGNOR-251743
Q15858	Q92915	2	binding	down-regulates activity	0.2	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253425
P38435	P02818	1	carboxylation	up-regulates activity	0.687	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265922
Q01484	Q00975	2	binding	up-regulates quantity	0.263	Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo.	SIGNOR-266707
Q9UQM7	P16070	1	phosphorylation	up-regulates activity	0.2	In previous studies we have demonstrated that a key control point for this receptor is the phosphorylation of CD44 on a conserved cytoplasmic serine residue, Ser(325). This modification is not required for efficient ligand binding, but is an essential component of CD44-dependent cell migration on a hyaluronan substratum. We demonstrate here that cd44 is phosphorylated to high stoichiometry in resting cells and that ca(2+)/calmodulin-dependent protein kinase ii is a cd44 ser(325) kinase.	SIGNOR-109502
Q15256	Q13164	1	dephosphorylation	down-regulates activity	0.45	In this study we concentrated on whether and how PTP-SL, a kinase-interacting motif-containing PTP, might be involved in the down-regulation of the ERK5 signal\|Whereas inactivation of ERK5 by PTP-SL monitored in vitro is most probably simply due to the dephosphorylation of tyrosine 220 in the activating TEY motif	SIGNOR-248721
P12235	Q06124	0	dephosphorylation	down-regulates activity	0.271	Specifically, SHP2-mediated dephosphorylation of ANT1 at Tyr 191 is essential for mitochondrial homeostasis and mitigation of NLRP3 inflammasome activation.\|The interaction between SHP2 and ANT1 (Fig.\u00a0 xref ), and the opposite effects of SHP2 and ANT1 shRNAs in the activation of NLRP3 inflammasome (Figs.\u00a0 xref and xref ) raised the possibility that the SHP2 may inhibit ANT1 to suppress NLRP3 inflammasome activation.\|To further determine which tyrosine phosphorylation site of ANT1 is dephosphorylated by SHP2, we created the dephosphorylated mutant of ANT1, in which tyrosine was replaced with phenylalanine (Y to F mutation).	SIGNOR-277124
O15085	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.903	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-260538
P04637	Q9C0B5	1	transcriptional regulation	up-regulates quantity by expression	0.2	Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y	SIGNOR-261150
Q15797	Q9P0J1	0	dephosphorylation	down-regulates	0.243	We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1.	SIGNOR-144876
P84022	P50750	0	phosphorylation	down-regulates activity	0.622	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161589
Q5SQI0	P0DPH8	1	acetylation	up-regulates quantity by stabilization	0.242	Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.\|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules	SIGNOR-272246
O95477	P02647	2	binding	up-regulates activity	0.79	The stimulation of cellular cholesterol and phospholipid efflux by apolipoprotein A-I is mediated by the activity of the ATP-binding cassette transporter A1 (ABCA1). ABCA1 forms a high affinity complex with apoA-I by binding amphipathic helices within the apolipoprotein. VFVNFA sequence is required for ABCA1 to form a complex with apoA-I and to transfer cholesterol to the apolipoprotein.	SIGNOR-252100
P43354	Q9UPW6	0	transcriptional regulation	down-regulates quantity	0.295	Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development	SIGNOR-268930
O15297	P04637	1	dephosphorylation	down-regulates activity	0.558	PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair.	SIGNOR-248319
Q13131	Q9H0B6	1	phosphorylation	up-regulates	0.2	Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582	SIGNOR-174681
O95257	Q15797	0	transcriptional regulation	up-regulates quantity	0.2	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268937
Q15796	Q96J02	0	ubiquitination	up-regulates	0.453	Itch promotes ubiquitination of smad2 and augments smad2 phosphorylation that requires an intact ligase activity of itch. Moreover, itch facilitates complex formation between tgf-beta receptor and smad2 and enhances tgf-beta-induced transcription.	SIGNOR-128647
P05164	P04264	2	binding	up-regulates quantity	0.247	CK1 and CK9 specifically bind MPO. MPO is internalized by endothelial cells through a direct interaction with the endothelial surface protein CK1	SIGNOR-251886
Q9UJD0	O14795	1	relocalization	up-regulates activity	0.266	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264384
P62136	Q8IWU2	0	phosphorylation	down-regulates activity	0.57	Kpi-2 kinase domain phosphorylated protein phosphatase-1 (pp1c) at thr(320), which attenuated pp1c activity.	SIGNOR-94631
Q99942	Q9P055	1	ubiquitination	down-regulates activity	0.509	RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins. This association results in Ubc13-dependent RNF5-mediated noncanonical ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but rather inhibits its association with Rpt5 and p97.	SIGNOR-271483
Q92831	Q16695	1	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269621
Q9BRZ2	Q86WV6	1	ubiquitination	up-regulates activity	0.2	In contrast, we found that TRIM56 preferentially promoted K63 linked ubiquitination of the same lysine residue of STING that was important for the dimer formation and TBK1 activation.\|Specifically, TRIM56 induces STING dimerization during dsDNA triggered signaling to potentiate antiviral responses while RNF5 may induce degradation of mitochondrial STING to suppress RLR induced antiviral responses.The findings that TRIM56 failed to interact with dsDNA and that there was no colocalization between TRIM56 and dsDNA within cells suggest that TRIM56 is unlikely to be a dsDNA sensor, and instead facilitates the STING function by ubiquitination.	SIGNOR-278621
P68400	Q08945	1	phosphorylation	down-regulates activity	0.703	CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. \| we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity.	SIGNOR-250961
Q09472	Q9H0K1	0	phosphorylation	down-regulates activity	0.278	Indeed, overexpression of SIK2 increased p300 phosphorylation at Ser89, while knockdown of SIK2 decreased it (Fig. 4B).	SIGNOR-278368
Q12972	P62136	2	binding	down-regulates activity	0.622	We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity.	SIGNOR-255657
P05412	P28482	0	phosphorylation	up-regulates activity	0.79	Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1.	SIGNOR-201943
P15259	Q13153	0	phosphorylation	down-regulates quantity by destabilization	0.2	The ability of Pak1 to phosphorylate wild-type PGAM2 was increased after exposure of the cells to etoposide (XREF_FIG).\|Bar, 20 \u00b5m. (E) Primary mouse embryonic fibroblasts at early passages were treated with 20 \u00b5M etoposide in the presence of 20 \u00b5M MG132, and cell lysates were immunoblotted with antibodies against Pak1 and phospho-Ser118 in phosphoglycerate mutase as indicated. (F) Pak1 kinase phosphorylates PGAM2 at Ser118 in vitro.	SIGNOR-280237
P17600	P17612	0	phosphorylation	down-regulates activity	0.338	Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I	SIGNOR-250058
Q96HP0	P31749	0	phosphorylation	up-regulates activity	0.372	Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons\|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). \| In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching	SIGNOR-275666
P28336	Q14344	2	binding	up-regulates	0.25	These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways.	SIGNOR-107028
P48729	O75581	1	phosphorylation	up-regulates	0.552	We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.Site ii, like site i, was phosphorylated, as detected by means of a phospho-specific antibody (ab1493, for phosphorylated t1493 in lrp6)	SIGNOR-143034
Q9NRF2	P40259	1	dephosphorylation	down-regulates activity	0.2	SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.	SIGNOR-268458
P63096	Q15391	2	binding	up-regulates activity	0.403	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-256723
P38405	P47901	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-256934
O14640	Q9NPG1	2	binding	up-regulates activity	0.659	When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.	SIGNOR-134288
O00254	P38405	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-256904
Q92835	P62993	2	binding	up-regulates activity	0.583	An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.	SIGNOR-268449
Q99683	O60674	0	phosphorylation	down-regulates quantity by destabilization	0.367	Furthermore, JAK2, but not JAK1, directly bound to and phosphorylated ASK1 at Tyr-718, leading to an enhanced association of ASK1 with SOCS1 and subsequent ASK1 degradation.	SIGNOR-276145
Q96EB6	O75376	1	null	up-regulates	0.621	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-253505
O94768	P05129	0	phosphorylation	down-regulates activity	0.2	These results suggest that phosphorylation of Ser350 plays an essential role in regulating translocation of DRAK2 to the nucleus from the cytoplasm, possibly by affecting the activity of the NLS. Ectopic expression of PKC-gamma induced cytoplasmic localization of DRAK2 and PKC-gamma phosphorylated Ser350 flanking the NLS.	SIGNOR-263178
P61073	P04233	2	binding	up-regulates	0.531	Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling.	SIGNOR-187461
P09471	P18825	2	binding	up-regulates activity	0.395	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-256978

Q01718

O00253

2

binding

down-regulates activity

0.441

The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins

SIGNOR-268696

P08069

P12931

0

phosphorylation

up-regulates activity

0.582

The insulin-like growth factor type I (IGF-I) receptor can become tyrosine phosphorylated and enzymatically activated either in response to ligand or because of the activity of the Src tyrosine kinaseWe mapped the sites of IGF-I receptor autophosphorylation to peptides representing three different receptor domains: tyrosines 943 and 950 in the juxtamembrane region; tyrosines 1131, 1135, and 1136 within the kinase domain; and tyrosine 1316 in the carboxyl-terminal domain.

SIGNOR-247193

Q12772

Q7KZF4

1

transcriptional regulation

up-regulates quantity by expression

0.342

These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression.

SIGNOR-259136

Q96B36

P42345

0

phosphorylation

down-regulates activity

0.904

We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1.

SIGNOR-178128

P12931

P78536

1

phosphorylation

up-regulates activity

0.458

These data suggests that Src mediates TACE activation in mechanically stressed cardiomyocytes and this mechanism could be exploited for specific blockade of TNFalpha secretion and its detrimental effects in congestive heart failure.|We found that the non receptor tyrosine kinase Src mediates TACE activation in mechanically stretched rat cardiomyocytes by phosphorylating the Tyr 702 residue within the intracellular tail of TACE.

SIGNOR-279115

Q16236

P48506

1

transcriptional regulation

up-regulates quantity by expression

0.47

In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).

SIGNOR-256277

Q15208

Q96RD6

1

phosphorylation

up-regulates activity

0.2

We identified 5 potential NDR1 substrates in the mouse brain and chose two for functional validation. We show that one NDR1 substrate is another kinase, AP-2 associated kinase-1 (AAK1) which regulates dendritic branching as a result of NDR1 phosphorylation. Another substrate is the Rab8 guanine nucleotide exchange factor (GEF) Rabin8 (a Sec2p homolog) which we find is involved in spine synapse formation.

SIGNOR-263032

Q9NPF5

P12931

0

phosphorylation

down-regulates activity

0.2

C-Src phosphorylates DMAP1 at Tyr246 and disrupts Bub3/DMAP1 complex formation.

SIGNOR-279431

Q13214

O75051

2

binding

up-regulates activity

0.652

We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.

SIGNOR-261812

P54646

O75385

2

phosphorylation

up-regulates

0.505

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

SIGNOR-186637

P04150

Q92831

1

relocalization

up-regulates activity

0.549

NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase

SIGNOR-269233

P40692

P04637

0

transcriptional regulation

up-regulates quantity

0.61

.... numerous potentially novel targets, including the DNA mismatch repair genes MLH1 and PMS2. Both of these genes were determined to be responsive to DNA damage and p53 activation in normal human fibroblasts, and have p53-response elements within their first intron.

SIGNOR-257605

Q00987

O15297

0

dephosphorylation

up-regulates

0.681

Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation.

SIGNOR-158328

P68400

Q9UBF6

1

phosphorylation

up-regulates

0.457

Ckbbp1 is phosphorylated in vivo and threonine to alanine mutation at residue 10 abrogates the phosphorylation of ckbbp1 observed in vivo, indicating that ckii is a major kinase that is responsible for in vivo phosphorylation of ckbbp1. As compared with the wild-type ckbbp1 or ckbbp1t10e (in which threonine 10 is replaced by glutamate), overexpression of nonphosphorylatable ckbbp1 (ckbbp1t10a) results in accumulation of ikappabalpha and p27kip1.

SIGNOR-101187

Q13131

P08559

1

phosphorylation

up-regulates activity

0.2

AMPKα phosphorylates PDHA subunit on Ser295 and Ser314 to activate PDH complex

SIGNOR-276837

P18075

P61160

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

Q92973

P35637

1

relocalization

up-regulates activity

0.642

The C-terminal nuclear localization sequence of FUsed in Sarcoma (FUS-NLS) is critical for its nuclear import mediated by transportin (Trn1).

SIGNOR-262101

P10646

P98155

2

binding

up-regulates

0.257

Binding studies revealed that full-length tfpi, but not the truncated tfpi molecule, is recognized by the very low density lipoprotein receptor (vldl receptor) indicating that this receptor is a novel high affinity endothelial cell receptor for tfpi

SIGNOR-106353

Q9H6Z9

P14618

1

hydroxylation

up-regulates activity

0.436

Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.

SIGNOR-267476

O43933

P50542

2

binding

up-regulates activity

0.548

Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. (Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner.

SIGNOR-253618

Q16539

Q9BY84

0

dephosphorylation

down-regulates

0.805

Mkp-7 binds to and inactivates p38 mapk and jnk/sapk, but not erk inhibited by dual specificity phosphatases, such as dusp1, dusp10, and dusp16(uniprot)

SIGNOR-108233

P55085

P19086

2

binding

up-regulates activity

0.334

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-257232

P09471

O15552

2

binding

up-regulates activity

0.307

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-257075

Q15910

Q14680

0

phosphorylation

up-regulates quantity by stabilization

0.329

We observed a MELK-mediated increase of EZH2 S220 phosphorylation along with a concomitant loss of EZH2 K222 ubiquitination, suggesting a phosphorylation-dependent regulation of EZH2 ubiquitination.

SIGNOR-277480

P06276

Q9H2X6

0

phosphorylation

down-regulates quantity

0.2

As shown in XREF_FIG, HIPK2 overexpression strongly reduced Myc-Che-1 levels, whereas it produced little effect on Che-1 T144A expression.|Notably, we found that HIPK2 phosphorylates a specific residue of Che-1, which is required for its interaction with Pin1 and for its degradation through the proteasome pathway.

SIGNOR-279190

Q16539

Q15672

1

phosphorylation

up-regulates

0.269

Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness. this ser 68 is phosphorylated by p38, c-jun n-terminal kinases (jnk), and extracellular signal-regulated kinases1/2 in vitro

SIGNOR-173409

P18848

P07814

1

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-269419

Q8WZ64

P60953

1

gtpase-activating protein

down-regulates activity

0.495

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-260455

P01106

Q15208

0

phosphorylation

down-regulates activity

0.282

Previously, we demonstrated that STK38 kinase mediates MYC phosphorylation.|STK38-WT overexpression dramatically reduced MYC half-life (4-fold), compared to control un induced cells (XREF_FIG), while STK38-KD overexpression led to increased MYC half-life (1.7 fold), illustrating an involvement in MYC protein turnover regulation (XREF_FIG).

SIGNOR-280142

P17676

P27361

0

phosphorylation

up-regulates

0.668

Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes.

SIGNOR-184917

P68400

P11388

1

phosphorylation

down-regulates quantity by destabilization

0.595

This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361.

SIGNOR-276300

Q92519

Q9HCE7

0

ubiquitination

down-regulates quantity by destabilization

0.41

In this study, we found that TRIB2 was up-regulated and exhibited high stability in liver cancer cells compared with other cells. We performed a structure-function analysis of TRIB2 and identified a domain (amino acids 1-5) at the N terminus that interacted with the E3 ubiquitin ligase Smurf1 and was critical for protein stability. Deletion of this domain extended TRIB2 half-life time accompanied with a more significant malignant property compared with wild type TRIB2.

SIGNOR-275432

P16104

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265405

Q9UQ13

P28482

0

phosphorylation

down-regulates quantity by destabilization

0.322

Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitates FBXW7 binding for ubiquitylation and degradation.

SIGNOR-277442

P15941

P00519

0

phosphorylation

up-regulates quantity by stabilization

0.455

The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site.

SIGNOR-260830

P00533

P04083

1

phosphorylation

up-regulates

0.508

The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf

SIGNOR-202776

P63092

P32245

2

binding

up-regulates activity

0.521

The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins

SIGNOR-268707

P31749

Q13107

1

phosphorylation

up-regulates quantity by stabilization

0.465

AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability.

SIGNOR-273482

P63000

Q2M1Z3

0

gtpase-activating protein

down-regulates activity

0.566

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-260489

P63000

Q8IWW6

0

gtpase-activating protein

down-regulates activity

0.546

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-260469

O60260

P37840

1

ubiquitination

down-regulates quantity by destabilization

0.2

Parkin is a protein of 465 amino acids, and its structure includes a ubiquitin homologous domain in its N terminus and two RING finger domains in its C terminus. Molecular studies have determined that parkin is an E3 ubiquitin ligase function, implicating parkin in the ubiquitin-proteasome system, and raising the possibility that mutations in the gene lead to loss or diminished function. Three substrates for the ubiquitin-ligase function of parkin have been identified to date.1. A 22kDa glycosolated form of alpha-synuclei|2. Parkin-associated endothelin receptor-like receptor (Pael-R).

SIGNOR-249705

P00734

P12259

1

null

up-regulates activity

0.882

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-263530

O14964

Q7Z6J0

0

ubiquitination

down-regulates quantity

0.246

Importantly, ubiquitination of Hrs mediated by POSH caused the reduction of Hrs level via the ubiquitin-proteasome pathway.

SIGNOR-278575

P18146

Q14774

0

transcriptional regulation

down-regulates quantity by repression

0.262

In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.

SIGNOR-261621

O00459

P36897

2

binding

up-regulates

0.343

These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.

SIGNOR-227531

Q6ISU1

P06239

2

binding

up-regulates activity

0.333

However, non-canonical mechanisms of p38alfa activation have been also described. One is apparently specific to antigen receptor stimulated t-lymphocytes. This involves phosphorylation of p38alfa on tyr323 by the tcr-proximal tyrosine kinase zap70 and p56lck.

SIGNOR-166658

Q13546

P21580

0

ubiquitination

down-regulates quantity

0.655

The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation.

SIGNOR-259978

Q9ULU4

O43623

1

transcriptional regulation

down-regulates quantity by repression

0.2

Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported

SIGNOR-262038

Q05209

P12931

1

dephosphorylation

up-regulates activity

0.542

PTP-PEST increases dephosphorylation of Src at Y527 and activates it.|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src).

SIGNOR-277086

Q04759

Q5JVS0

1

phosphorylation

down-regulates activity

0.303

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249256

Q05513

P08670

1

phosphorylation

up-regulates activity

0.2

Results suggest that aPKCs target multiple activation sites (Ser33/39/56) on Vimentin and therefore is essential for VIF dynamics regulation during the metastasis of prostate cancer cells.

SIGNOR-277622

Q02224

Q16181

2

binding

up-regulates activity

0.2

These findings reveal a key role for the SEPT7-CENP-E interaction in the distribution of CENP-E to the kinetochore and achieving chromosome alignment. We propose that SEPT7 forms a link between kinetochore distribution of CENP-E and the mitotic spindle checkpoint.

SIGNOR-252040

P63092

Q99677

2

binding

up-regulates activity

0.385

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 ‚â• -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 ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256785

P15336

Q13153

0

phosphorylation

down-regulates activity

0.2

Overall, our results unequivocally confirmed that Pak1 physically interacts with ATF2 and phosphorylates ATF2 on the Ser62 residue, and this process secludes ATF2 in the cytoplasm.

SIGNOR-279377

P25116

P51813

0

phosphorylation

down-regulates activity

0.2

As shown in xref \u2013 xref , BMX overexpression increased PAR1-WT phosphorylation but had no effect on PAR1 Y 381 FY 383 F mutant, indicating that BMX phosphorylated PAR1 at Y 381 and Y 383 .|Mechanically , BMX represses PAR1 signaling in ECs by promoting PAR1 phosphorylation and internalization .

SIGNOR-279593

Q13480

P18031

0

dephosphorylation

down-regulates activity

0.38

Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well.|The results indicate that PTP1B completely dephosphorylated Gab1 and the mutant protein failed to dephosphorylate Gab1 (Figure\u00a0 xref C).

SIGNOR-276965

P42229

P05019

1

transcriptional regulation

up-regulates quantity by expression

0.433

Growth hormone induces insulin-like growth factor-I gene transcription by a synergistic action of STAT5 and HNF-1α

SIGNOR-251743

Q15858

Q92915

2

binding

down-regulates activity

0.2

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253425

P38435

P02818

1

carboxylation

up-regulates activity

0.687

Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.

SIGNOR-265922

Q01484

Q00975

2

binding

up-regulates quantity

0.263

Here, we demonstrate that ankyrin-B associates with Cav2.1 and Cav2.2 in cortex, cerebellum, and brain stem. Additionally, using in vitro and in vivo techniques, we demonstrate that ankyrin-B, via its membrane-binding domain, associates with a highly conserved motif in the DII/III loop domain of Cav2.1 and Cav2.2. Collectively, our findings identify an interaction between ankyrin-B and both Cav2.1 and Cav2.2 at the amino acid level that is necessary for proper Cav2.1 and Cav2.2 targeting in vivo.

SIGNOR-266707

Q9UQM7

P16070

1

phosphorylation

up-regulates activity

0.2

In previous studies we have demonstrated that a key control point for this receptor is the phosphorylation of CD44 on a conserved cytoplasmic serine residue, Ser(325). This modification is not required for efficient ligand binding, but is an essential component of CD44-dependent cell migration on a hyaluronan substratum. We demonstrate here that cd44 is phosphorylated to high stoichiometry in resting cells and that ca(2+)/calmodulin-dependent protein kinase ii is a cd44 ser(325) kinase.

SIGNOR-109502

Q15256

Q13164

1

dephosphorylation

down-regulates activity

0.45

In this study we concentrated on whether and how PTP-SL, a kinase-interacting motif-containing PTP, might be involved in the down-regulation of the ERK5 signal|Whereas inactivation of ERK5 by PTP-SL monitored in vitro is most probably simply due to the dephosphorylation of tyrosine 220 in the activating TEY motif

SIGNOR-248721

P12235

Q06124

0

dephosphorylation

down-regulates activity

0.271

Specifically, SHP2-mediated dephosphorylation of ANT1 at Tyr 191 is essential for mitochondrial homeostasis and mitigation of NLRP3 inflammasome activation.|The interaction between SHP2 and ANT1 (Fig.\u00a0 xref ), and the opposite effects of SHP2 and ANT1 shRNAs in the activation of NLRP3 inflammasome (Figs.\u00a0 xref and xref ) raised the possibility that the SHP2 may inhibit ANT1 to suppress NLRP3 inflammasome activation.|To further determine which tyrosine phosphorylation site of ANT1 is dephosphorylated by SHP2, we created the dephosphorylated mutant of ANT1, in which tyrosine was replaced with phenylalanine (Y to F mutation).

SIGNOR-277124

O15085

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.903

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-260538

P04637

Q9C0B5

1

transcriptional regulation

up-regulates quantity by expression

0.2

Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y

SIGNOR-261150

Q15797

Q9P0J1

0

dephosphorylation

down-regulates

0.243

We show that the mammalian pdps are important in dephosphorylation of bmp-activated smad1 but not tgf-beta-activated smad2 or smad3. Thus, pdps specifically inactivate smads in the bmp/dpp pathway. [...] These observations suggest that pdp1 and pdp2 are important for dephosphorylation of smad1.

SIGNOR-144876

P84022

P50750

0

phosphorylation

down-regulates activity

0.622

Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.

SIGNOR-161589

Q5SQI0

P0DPH8

1

acetylation

up-regulates quantity by stabilization

0.242

Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules

SIGNOR-272246

O95477

P02647

2

binding

up-regulates activity

0.79

The stimulation of cellular cholesterol and phospholipid efflux by apolipoprotein A-I is mediated by the activity of the ATP-binding cassette transporter A1 (ABCA1). ABCA1 forms a high affinity complex with apoA-I by binding amphipathic helices within the apolipoprotein. VFVNFA sequence is required for ABCA1 to form a complex with apoA-I and to transfer cholesterol to the apolipoprotein.

SIGNOR-252100

P43354

Q9UPW6

0

transcriptional regulation

down-regulates quantity

0.295

Satb2 represses the transcription of Nr4a2. The misexpression of Nr4a2 together with Ctip2 induces expression of SubC-specific genes in wild-type Rsp, and simultaneous knockdown of these two genes in Rsp Satb2-mutant cells prevents their fate transition to SubC identity. Thus, Satb2 serves as a determinant gene in the Rsp regionalization by repressing Nr4a2 and Ctip2 during cortical development

SIGNOR-268930

O15297

P04637

1

dephosphorylation

down-regulates activity

0.558

PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair.

SIGNOR-248319

Q13131

Q9H0B6

1

phosphorylation

up-regulates

0.2

Consistent with phosphorylation of both ser545 and ser582 of klc2 contributing to its 14-3-3 binding, a ser545ala mutant of klc2 could be phosphorylated in vitro by ampk on ser582

SIGNOR-174681

O95257

Q15797

0

transcriptional regulation

up-regulates quantity

0.2

Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation

SIGNOR-268937

Q15796

Q96J02

0

ubiquitination

up-regulates

0.453

Itch promotes ubiquitination of smad2 and augments smad2 phosphorylation that requires an intact ligase activity of itch. Moreover, itch facilitates complex formation between tgf-beta receptor and smad2 and enhances tgf-beta-induced transcription.

SIGNOR-128647

P05164

P04264

2

binding

up-regulates quantity

0.247

CK1 and CK9 specifically bind MPO. MPO is internalized by endothelial cells through a direct interaction with the endothelial surface protein CK1

SIGNOR-251886

Q9UJD0

O14795

1

relocalization

up-regulates activity

0.266

N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle

SIGNOR-264384

P62136

Q8IWU2

0

phosphorylation

down-regulates activity

0.57

Kpi-2 kinase domain phosphorylated protein phosphatase-1 (pp1c) at thr(320), which attenuated pp1c activity.

SIGNOR-94631

Q99942

Q9P055

1

ubiquitination

down-regulates activity

0.509

RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins. This association results in Ubc13-dependent RNF5-mediated noncanonical ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but rather inhibits its association with Rpt5 and p97.

SIGNOR-271483

Q92831

Q16695

1

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269621

Q9BRZ2

Q86WV6

1

ubiquitination

up-regulates activity

0.2

In contrast, we found that TRIM56 preferentially promoted K63 linked ubiquitination of the same lysine residue of STING that was important for the dimer formation and TBK1 activation.|Specifically, TRIM56 induces STING dimerization during dsDNA triggered signaling to potentiate antiviral responses while RNF5 may induce degradation of mitochondrial STING to suppress RLR induced antiviral responses.The findings that TRIM56 failed to interact with dsDNA and that there was no colocalization between TRIM56 and dsDNA within cells suggest that TRIM56 is unlikely to be a dsDNA sensor, and instead facilitates the STING function by ubiquitination.

SIGNOR-278621

P68400

Q08945

1

phosphorylation

down-regulates activity

0.703

CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity.

SIGNOR-250961

Q09472

Q9H0K1

0

phosphorylation

down-regulates activity

0.278

Indeed, overexpression of SIK2 increased p300 phosphorylation at Ser89, while knockdown of SIK2 decreased it (Fig. 4B).

SIGNOR-278368

Q12972

P62136

2

binding

down-regulates activity

0.622

We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity.

SIGNOR-255657

P05412

P28482

0

phosphorylation

up-regulates activity

0.79

Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1.

SIGNOR-201943

P15259

Q13153

0

phosphorylation

down-regulates quantity by destabilization

0.2

The ability of Pak1 to phosphorylate wild-type PGAM2 was increased after exposure of the cells to etoposide (XREF_FIG).|Bar, 20 \u00b5m. (E) Primary mouse embryonic fibroblasts at early passages were treated with 20 \u00b5M etoposide in the presence of 20 \u00b5M MG132, and cell lysates were immunoblotted with antibodies against Pak1 and phospho-Ser118 in phosphoglycerate mutase as indicated. (F) Pak1 kinase phosphorylates PGAM2 at Ser118 in vitro.

SIGNOR-280237

P17600

P17612

0

phosphorylation

down-regulates activity

0.338

Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I

SIGNOR-250058

Q96HP0

P31749

0

phosphorylation

up-regulates activity

0.372

Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching

SIGNOR-275666

P28336

Q14344

2

binding

up-regulates

0.25

These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways.

SIGNOR-107028

P48729

O75581

1

phosphorylation

up-regulates

0.552

We show that wnt induces sequential phosphorylation of lrp6 by gsk3 and casein kinase 1, and this dual phosphorylation promotes the engagement of lrp6 with the scaffolding protein axin.Site ii, like site i, was phosphorylated, as detected by means of a phospho-specific antibody (ab1493, for phosphorylated t1493 in lrp6)

SIGNOR-143034

Q9NRF2

P40259

1

dephosphorylation

down-regulates activity

0.2

SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.

SIGNOR-268458

P63096

Q15391

2

binding

up-regulates activity

0.403

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-256723

P38405

P47901

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-256934

O14640

Q9NPG1

2

binding

up-regulates activity

0.659

When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.

SIGNOR-134288

O00254

P38405

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-256904

Q92835

P62993

2

binding

up-regulates activity

0.583

An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.

SIGNOR-268449

Q99683

O60674

0

phosphorylation

down-regulates quantity by destabilization

0.367

Furthermore, JAK2, but not JAK1, directly bound to and phosphorylated ASK1 at Tyr-718, leading to an enhanced association of ASK1 with SOCS1 and subsequent ASK1 degradation.

SIGNOR-276145

Q96EB6

O75376

1

null

up-regulates

0.621

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-253505

O94768

P05129

0

phosphorylation

down-regulates activity

0.2

These results suggest that phosphorylation of Ser350 plays an essential role in regulating translocation of DRAK2 to the nucleus from the cytoplasm, possibly by affecting the activity of the NLS. Ectopic expression of PKC-gamma induced cytoplasmic localization of DRAK2 and PKC-gamma phosphorylated Ser350 flanking the NLS.

SIGNOR-263178

P61073

P04233

2

binding

up-regulates

0.531

Cd74 forms functional complexes with cxcr4 that mediate mif-specific signaling.

SIGNOR-187461

P09471

P18825

2

binding

up-regulates activity

0.395

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-256978