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
P09467	O75385	0	phosphorylation	down-regulates activity	0.2	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274031
P19838	P20749	2	binding	up-regulates activity	0.587	In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription.	SIGNOR-254789
Q9Y6B2	Q99608	2	binding	up-regulates activity	0.375	The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation.	SIGNOR-237614
P14780	P01023	2	cleavage	down-regulates quantity by destabilization	0.492	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.\|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261740
P08173	P63096	2	binding	up-regulates activity	0.454	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-256686
P31751	Q00613	1	phosphorylation	up-regulates activity	0.309	AKT2 also phosphorylated S326 of HSF1 but showed weak ability to activate HSF1.\|AKT2 promoted a significant increase in HSF1 activity , but the effect was modest while AKT3 had no significant effect on HSF1 activity ( Fig. 1A-C ) .	SIGNOR-279779
Q01892	P68400	0	phosphorylation	down-regulates	0.429	Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability	SIGNOR-73891
O00631	Q9UQM7	0	phosphorylation	down-regulates activity	0.241	SLN is also phosphorylated by CaMKII at Thr 5, and a phosphorylation mimic (Thr5Glu mutation) abolishes the inhibitory function of ectopically expressed SLN in adult rat ventricular myocytes\| Thr 5 interacts with SERCA Trp 932, and phosphorylation at this site would cause a steric clash that destabilizes binding	SIGNOR-264778
O75385	Q96PU5	0	ubiquitination	down-regulates quantity by destabilization	0.361	NEDD4L ubiquitylates ULK1 at lysine 925 and lysine 933.\|Next, we found that down-regulation of the ULK1 protein by NEDD4L is blocked by proteasome inhibitors (MG132 and lactacystin), but not by lysosomal inhibitors (leupeptin and Clq; XREF_FIG and S2 C), indicating that NEDD4L triggers ULK1 degradation exclusively through the proteasome pathway.	SIGNOR-278523
O94759	P17252	0	phosphorylation	up-regulates activity	0.2	ROS production in endothelial cells or directly applying ROS induced PKC\u03b1 activation and phosphorylation of TRPM2 at Ser 39.\|ROS production in endothelial cells or directly applying ROS induced PKCalpha activation and phosphorylation of TRPM2 at Ser 39.	SIGNOR-280082
P36888	Q12913	0	dephosphorylation	down-regulates activity	0.49	Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro.\|The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation.	SIGNOR-277092
P68400	Q8N163	1	phosphorylation	up-regulates activity	0.2	CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. \|In our results, CK2alpha affected the\|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1	SIGNOR-267666
P28562	Q06330	2	binding	up-regulates	0.249	Notch induction of mkp-1 depends on an rbp-j-dependent mechanism.	SIGNOR-236851
Q07817	Q9BXH1	2	binding	down-regulates activity	0.761	Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.	SIGNOR-133811
Q9UHD2	O14920	2	binding	up-regulates	0.403	A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway.	SIGNOR-121576
P01008	P00740	1	cleavage	down-regulates activity	0.897	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264140
P06241	Q9Y6K9	1	phosphorylation	down-regulates activity	0.357	Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.	SIGNOR-276371
P05412	P28562	0	dephosphorylation	down-regulates activity	0.455	However, adenovirus mediated overexpression of MKP-1 only slightly decreased JNK and c-Jun phosphorylation compared with the severe inactivation of JNK activities induced by MKK7 knockdown.\|The results suggested that HDACI-induced MKP-1 contributes to inactivation of JNK instead of ERK, consistent with the previous reports in other cell types	SIGNOR-277102
P20393	P49841	0	phosphorylation	up-regulates	0.282	We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock.	SIGNOR-144570
O94875	P22681	0	ubiquitination	down-regulates	0.512	Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl	SIGNOR-96325
Q14511	Q06124	0	dephosphorylation	down-regulates activity	0.488	In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.\|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity.	SIGNOR-277083
Q92914	Q9UQD0	2	binding	down-regulates activity	0.253	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-253414
P27986	Q6ZUJ8	2	binding	up-regulates	0.626	Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling	SIGNOR-191673
P60484	P23528	1	dephosphorylation	up-regulates activity	0.441	Unexpectedly, cofilin-1 activation by PGE 2 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated.\|Unexpectedly, cofilin-1 dephosphorylation and activation in our model was mediated by the protein phosphatase activity of PTEN.	SIGNOR-276980
P17612	P07196	1	phosphorylation	down-regulates activity	0.2	Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L.	SIGNOR-252401
Q14247	P00519	0	phosphorylation	up-regulates activity	0.424	Because phosphorylation by c-Abl augments nmMLCK-cortactin interaction to a greater degree than does pp60src phosphorylation, it is likely that phosphorylation sites on nmMLCK unique to c-Abl (i.e., other than Y464 and Y846) are responsible for this enhanced protein-protein interaction.\|Moreover, our data indicate that cortactin is itself rapidly phosphorylated on Y486 by c-Abl in EC after S1P (Figure 9).	SIGNOR-278504
O15111	Q15717	1	phosphorylation	down-regulates quantity by destabilization	0.323	Furthermore, mutational analysis indicates that IKKα-dependent phosphorylation at Ser-304 is crucial to the binding of HuR to β-TrCP1. Mechanistically, this HuR degradation pathway differs from that reported for heat shock and hypoxia, which underlies the complexity in the regulation of HuR turnover under different stress stimuli.	SIGNOR-276422
P18545	P16499	2	binding	down-regulates activity	0.866	Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B	SIGNOR-260010
P15336	P28482	0	phosphorylation	up-regulates	0.733	Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.	SIGNOR-90517
P23470	P43403	1	dephosphorylation	up-regulates activity	0.26	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254733
P62136	Q8WVI7	2	binding	down-regulates activity	0.389	IPP5, a novel inhibitor of protein phosphatase 1, suppresses tumor growth and progression of cervical carcinoma cells by inducing G2/M arrest	SIGNOR-275726
P41252	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-269406
P08047	P01137	1	transcriptional regulation	up-regulates quantity by expression	0.296	MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-β mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-β production	SIGNOR-251740
P28324	Q16549	0	phosphorylation	up-regulates	0.2	In contrast, the tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387	SIGNOR-47771
O95837	Q9BPV8	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-257027
P32314	P51812	0	phosphorylation	down-regulates quantity by destabilization	0.2	Importantly, we identified RSK2 kinase as the upstream kinase for the FOXN2 phosphodegron. The Ser365 and Ser369 sites in a conserved DSGYAS motif are responsible for the ubiquitination of FOXN2 by β-Trcp.	SIGNOR-273841
Q05655	P21730	1	phosphorylation	down-regulates	0.2	Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation.	SIGNOR-73967
Q8TAP9	P06493	0	phosphorylation	up-regulates	0.341	Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1	SIGNOR-153308
P0C0S8	Q9BX84	0	phosphorylation	down-regulates activity	0.2	We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1.	SIGNOR-276008
Q9Y5X3	Q14185	2	binding	up-regulates activity	0.346	SNX5 Is a Novel Binding Partner of the DHR1 Domain of DOCK180. In summary, we found that DOCK180 regulates transport of CI-MPR via SNX5 binding.	SIGNOR-269441
O75582	P28482	0	phosphorylation	up-regulates	0.617	Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.	SIGNOR-131311
P22455	P40763	1	phosphorylation	up-regulates activity	0.402	Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.	SIGNOR-251142
P51608	P41145	1	post transcriptional regulation	up-regulates quantity by expression	0.272	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264677
P35222	P37231	2	binding	down-regulates activity	0.538	Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain	SIGNOR-256072
P03372	Q14164	0	phosphorylation	up-regulates	0.341	Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna.	SIGNOR-161834
O15530	P07949	0	phosphorylation	up-regulates activity	0.2	Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1.	SIGNOR-235863
Q13501	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	Once activated, parkin interacts with and subsequently ubiquitinates p62 at the K13 residue, resulting in the degradation of p62 via the proteasomal dependent pathway.	SIGNOR-278524
P35813	Q16539	1	dephosphorylation	down-regulates activity	0.408	Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay	SIGNOR-59618
Q8WZ19	Q13618	2	binding	up-regulates activity	0.536	BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264233
P07225	P30530	2	binding	up-regulates	0.464	We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function.	SIGNOR-34483
P38405	Q96G91	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-256931
Q08209	Q92934	1	dephosphorylation	up-regulates activity	0.471	Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD\|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.	SIGNOR-248694
P19784	Q99250	1	phosphorylation	up-regulates activity	0.2	We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. \| inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.	SIGNOR-275758
P61586	P63167	0	gtpase-activating protein	down-regulates activity	0.273	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-260501
Q92985	P03230	0	sumoylation	down-regulates activity	0.2	One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses.	SIGNOR-266951
Q14511	O14965	2	binding	up-regulates activity	0.57	HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.	SIGNOR-262653
Q13555	Q14524	1	phosphorylation	up-regulates activity	0.291	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).\|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. \| Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275779
P62993	P15498	2	binding	up-regulates	0.686	Recently, we have shown that the proto-oncogene vav product (vav) is also tyrosine-phosphorylated by treatment with gm-csf and epo and is constitutively associated with the sh3 domain of grb2/ash in ut-7.	SIGNOR-49362
Q9Y4A5	P35222	2	binding	up-regulates	0.58	The beta-cat c-terminal activation domain associates with trrap/tip60 and mixed-lineage-leukemia (mll1/mll2) set1-type chromatin-modifying complexes in vitro, and we show that beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo.	SIGNOR-144966
P52565	P17252	0	phosphorylation	down-regulates activity	0.449	PKCalpha phosphorylates RhoGDIalpha at Ser34 to reduce its affinity for RhoA (but not for Rac1 or Cdc42) .	SIGNOR-279097
Q9UQM7	P09917	1	phosphorylation	up-regulates activity	0.2	Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export\|We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques\|Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca2+/calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO.	SIGNOR-264408
P10721	P22681	2	phosphorylation	up-regulates activity	0.618	The activated KIT in turn induces phosphorylation and activation of Cbl proteins.	SIGNOR-279199
P63092	P25100	2	binding	up-regulates activity	0.291	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-256808
P11233	O14965	0	phosphorylation	up-regulates activity	0.45	Specifically, the mitotic kinase Aurora A phosphorylates Ser 194 of RALA, relocalizing it to the mitochondria, where it concentrates RALBP1 and DRP1.\|These data suggest that Aurora A promotes mitochondrial fission at mitosis through RalA and RalBP1.	SIGNOR-278351
O95071	P61077	0	ubiquitination	up-regulates activity	0.462	Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks.	SIGNOR-272669
P46108	Q8TEW6	2	binding	up-regulates	0.46	Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells.	SIGNOR-100996
P23258	Q96SN8	2	binding	up-regulates activity	0.652	Immunoprecipitation of CDK5RAP2 specifically coprecipitated _TuRC components, as detected on immunoblots of _-tubulin and GCP3 (Figure 3A).\| Perturbing CDK5RAP2 function delocalized gamma-tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in gammaTuRC attachment and therefore in the microtubule organizing function of the centrosome.	SIGNOR-260310
P35813	P24941	1	dephosphorylation	down-regulates activity	0.292	Moreover, purified recombinant PP2C alpha and PP2C beta 2 proteins efficiently dephosphorylated monomeric Cdk2/Cdk6 in vitro.	SIGNOR-277107
P78536	P15941	1	cleavage	down-regulates	0.308	These characteristics along with studies conducted with cell lines genetically deficient in various adams (for a disintegrin and metalloprotease) identified tumor necrosis factor-alpha converting enzyme (tace)/adam 17 as a muc1 sheddase.	SIGNOR-95630
Q01196	P15976	2	binding	up-regulates activity	0.643	We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin-dependent kinases. Furthermore, targeting of RUNX1 by GATA-1 for phosphorylation may convert RUNX1 from a repressor to an activator. This is a potential mechanism of transcriptional cooperation and may be an essential step in megakaryocytic differentiation.	SIGNOR-254194
P01133	P00533	2	binding	up-regulates activity	0.949	Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase.	SIGNOR-186159
O43663	P53350	0	phosphorylation	down-regulates activity	0.723	Plk1 negatively regulates PRC1 to prevent premature midzone formation before cytokinesis.\|Plk1, but not Cdk1, phosphorylates PRC1 on Thr-602 to prevent premature midzone assembly in metaphase.	SIGNOR-279645
P63092	Q13255	2	binding	up-regulates activity	0.407	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264077
P41968	P38405	2	binding	up-regulates activity	0.289	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-256748
Q9UK99	Q9H2X6	2	binding	down-regulates quantity by destabilization	0.404	O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.	SIGNOR-271741
P10828	P28482	0	phosphorylation	down-regulates activity	0.412	We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.	SIGNOR-102216
Q96F46	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.2	Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.	SIGNOR-277205
P55040	P27348	2	binding	up-regulates quantity by stabilization	0.266	In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. (Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase	SIGNOR-261724
Q14693	P35790	0	phosphorylation	down-regulates activity	0.273	Because CKI is a constitutively active kinase and ubiquitously distributed in many cell types, high mTORC1 activity depending on nutritional status may be a physiological cue for Lipin1 degradation mediated by CKI and beta-TRCP.\|Thus, we propose that mTORC1 may function as a priming kinase for CKI to promote the phosphorylation of the degron motif in Lipin1.	SIGNOR-280228
P12931	O14920	1	phosphorylation	up-regulates	0.362	These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation.	SIGNOR-99318
O43353	Q8WWF5	0	ubiquitination	down-regulates quantity by destabilization	0.2	Collectively, ZNRF4 degrades RIP2 protein by targeting the RIP2CARD domain in an E3-ubiquitin ligase activity dependent manner.\|Here we show that ZNRF4 induces K48-linked ubiquitination of RIP2 and promotes RIP2 degradation.	SIGNOR-278684
Q9H3R0	P42574	0	cleavage	down-regulates activity	0.2	JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels.	SIGNOR-263870
P51449	Q16552	1	transcriptional regulation	up-regulates	0.54	We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells	SIGNOR-255029
Q15366	P28482	0	phosphorylation	up-regulates quantity by stabilization	0.318	We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B).	SIGNOR-262912
P12931	P01116	1	phosphorylation	up-regulates activity	0.658	Src phosphorylation promotes the intrinsic exchange rate of KRAS Q61H.\|Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells.	SIGNOR-278990
Q9NWZ3	Q01638	2	binding	up-regulates activity	0.604	As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.	SIGNOR-277705
P34130	Q16620	2	binding	up-regulates	0.94	Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb.	SIGNOR-31644
Q8NFZ3	P78352	1	relocalization	up-regulates activity	0.2	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264190
Q08379	P06493	0	phosphorylation	down-regulates	0.674	Cdc2 kinase directly phosphorylates the cis-golgi matrix protein gm130 and is required for golgi fragmentation in mitosis. Mitotic fragmentation of the golgi apparatus can be largely explained by disruption of the interaction between gm130 and the vesicle-docking protein p115. Here we identify a single serine (ser-25) in gm130 as the key phosphorylated target and cdc2 as the responsible kinase	SIGNOR-60281
O43524	Q13547	0	deacetylation	up-regulates activity	0.368	The ability of HDAC1 to cause muscle atrophy required its deacetylase activity and was linked to the induction of several atrophy genes by HDAC1, including atrogin-1, which required deacetylation of FoxO3a	SIGNOR-256486
Q14934	P45983	0	phosphorylation	up-regulates activity	0.467	Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif.\|Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose dependent manner by JNK1 or JNK2.	SIGNOR-280033
P02749	P00747	0	cleavage	down-regulates activity	0.458	Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form\| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI.	SIGNOR-266996
P12931	P20936	1	phosphorylation	down-regulates	0.615	The phosphorylation of p120-gap by p60c-src inhibited its ability to stimulate the ha-ras-gtpase activity	SIGNOR-86008
Q14164	P03372	1	phosphorylation	up-regulates	0.341	Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna.	SIGNOR-161834
O00712	Q9HD90	1	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268898
P10767	P22455	2	binding	up-regulates	0.732	Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.	SIGNOR-18570
P25445	P25445	2	binding	up-regulates activity	0.2	The fas receptor, upon binding to the fasl, trimerizes	SIGNOR-85991
P46531	Q9UBP5	2	binding	down-regulates	0.767	Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression.	SIGNOR-146690
P62987	O60260	2	binding	up-regulates activity	0.2	The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.	SIGNOR-270344
P01023	P14091	0	cleavage	down-regulates quantity by destabilization	0.38	Disruption of structural and functional integrity of alpha 2-macroglobulin by cathepsin E\|Analysis of the N-terminal amino-acid sequences of these proteins revealed that alpha 2M was selectively cleaved at the Phe811-Leu812 bond in about 100mer downstream of the bait region.	SIGNOR-266977

P09467

O75385

0

phosphorylation

down-regulates activity

0.2

Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).

SIGNOR-274031

P19838

P20749

2

binding

up-regulates activity

0.587

In the present study, we report that regulation of CTCF by extracellular stress signals is dependent upon activations of an oxidative stress-regulated protein Bcl-3. We found that activated Bcl-3 was able to bind to the κB sites identified in the CTCF promoter region. Bcl-3 was activated by UV irradiation to interact with NF-κB p50 by forming a Bcl-3/p50 heterodimer complex. The Bcl-3/p50 complex suppressed CTCF promoter activity to down-regulate CTCF transcription.

SIGNOR-254789

Q9Y6B2

Q99608

2

binding

up-regulates activity

0.375

The Prader-Willi syndrome protein necdin interacts with the E1A-like inhibitor of differentiation EID-1 and promotes myoblast differentiation.

SIGNOR-237614

P14780

P01023

2

cleavage

down-regulates quantity by destabilization

0.492

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

SIGNOR-261740

P08173

P63096

2

binding

up-regulates activity

0.454

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-256686

P31751

Q00613

1

phosphorylation

up-regulates activity

0.309

AKT2 also phosphorylated S326 of HSF1 but showed weak ability to activate HSF1.|AKT2 promoted a significant increase in HSF1 activity , but the effect was modest while AKT3 had no significant effect on HSF1 activity ( Fig. 1A-C ) .

SIGNOR-279779

Q01892

P68400

0

phosphorylation

down-regulates

0.429

Serine residues 37 in the transactivation domain and 129, 144 and 146 in the pest domain of spi-b are phosphorylated by ckii in vitro. The ckii phosphorylation sites mapped in vitro are phosphorylated in vivo. Mutations of the ckii phosphorylation sites increase the ability of spi-b to transactivate. Spi-b phosphorylation by ckii reduces its stability

SIGNOR-73891

O00631

Q9UQM7

0

phosphorylation

down-regulates activity

0.241

SLN is also phosphorylated by CaMKII at Thr 5, and a phosphorylation mimic (Thr5Glu mutation) abolishes the inhibitory function of ectopically expressed SLN in adult rat ventricular myocytes| Thr 5 interacts with SERCA Trp 932, and phosphorylation at this site would cause a steric clash that destabilizes binding

SIGNOR-264778

O75385

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.361

NEDD4L ubiquitylates ULK1 at lysine 925 and lysine 933.|Next, we found that down-regulation of the ULK1 protein by NEDD4L is blocked by proteasome inhibitors (MG132 and lactacystin), but not by lysosomal inhibitors (leupeptin and Clq; XREF_FIG and S2 C), indicating that NEDD4L triggers ULK1 degradation exclusively through the proteasome pathway.

SIGNOR-278523

O94759

P17252

0

phosphorylation

up-regulates activity

0.2

ROS production in endothelial cells or directly applying ROS induced PKC\u03b1 activation and phosphorylation of TRPM2 at Ser 39.|ROS production in endothelial cells or directly applying ROS induced PKCalpha activation and phosphorylation of TRPM2 at Ser 39.

SIGNOR-280082

P36888

Q12913

0

dephosphorylation

down-regulates activity

0.49

Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro.|The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation.

SIGNOR-277092

P68400

Q8N163

1

phosphorylation

up-regulates activity

0.2

CK2alphawas bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2alphawas evidenced by co-immunoprecipitation of CK2alphaand DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. |In our results, CK2alpha affected the|These results suggest that DBC1 may be involved in the progression of gastric carcinoma by inducing the EMT and that it is closely associated with CK2alpha-mediated phosphorylation of DBC1. phosphorylation of Thr454 on DBC1

SIGNOR-267666

P28562

Q06330

2

binding

up-regulates

0.249

Notch induction of mkp-1 depends on an rbp-j-dependent mechanism.

SIGNOR-236851

Q07817

Q9BXH1

2

binding

down-regulates activity

0.761

Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.

SIGNOR-133811

Q9UHD2

O14920

2

binding

up-regulates

0.403

A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway.

SIGNOR-121576

P01008

P00740

1

cleavage

down-regulates activity

0.897

Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1

SIGNOR-264140

P06241

Q9Y6K9

1

phosphorylation

down-regulates activity

0.357

Either IKKγ/NEMO WT or the Y374F mutant was coexpressed with each member of the Src family protein tyrosine kinases (SF-PTKs) in HEK 293T cells. Our study thus demonstrates that the Y374 or S377 residue located at the C-terminal proline-rich domain of human IKKγ/NEMO undergoes phosphorylation upon TNF-α treatment or KvFLIP expression, respectively, resulting in the suppression of IKKγ/NEMO activity to induce NF-κB activation.

SIGNOR-276371

P05412

P28562

0

dephosphorylation

down-regulates activity

0.455

However, adenovirus mediated overexpression of MKP-1 only slightly decreased JNK and c-Jun phosphorylation compared with the severe inactivation of JNK activities induced by MKK7 knockdown.|The results suggested that HDACI-induced MKP-1 contributes to inactivation of JNK instead of ERK, consistent with the previous reports in other cell types

SIGNOR-277102

P20393

P49841

0

phosphorylation

up-regulates

0.282

We show here that gsk3beta phosphorylates and stabilizes the orphan nuclear receptor rev-erbalpha, a negative component of the circadian clock.

SIGNOR-144570

O94875

P22681

0

ubiquitination

down-regulates

0.512

Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl

SIGNOR-96325

Q14511

Q06124

0

dephosphorylation

down-regulates activity

0.488

In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity.

SIGNOR-277083

Q92914

Q9UQD0

2

binding

down-regulates activity

0.253

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-253414

P27986

Q6ZUJ8

2

binding

up-regulates

0.626

Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling

SIGNOR-191673

P60484

P23528

1

dephosphorylation

up-regulates activity

0.441

Unexpectedly, cofilin-1 activation by PGE 2 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated.|Unexpectedly, cofilin-1 dephosphorylation and activation in our model was mediated by the protein phosphatase activity of PTEN.

SIGNOR-276980

P17612

P07196

1

phosphorylation

down-regulates activity

0.2

Phosphorylation of neurofilament-L protein (NF-L) by the catalytic subunit of cAMP-dependent protein kinase (A-kinase) inhibits the reassembly of NF-L and disassembles filamentous NF-L.

SIGNOR-252401

Q14247

P00519

0

phosphorylation

up-regulates activity

0.424

Because phosphorylation by c-Abl augments nmMLCK-cortactin interaction to a greater degree than does pp60src phosphorylation, it is likely that phosphorylation sites on nmMLCK unique to c-Abl (i.e., other than Y464 and Y846) are responsible for this enhanced protein-protein interaction.|Moreover, our data indicate that cortactin is itself rapidly phosphorylated on Y486 by c-Abl in EC after S1P (Figure 9).

SIGNOR-278504

O15111

Q15717

1

phosphorylation

down-regulates quantity by destabilization

0.323

Furthermore, mutational analysis indicates that IKKα-dependent phosphorylation at Ser-304 is crucial to the binding of HuR to β-TrCP1. Mechanistically, this HuR degradation pathway differs from that reported for heat shock and hypoxia, which underlies the complexity in the regulation of HuR turnover under different stress stimuli.

SIGNOR-276422

P18545

P16499

2

binding

down-regulates activity

0.866

Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B

SIGNOR-260010

P15336

P28482

0

phosphorylation

up-regulates

0.733

Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.

SIGNOR-90517

P23470

P43403

1

dephosphorylation

up-regulates activity

0.26

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254733

P62136

Q8WVI7

2

binding

down-regulates activity

0.389

IPP5, a novel inhibitor of protein phosphatase 1, suppresses tumor growth and progression of cervical carcinoma cells by inducing G2/M arrest

SIGNOR-275726

P41252

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-269406

P08047

P01137

1

transcriptional regulation

up-regulates quantity by expression

0.296

MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-β mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-β production

SIGNOR-251740

P28324

Q16549

0

phosphorylation

up-regulates

0.2

In contrast, the tcf sap-1a is efficiently phosphorylated by p38 map kinase in vitro and in vivo on the homologous residues ser381 and ser387

SIGNOR-47771

O95837

Q9BPV8

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-257027

P32314

P51812

0

phosphorylation

down-regulates quantity by destabilization

0.2

Importantly, we identified RSK2 kinase as the upstream kinase for the FOXN2 phosphodegron. The Ser365 and Ser369 sites in a conserved DSGYAS motif are responsible for the ubiquitination of FOXN2 by β-Trcp.

SIGNOR-273841

Q05655

P21730

1

phosphorylation

down-regulates

0.2

Whole cell phosphorylation assays with specific inhibitors as well as in vitro phosphorylation assays with recombinant enzymes and peptide substrates revealed that phosphorylation of ser-334 is regulated by protein kinase c-beta this study is among the first to analyze in a detailed manner, using a non-mutational approach, modifications of a defined phosphorylation site in a g protein-coupled receptor and to correlate these findings with functional parameters of receptor deactivation.

SIGNOR-73967

Q8TAP9

P06493

0

phosphorylation

up-regulates

0.341

Ttdn1 is phosphorylated by cdk1 in vitro and in vivo. Ttdn1 is phosphorylated at multiple residues, including ser93 and ser104. Mutation of thr120 of ttdn1 abolishes its interaction with plk1, suggesting phosphorylation of thr120 in the consensus plk1-binding motif is required for its interaction with plk1

SIGNOR-153308

P0C0S8

Q9BX84

0

phosphorylation

down-regulates activity

0.2

We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1.

SIGNOR-276008

Q9Y5X3

Q14185

2

binding

up-regulates activity

0.346

SNX5 Is a Novel Binding Partner of the DHR1 Domain of DOCK180. In summary, we found that DOCK180 regulates transport of CI-MPR via SNX5 binding.

SIGNOR-269441

O75582

P28482

0

phosphorylation

up-regulates

0.617

Together, our in vivo and in vitro studies indicate that the pkc/c-raf/mek/erk pathway plays a major role in the s6k1 activation in hypertrophic cardiac growth.

SIGNOR-131311

P22455

P40763

1

phosphorylation

up-regulates activity

0.402

Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.

SIGNOR-251142

P51608

P41145

1

post transcriptional regulation

up-regulates quantity by expression

0.272

MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.

SIGNOR-264677

P35222

P37231

2

binding

down-regulates activity

0.538

Oncogenic beta-catenin resists proteasomal degradation by inhibiting PPARgamma activity, which requires its TCF/LEF binding domain

SIGNOR-256072

P03372

Q14164

0

phosphorylation

up-regulates

0.341

Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna.

SIGNOR-161834

O15530

P07949

0

phosphorylation

up-regulates activity

0.2

Ret/ptc (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (pdk1) ret/ptc phosphorylates a specific tyrosine (y9) residue located in the n-terminal region of pdk1.

SIGNOR-235863

Q13501

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

Once activated, parkin interacts with and subsequently ubiquitinates p62 at the K13 residue, resulting in the degradation of p62 via the proteasomal dependent pathway.

SIGNOR-278524

P35813

Q16539

1

dephosphorylation

down-regulates activity

0.408

Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay

SIGNOR-59618

Q8WZ19

Q13618

2

binding

up-regulates activity

0.536

BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.

SIGNOR-264233

P07225

P30530

2

binding

up-regulates

0.464

We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function.

SIGNOR-34483

P38405

Q96G91

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-256931

Q08209

Q92934

1

dephosphorylation

up-regulates activity

0.471

Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.

SIGNOR-248694

P19784

Q99250

1

phosphorylation

up-regulates activity

0.2

We found that the ankyrin-binding motif of Na(v)1.2 that determines channel concentration at the AIS depends on a glutamate residue (E1111), but also on several serine residues (S1112, S1124, and S1126). We showed that phosphorylation of these residues by protein kinase CK2 (CK2) regulates Na(v) channel interaction with ankyrins. | inhibition of CK2 activity reduced sodium channel accumulation at the AIS of neurons. In conclusion, CK2 contributes to sodium channel organization by regulating their interaction with ankyrin G.

SIGNOR-275758

P61586

P63167

0

gtpase-activating protein

down-regulates activity

0.273

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-260501

Q92985

P03230

0

sumoylation

down-regulates activity

0.2

One mechanism by which LMP1 regulates cellular activation is through the induction of protein posttranslational modifications. We have now identified a specific target of LMP1-induced sumoylation, interferon regulatory factor 7 (IRF7). We hypothesize that during EBV latency, LMP1 induces the sumoylation of IRF7, limiting its transcriptional activity and modulating the activation of innate immune responses.

SIGNOR-266951

Q14511

O14965

2

binding

up-regulates activity

0.57

HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.

SIGNOR-262653

Q13555

Q14524

1

phosphorylation

up-regulates activity

0.291

Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate–activated protein kinase (AMPK)–dependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5

SIGNOR-275779

P62993

P15498

2

binding

up-regulates

0.686

Recently, we have shown that the proto-oncogene vav product (vav) is also tyrosine-phosphorylated by treatment with gm-csf and epo and is constitutively associated with the sh3 domain of grb2/ash in ut-7.

SIGNOR-49362

Q9Y4A5

P35222

2

binding

up-regulates

0.58

The beta-cat c-terminal activation domain associates with trrap/tip60 and mixed-lineage-leukemia (mll1/mll2) set1-type chromatin-modifying complexes in vitro, and we show that beta-cat promotes h3k4 trimethylation at the c-myc gene in vivo.

SIGNOR-144966

P52565

P17252

0

phosphorylation

down-regulates activity

0.449

PKCalpha phosphorylates RhoGDIalpha at Ser34 to reduce its affinity for RhoA (but not for Rac1 or Cdc42) .

SIGNOR-279097

Q9UQM7

P09917

1

phosphorylation

up-regulates activity

0.2

Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export|We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques|Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca2+/calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO.

SIGNOR-264408

P10721

P22681

2

phosphorylation

up-regulates activity

0.618

The activated KIT in turn induces phosphorylation and activation of Cbl proteins.

SIGNOR-279199

P63092

P25100

2

binding

up-regulates activity

0.291

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-256808

P11233

O14965

0

phosphorylation

up-regulates activity

0.45

Specifically, the mitotic kinase Aurora A phosphorylates Ser 194 of RALA, relocalizing it to the mitochondria, where it concentrates RALBP1 and DRP1.|These data suggest that Aurora A promotes mitochondrial fission at mitosis through RalA and RalBP1.

SIGNOR-278351

O95071

P61077

0

ubiquitination

up-regulates activity

0.462

Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with gamma-H2AX nuclear foci in DNA breaks.

SIGNOR-272669

P46108

Q8TEW6

2

binding

up-regulates

0.46

Insulin receptor-phosphorylated irs5/dok4 associates with rasgap, crk, src, and fyn, but not phosphatidylinositol 3-kinase p85, grb2, shp-2, nck, or phospholipase cgamma src homology 2 domains, and activates mapk in cells.

SIGNOR-100996

P23258

Q96SN8

2

binding

up-regulates activity

0.652

Immunoprecipitation of CDK5RAP2 specifically coprecipitated _TuRC components, as detected on immunoblots of _-tubulin and GCP3 (Figure 3A).| Perturbing CDK5RAP2 function delocalized gamma-tubulin from the centrosomes and inhibited centrosomal microtubule nucleation, thus leading to disorganization of interphase microtubule arrays and formation of anastral mitotic spindles. Together, CDK5RAP2 is a pericentriolar structural component that functions in gammaTuRC attachment and therefore in the microtubule organizing function of the centrosome.

SIGNOR-260310

P35813

P24941

1

dephosphorylation

down-regulates activity

0.292

Moreover, purified recombinant PP2C alpha and PP2C beta 2 proteins efficiently dephosphorylated monomeric Cdk2/Cdk6 in vitro.

SIGNOR-277107

P78536

P15941

1

cleavage

down-regulates

0.308

These characteristics along with studies conducted with cell lines genetically deficient in various adams (for a disintegrin and metalloprotease) identified tumor necrosis factor-alpha converting enzyme (tace)/adam 17 as a muc1 sheddase.

SIGNOR-95630

Q01196

P15976

2

binding

up-regulates activity

0.643

We and others have previously shown that RUNX1 and GATA-1 physically interact and cooperate in the activation of megakaryocytic promoters such as alpha IIb integrin and glycoprotein Ibalpha. In particular, we will elaborate on recent data which suggest that GATA-1 targets RUNX1 for modification, in particular phosphorylation by cyclin-dependent kinases. Furthermore, targeting of RUNX1 by GATA-1 for phosphorylation may convert RUNX1 from a repressor to an activator. This is a potential mechanism of transcriptional cooperation and may be an essential step in megakaryocytic differentiation.

SIGNOR-254194

P01133

P00533

2

binding

up-regulates activity

0.949

Epidermal growth factor (egf) regulates cell proliferation and differentiation by binding to the egf receptor (egfr) extracellular region, comprising domains i-iv, with the resultant dimerization of the receptor tyrosine kinase.

SIGNOR-186159

O43663

P53350

0

phosphorylation

down-regulates activity

0.723

Plk1 negatively regulates PRC1 to prevent premature midzone formation before cytokinesis.|Plk1, but not Cdk1, phosphorylates PRC1 on Thr-602 to prevent premature midzone assembly in metaphase.

SIGNOR-279645

P63092

Q13255

2

binding

up-regulates activity

0.407

MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.

SIGNOR-264077

P41968

P38405

2

binding

up-regulates activity

0.289

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-256748

Q9UK99

Q9H2X6

2

binding

down-regulates quantity by destabilization

0.404

O clarify the role of PML in transcription regulation, we purified the PML complex and identified Fbxo3 (Fbx3), Skp1, and Cullin1 as novel components of this complex. Fbx3 formed SCF(Fbx3) ubiquitin ligase and promoted the degradation of HIPK2 and p300 by the ubiquitin-proteasome pathway.

SIGNOR-271741

P10828

P28482

0

phosphorylation

down-regulates activity

0.412

We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.

SIGNOR-102216

Q96F46

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.

SIGNOR-277205

P55040

P27348

2

binding

up-regulates quantity by stabilization

0.266

In order to address whether Gem binds specific isoforms of 14-3-3, we determined the coassociation of Gem and 14-3-3 in the neuroblastoma cell line SY5Y. 14-3-3ζ, -γ, -τ, and -β were observed to bind to Gem. 14-3-3-bound Gem has a twofold-longer half-life than nonbound Gem (Fig. (Fig.6).6). A similar increase in protein stability following 14-3-3 binding has been described for the Wee1 kinase

SIGNOR-261724

Q14693

P35790

0

phosphorylation

down-regulates activity

0.273

Because CKI is a constitutively active kinase and ubiquitously distributed in many cell types, high mTORC1 activity depending on nutritional status may be a physiological cue for Lipin1 degradation mediated by CKI and beta-TRCP.|Thus, we propose that mTORC1 may function as a priming kinase for CKI to promote the phosphorylation of the degron motif in Lipin1.

SIGNOR-280228

P12931

O14920

1

phosphorylation

up-regulates

0.362

These results indicate that c-src can associate with ikkbeta and phosphorylate its tyrosine residues after tnf-alfa or tpa stimulation.

SIGNOR-99318

O43353

Q8WWF5

0

ubiquitination

down-regulates quantity by destabilization

0.2

Collectively, ZNRF4 degrades RIP2 protein by targeting the RIP2CARD domain in an E3-ubiquitin ligase activity dependent manner.|Here we show that ZNRF4 induces K48-linked ubiquitination of RIP2 and promotes RIP2 degradation.

SIGNOR-278684

Q9H3R0

P42574

0

cleavage

down-regulates activity

0.2

JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels.

SIGNOR-263870

P51449

Q16552

1

transcriptional regulation

up-regulates

0.54

We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells

SIGNOR-255029

Q15366

P28482

0

phosphorylation

up-regulates quantity by stabilization

0.318

We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B).

SIGNOR-262912

P12931

P01116

1

phosphorylation

up-regulates activity

0.658

Src phosphorylation promotes the intrinsic exchange rate of KRAS Q61H.|Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells.

SIGNOR-278990

Q9NWZ3

Q01638

2

binding

up-regulates activity

0.604

As shown in Figure 3D, MyD88, IRAK, IRAK4, and TRAF6 are all recruited to ST2 upon IL-33 stimulation.

SIGNOR-277705

P34130

Q16620

2

binding

up-regulates

0.94

Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb.

SIGNOR-31644

Q8NFZ3

P78352

1

relocalization

up-regulates activity

0.2

Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.

SIGNOR-264190

Q08379

P06493

0

phosphorylation

down-regulates

0.674

Cdc2 kinase directly phosphorylates the cis-golgi matrix protein gm130 and is required for golgi fragmentation in mitosis. Mitotic fragmentation of the golgi apparatus can be largely explained by disruption of the interaction between gm130 and the vesicle-docking protein p115. Here we identify a single serine (ser-25) in gm130 as the key phosphorylated target and cdc2 as the responsible kinase

SIGNOR-60281

O43524

Q13547

0

deacetylation

up-regulates activity

0.368

The ability of HDAC1 to cause muscle atrophy required its deacetylase activity and was linked to the induction of several atrophy genes by HDAC1, including atrogin-1, which required deacetylation of FoxO3a

SIGNOR-256486

Q14934

P45983

0

phosphorylation

up-regulates activity

0.467

Here, we showed that the nuclear factor of activated T3 (NFAT3) is phosphorylated by JNK1 or JNK2 at Ser(213) and Ser(217), which are located in the conserved SP motif.|Moreover, a 3xNFAT-luc reporter gene assay indicated that NFAT3 transcriptional activity was increased in a dose dependent manner by JNK1 or JNK2.

SIGNOR-280033

P02749

P00747

0

cleavage

down-regulates activity

0.458

Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI.

SIGNOR-266996

P12931

P20936

1

phosphorylation

down-regulates

0.615

The phosphorylation of p120-gap by p60c-src inhibited its ability to stimulate the ha-ras-gtpase activity

SIGNOR-86008

Q14164

P03372

1

phosphorylation

up-regulates

0.341

Here, we show that ikkepsilon interacts with and phosphorylates estrogen receptor alpha (eralpha) on serine 167 in vitro and in vivo. As a result, ikkepsilon induces eralpha transactivation activity and enhances eralpha binding to dna.

SIGNOR-161834

O00712

Q9HD90

1

transcriptional regulation

up-regulates quantity

0.2

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268898

P10767

P22455

2

binding

up-regulates

0.732

Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.

SIGNOR-18570

P25445

2

binding

up-regulates activity

0.2

The fas receptor, upon binding to the fasl, trimerizes

SIGNOR-85991

P46531

Q9UBP5

2

binding

down-regulates

0.767

Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression.

SIGNOR-146690

P62987

O60260

2

binding

up-regulates activity

0.2

The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator.

SIGNOR-270344

P01023

P14091

0

cleavage

down-regulates quantity by destabilization

0.38

Disruption of structural and functional integrity of alpha 2-macroglobulin by cathepsin E|Analysis of the N-terminal amino-acid sequences of these proteins revealed that alpha 2M was selectively cleaved at the Phe811-Leu812 bond in about 100mer downstream of the bait region.

SIGNOR-266977