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
O95622	P08754	2	binding	down-regulates activity	0.519	Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3	SIGNOR-278076
P49959	P23443	0	phosphorylation	down-regulates quantity by destabilization	0.2	MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro.	SIGNOR-265944
P53350	Q8TF76	2	phosphorylation	up-regulates activity	0.2	Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis.	SIGNOR-275421
Q13136	P10586	1	relocalization	up-regulates activity	0.8	We have identified a novel cytoplasmic 160 kDa phosphoserine protein termed LAR-interacting protein 1 (LIP.1), which binds to the LAR membrane-distal D2 protein tyrosine phosphatase domain and appears to localize LAR to focal adhesions.	SIGNOR-264141
Q13362-1	Q13315	0	phosphorylation	up-regulates activity	0.378	In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth.	SIGNOR-276318
Q15633	P23443	0	phosphorylation	up-regulates activity	0.322	We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.	SIGNOR-274068
P35452	Q9ULX9	2	binding	down-regulates activity	0.381	Hoxd12 and MHox, that interact with v-/c-Maf, using the phage display method. The Hox proteins also could associate with the other Maf protein family members, MafB, MafK, MafF, and MafG, but not with Jun and Fos. The Hox proteins negatively regulated the DNA binding, transactivation and cell-transforming abilities of Maf.	SIGNOR-221884
Q9NZQ7	Q9Y2A9	0	glycosylation	up-regulates activity	0.2	These results further suggested that B3GNT3 mediates PD-L1 and PD-1 interaction through N-linked glycosylation instead of O-linked glycosylation	SIGNOR-275389
P19086	Q8TDV5	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-257308
Q96A00	Q05513	0	phosphorylation	up-regulates activity	0.277	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.	SIGNOR-249261
O15111	P51608	1	phosphorylation	up-regulates activity	0.2	Representative confocal micrographs of 4th day differentiating cultures are shown. (C) IKK\u03b1 promotes MeCP2-dependent BDNF expression.\|The characterization of IKK\u03b1-mediated phosphorylation of MeCP2 at Ser421 and other residues and their effects on the activity of MeCP2 is a topic of current work in our laboratory.	SIGNOR-279459
Q14676	Q969R5	2	binding	up-regulates activity	0.2	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266786
O60716	P27361	0	phosphorylation	down-regulates activity	0.293	Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation.	SIGNOR-277506
Q09472	Q86Y01	2	binding	up-regulates	0.381	We found that a significant fraction of dtx1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300.	SIGNOR-110629
P20671	Q86Y13	0	monoubiquitination	up-regulates activity	0.2	2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271753
Q92945	P31749	0	phosphorylation	down-regulates activity	0.703	Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome.	SIGNOR-252497
Q14160	Q05086	0	polyubiquitination	down-regulates quantity by destabilization	0.552	Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase	SIGNOR-272573
Q9UQC2	Q06124	0	dephosphorylation	down-regulates	0.742	Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2.	SIGNOR-124958
Q9Y5J3	Q15208	0	phosphorylation	up-regulates activity	0.358	We have identified two related kinases, STK38 (serine/threonine kinase 38) and STK38L (serine/threonine kinase 38 like), which interact with and phosphorylate HEY1 at Ser-68.	SIGNOR-279489
Q8IW93	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.636	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-260543
P38435	Q14393	1	carboxylation	up-regulates activity	0.525	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-265923
Q13043	Q6ZVD8	0	dephosphorylation	up-regulates activity	0.2	PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis.	SIGNOR-248730
Q12778	P46527	1	transcriptional regulation	up-regulates quantity by expression	0.627	To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter.	SIGNOR-277739
Q9NRC1	P28370	0	transcriptional regulation	down-regulates quantity by repression	0.2	Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes.	SIGNOR-268991
Q07817	P55957	2	binding	down-regulates activity	0.859	Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer.	SIGNOR-209675
P30622	P53350	0	phosphorylation	up-regulates	0.703	Furthermore, we provide evidence that plk1 phosphorylation of clip-170 at s195 enhances its association with ck2	SIGNOR-167172
O60934	Q13315	2	binding	up-regulates	0.856	Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm	SIGNOR-134508
Q99717	O00238	0	phosphorylation	up-regulates activity	0.68	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255260
P23458	P52333	2	phosphorylation	up-regulates	0.536	Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.	SIGNOR-152914
Q8IYU2	P24385	1	ubiquitination	down-regulates quantity by destabilization	0.307	Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1.	SIGNOR-271405
Q9NRF2	P04629	2	binding	up-regulates	0.54	The adapter protein sh2-b has been shown to bind to activated nerve growth factor (ngf) receptor trka and has been implicated in ngf-induced neuronal differentiation and the survival of sympathetic neurons.	SIGNOR-124198
Q8WXX7	O15409	0	transcriptional regulation	up-regulates quantity by expression	0.325	By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.	SIGNOR-266832
P54727	Q96IV0	2	binding	up-regulates activity	0.82	The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome.	SIGNOR-261061
P16070	P17612	0	phosphorylation	up-regulates	0.2	Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains.	SIGNOR-147208
Q7Z570	Q15327	1	transcriptional regulation	up-regulates quantity by expression	0.2	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3).	SIGNOR-269461
Q96A00	Q15139	0	phosphorylation	up-regulates activity	0.2	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.	SIGNOR-249260
P49023	O14522	0	dephosphorylation	down-regulates activity	0.462	To this end, using a phospho-proteomics approach, we identified and validated paxillin and STAT3 as the substrates of PTPRT [15, 16]\|the PTPRT target site on paxillin is a previously uncharacterized tyrosine-88 residue (paxillin Y88)\|In this study, we also show how pY88 paxillin transduces a signal to activate Akt	SIGNOR-263978
P22681	P16333	1	ubiquitination	down-regulates quantity by destabilization	0.644	Taken together, these results show that lysine 178 in Nck1 is the acceptor site for ubiquitin transferred by c-Cbl, and that the ubiquitination of Nck1 by c-Cbl is blocked in the presence of synaptopodin.	SIGNOR-278606
Q13191	P62993	2	binding	up-regulates activity	0.567	Here we show that in unstimulated Jurkat cells Cbl is co-immunoprecipitated with monoclonal antibody against Grb2.	SIGNOR-236051
P08254	P07585	1	cleavage	down-regulates quantity by destabilization	0.673	Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.	SIGNOR-256353
Q13224	O15409	0	transcriptional regulation	up-regulates quantity by expression	0.318	By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.	SIGNOR-266834
Q9NX09	P49815	2	binding	up-regulates activity	0.639	Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex.	SIGNOR-277469
P29350	P14618	1	dephosphorylation	down-regulates activity	0.2	SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs.\|SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated hepatocellular carcinoma cells.\|SHP-1 dephosphorylates p-PKM2Y105 and further affects the nucleus-related cell proliferation.	SIGNOR-276997
P49841	P10415	1	phosphorylation	down-regulates quantity by destabilization	0.2	A previous study has demonstrated that GSK3B triggers the degradation of BCL2 by inducing phosphorylation of BCL2 at Ser70, which induced autophagy by interrupting the interaction between BECN1 and BCL2 [32].	SIGNOR-279784
P19474	Q9UJV9	1	ubiquitination	down-regulates quantity	0.638	Furthermore, overexpression of TRIM21 in mDCs led to lower expression of DDX41 in these mDCs and up to 70% less IFN-beta production by mDCs in response to intracellular DNA (XREF_FIG).\|Here we report that the E3 ligase TRIM21 negatively regulated the type I interferon response in myeloid dendritic cells (mDCs) and monocytes that had been induced by cytosolic double stranded DNA (dsDNA), mainly by promoting the ubiquitination and degradation of DDX41.	SIGNOR-278790
P61073	P11309	0	phosphorylation	up-regulates quantity	0.365	Pim-1 and Pim-3 enhance phosphorylation and cell surface expression of CXCR4.\|When the in vitro phosphorylated fragments were detected with the anti-phospho (Ser339)-CXCR4 antibody, it became evident that both Pim-1 and Pim-3, but not Pim-2 can phosphorylate CXCR4 on Ser339 (XREF_FIG).	SIGNOR-278450
P12931	P08069	1	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
O95786	Q14258	0	ubiquitination	up-regulates activity	0.803	Lys63 linked polyubiquitination of RIG-I at Lys 172 catalyzed by TRIM25 is an important step for RIG-I activation.	SIGNOR-278730
O60674	P26951	2	binding	up-regulates	0.615	Indeed, only upon fibronectin adhesion is janus kinase 2 (jak2) recruited to the beta1 integrin-il-3r complex and triggers il-3r beta common phosphorylation, leading to the formation of docking sites for activated stat5a.	SIGNOR-134859
Q16649	O15534	1	transcriptional regulation	down-regulates quantity by repression	0.346	E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. All PAR proteins activate, whereas E4BP4 suppresses the mPer1 promoter through the same sequence	SIGNOR-268056
Q9ULV1	O14640	2	binding	up-regulates activity	0.598	Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin.	SIGNOR-258955
Q8NBJ5	P02462	1	glycosylation	up-regulates activity	0.402	Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261155
Q9NQC7	Q9UQM7	0	phosphorylation	up-regulates activity	0.307	NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity.	SIGNOR-266442
Q8IYD8	A8MT69	2	binding	up-regulates	0.2	We also provide biochemical evidence that mhf1 and mhf2 assemble into a heterodimer that binds dna and enhances the dna branch migration activity of fancm. These findings reveal critical roles of the mhf1-mhf2 dimer in dna damage repair and genome maintenance through fancm.	SIGNOR-164729
P15036	P21815	1	transcriptional regulation	up-regulates quantity by expression	0.2	Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin	SIGNOR-259873
Q9C0E8	Q53G59	2	binding	up-regulates activity	0.2	Lunapark Is Ubiquitylated by the CRL3KLHL12 Ubiquitin Ligase Complex. Taken together, these results demonstrate that Lunapark is ubiquitylated by the CRL3KLHL12 ubiquitin ligase, and the CRL3KLHL12-dependent ubiquitylation of Lunapark does not lead to its proteasomal degradation. Inhibition of Lunapark Ubiquitylation Affects Lysosomal Recruitment of mTORC1	SIGNOR-272197
P00519	Q8N2M8	1	phosphorylation	up-regulates activity	0.2	In biochemical assays and in Xenopus growth cones we find that Abl kinase activity enhances the association or co-localization of CLASP2 and F-actin, consistent with previous reports of CLASP binding to actin [Tsvetkov et al., ].\|In vitro, Abl phosphorylates CLASP with a Km of 1.89 \u00b5M, indicating that CLASP is a bona fide substrate.	SIGNOR-280166
Q9P275	P04179	1	deubiquitination	up-regulates quantity by stabilization	0.319	Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36\|Finally, USP36 was shown to be a specific deubiquitinating enzyme that reduces the ubiquitination level of SOD2 and was involved in SOD2 protein stability by extending its half-life.	SIGNOR-272280
Q8WVD3	P06493	0	phosphorylation	up-regulates activity	0.2	Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner.Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner.	SIGNOR-277832
O43293	O14974	1	phosphorylation	down-regulates activity	0.547	We conclude from our results Par-4 operates through a "padlock" model in which binding of Par-4 to MYPT1 activates MP by blocking access to the inhibitory phosphorylation sites, and inhibitory phosphorylation of MYPT1 by ZIPK requires "unlocking" of Par-4 by phosphorylation and displacement of Par-4 from the MP complex.\|We have also demonstrated that Par-4 is required for agonist induced, ZIPK mediated inhibition of MYPT1 and thus is an important amplifier of inputs to MP.	SIGNOR-279030
Q00535	O95817	1	phosphorylation	down-regulates quantity by destabilization	0.2	CDK5-mediated phosphorylation on S297 promotes BAG3 degradation.	SIGNOR-277502
P53805	P27361	0	phosphorylation	up-regulates activity	0.38	Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively \|Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin.	SIGNOR-249478
Q9Y243	P55211	1	phosphorylation	down-regulates	0.518	Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity	SIGNOR-61565
Q9ULX6	Q08211	2	binding	up-regulates activity	0.544	We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA.	SIGNOR-260950
P25963	P12931	0	phosphorylation	down-regulates quantity by destabilization	0.688	C-src phosphorylates IkappaB On tyrosine 42\|NF-kappaB is sequestered in the cytosol by IkappaBalpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation.	SIGNOR-60879
P17252	Q16625	1	phosphorylation	up-regulates activity	0.363	Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X.	SIGNOR-249105
Q13950	P17844	2	binding	up-regulates	0.453	P68 (ddx5) interacts with runx2 and regulates osteoblast differentiation. / p68 is a novel co-activator for runx2	SIGNOR-236974
Q5SQI0	O43318	0	phosphorylation	up-regulates activity	0.2	Here we report TGF-beta-activated kinase 1 (TAK1) as a key activator of alphaTAT1. TAK1 directly interacts with and phosphorylates alphaTAT1 at Ser237 to critically enhance its catalytic activity	SIGNOR-272243
P49840	Q92908	1	phosphorylation	down-regulates quantity by destabilization	0.265	Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin	SIGNOR-253156
P61077	O95071	1	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
Q9UN36	O00141	0	phosphorylation	up-regulates	0.395	Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344	SIGNOR-129676
P06493	P23443	1	phosphorylation	up-regulates	0.384	Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1.	SIGNOR-111507
Q9UNW9	Q16566	0	phosphorylation	up-regulates quantity	0.255	CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. Conversely, Nova-2 with single or double mutations to alanine (2A and 1A2A) was predominantly nuclear, like the WT (Figures 5H and and5I).5I). In contrast, glutamate mutations at site 3 had no effect on Nova-2 localization (Figures 5H and and5I)5I) or on Nova-2 binding to RNA (Figure S5E). These results showed that active CaMKIV reduces Nova-2 nuclear localization by phosphorylating sites 1 and 2 (S25, T27).	SIGNOR-273521
Q9BQN1	Q8N752	2	binding	up-regulates quantity	0.2	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273760
Q9NR19	Q9GZQ8	1	transcriptional regulation	up-regulates quantity by expression	0.2	As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;	SIGNOR-276562
P01178-PRO_0000020495	Q9UIQ6	0	cleavage	down-regulates quantity by destabilization	0.2	It has been shown that the steady state of the mature OT form can be controlled by an oxytocinase (P-LAP) that is produced in periphery and centrally by the OT-magnocellular neurons. Noticeably, P-LAP is also expressed in parvocellular OT neurons and in other brain structures\| The OT intermediate forms are produced from E16.5 (see above) but the mature amidated OT form is detected only from birth. The released mature form is then degraded by an oxytocinase (PLAP)	SIGNOR-268552
P10275	P17844	2	binding	up-regulates	0.319	P68 is a nuclear protein and interacts with ar / p68 co-occupies the active psa promoter at are regions and enhances ar transcriptional activity	SIGNOR-181456
P42224	P12931	0	phosphorylation	up-regulates activity	0.559	The tyr701 phosphorylation of signal transducer and activator of transcription 1 (stat1) induced by interferon-gamma (ifn-gamma) and 12-o-tetradecanoylphorbol 13-acetate (tpa) was inhibited by the protein kinase c (pkc) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the src kinase inhibitor pp2. An association between c-src and stat1 was increased by ifn-gamma and tpa, indicating the direct phosphorylation of stat1 by pkc-dependent c-src activation.	SIGNOR-235696
Q9UKT5	P51114	2	binding	down-regulates quantity by destabilization	0.455	Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinomaThe Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCFFbxo4 complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCFFbxo4.	SIGNOR-272795
P04183	P24941	0	phosphorylation	down-regulates	0.296	Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.	SIGNOR-95578
P28482	P35398	1	phosphorylation	down-regulates	0.26	We identified the extracellular signal-regulated kinase 2 (erk-2) as roralpha4 phosphorylating kinase in vitro. The primary sequence of roralpha4 contains an erk-2 recognition motif (p-l-t(128)-p) within the hinge domain, and mutation of thr-128 to ala prevents roralpha4 phosphorylation by erk. The roralpha4-t128a mutant exhibits an increased dna-binding affinity, an increased transcriptional activity	SIGNOR-154914
P05114	P17252	0	phosphorylation	down-regulates	0.307	Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.	SIGNOR-76286
Q99873	P35637	1	methylation	down-regulates activity	0.485	PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis.	SIGNOR-262274
Q13627	O43597	1	phosphorylation	down-regulates	0.304	We identify dyrk1a as one of the protein kinases of sprouty2. We show that dyrk1a interacts with and regulates the phosphorylation status of sprouty2. Moreover, we identify thr75 on sprouty2 as a dyrk1a phosphorylation site in vitro and in vivo.	SIGNOR-179828
Q14526	P40763	2	binding	down-regulates quantity by repression	0.367	HIC1 interacts with the DNA binding domain of STAT3 and suppresses the binding of STAT3 to its target gene promoters. HIC1 C-terminal domain binds to STAT3. HIC1 mutant defective in STAT3 interaction reduced its repressive effect on STAT3 DNA binding activity, the reporter activity and gene expression of the VEGF and c-Myc genes, and cell growth in MDA-MB 231 cells.	SIGNOR-254246
P30307	P27448	0	phosphorylation	down-regulates activity	0.485	C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function.	SIGNOR-250176
Q96ST3	Q12986	2	binding	up-regulates activity	0.373	we investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression.	SIGNOR-226360
P16220	Q16566	0	phosphorylation	up-regulates activity	0.708	Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb. All these kinases target CREB on S133 to activate CREB.	SIGNOR-102722
Q9Y271	P63096	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-256740
P39905	P07949	2	binding	up-regulates	0.91	A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling	SIGNOR-49094
P31751	P24666	0	dephosphorylation	down-regulates activity	0.2	Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.\|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3	SIGNOR-248456
Q92914	Q14524	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-253418
Q9UKT4	P06493	0	phosphorylation	down-regulates quantity by destabilization	0.753	We find that both Emi1 phosphorylation by cyclin and Cdc2 and phosphorylation on a consensus site (DSGxxS) direct recruitment of betaTrCP and subsequent Emi1 ubiquitination and destruction.	SIGNOR-279143
P84022	P67775	0	dephosphorylation	down-regulates	0.2	Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a.	SIGNOR-167480
P78527	Q00839	1	phosphorylation	up-regulates	0.375	We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks	SIGNOR-185058
P49915	P04637	2	binding	up-regulates	0.378	In response to genotoxic stress or nucleotide deprivation, gmps becomes nuclear and facilitates p53 stabilization by promoting its transfer from mdm2 to a gmps-usp7 deubiquitylation complex.	SIGNOR-204409
Q8NEB9	Q92622	2	binding	down-regulates	0.2	The run or cysteine-rich domain of rubicon appears to be inhibitory to the binding of rubicon to beclin 1 and vps34	SIGNOR-184547
Q93008	P06493	0	phosphorylation	up-regulates activity	0.279	Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis.	SIGNOR-275608
P55085	P07478	0	cleavage	up-regulates activity	0.2	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263606
Q13887	Q9H0M0	0	ubiquitination	up-regulates activity	0.459	WWP1 and Smurf2 were adopted to induce ubiquitination of endogenous KLF5 protein in cells.\|WWP1 or Smurf2 degrades KLF5 by ubiquitination to repress fracture healing.	SIGNOR-278683

O95622

P08754

2

binding

down-regulates activity

0.519

Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3

SIGNOR-278076

P49959

P23443

0

phosphorylation

down-regulates quantity by destabilization

0.2

MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro.

SIGNOR-265944

P53350

Q8TF76

2

phosphorylation

up-regulates activity

0.2

Phosphorylation by Cyclin B-Cdk1 allows Haspin to bind Plk1-PBD. Phosphorylation of Haspin at T128 and Plk1 target sites is required for full H3T3ph generation and normal Aurora B localization in mitosis.

SIGNOR-275421

Q13136

P10586

1

relocalization

up-regulates activity

0.8

We have identified a novel cytoplasmic 160 kDa phosphoserine protein termed LAR-interacting protein 1 (LIP.1), which binds to the LAR membrane-distal D2 protein tyrosine phosphatase domain and appears to localize LAR to focal adhesions.

SIGNOR-264141

Q13362-1

Q13315

0

phosphorylation

up-regulates activity

0.378

In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth.

SIGNOR-276318

Q15633

P23443

0

phosphorylation

up-regulates activity

0.322

We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.

SIGNOR-274068

P35452

Q9ULX9

2

binding

down-regulates activity

0.381

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

SIGNOR-221884

Q9NZQ7

Q9Y2A9

0

glycosylation

up-regulates activity

0.2

These results further suggested that B3GNT3 mediates PD-L1 and PD-1 interaction through N-linked glycosylation instead of O-linked glycosylation

SIGNOR-275389

P19086

Q8TDV5

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-257308

Q96A00

Q05513

0

phosphorylation

up-regulates activity

0.277

A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.

SIGNOR-249261

O15111

P51608

1

phosphorylation

up-regulates activity

0.2

Representative confocal micrographs of 4th day differentiating cultures are shown. (C) IKK\u03b1 promotes MeCP2-dependent BDNF expression.|The characterization of IKK\u03b1-mediated phosphorylation of MeCP2 at Ser421 and other residues and their effects on the activity of MeCP2 is a topic of current work in our laboratory.

SIGNOR-279459

Q14676

Q969R5

2

binding

up-regulates activity

0.2

L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.

SIGNOR-266786

O60716

P27361

0

phosphorylation

down-regulates activity

0.293

Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation.

SIGNOR-277506

Q09472

Q86Y01

2

binding

up-regulates

0.381

We found that a significant fraction of dtx1 proteins were localized in the nucleus and physically interacted with the transcriptional coactivator p300.

SIGNOR-110629

P20671

Q86Y13

0

monoubiquitination

up-regulates activity

0.2

2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.

SIGNOR-271753

Q92945

P31749

0

phosphorylation

down-regulates activity

0.703

Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome.

SIGNOR-252497

Q14160

Q05086

0

polyubiquitination

down-regulates quantity by destabilization

0.552

Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase

SIGNOR-272573

Q9UQC2

Q06124

0

dephosphorylation

down-regulates

0.742

Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2.

SIGNOR-124958

Q9Y5J3

Q15208

0

phosphorylation

up-regulates activity

0.358

We have identified two related kinases, STK38 (serine/threonine kinase 38) and STK38L (serine/threonine kinase 38 like), which interact with and phosphorylate HEY1 at Ser-68.

SIGNOR-279489

Q8IW93

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.636

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-260543

P38435

Q14393

1

carboxylation

up-regulates activity

0.525

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-265923

Q13043

Q6ZVD8

0

dephosphorylation

up-regulates activity

0.2

PHLPPs dephosphorylate Mst1 on the T387 inhibitory site, which activate Mst1 and its downstream effectors p38 and JNK to induce apoptosis.

SIGNOR-248730

Q12778

P46527

1

transcriptional regulation

up-regulates quantity by expression

0.627

To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter.

SIGNOR-277739

Q9NRC1

P28370

0

transcriptional regulation

down-regulates quantity by repression

0.2

Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes.

SIGNOR-268991

Q07817

P55957

2

binding

down-regulates activity

0.859

Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer.

SIGNOR-209675

P30622

P53350

0

phosphorylation

up-regulates

0.703

Furthermore, we provide evidence that plk1 phosphorylation of clip-170 at s195 enhances its association with ck2

SIGNOR-167172

O60934

Q13315

2

binding

up-regulates

0.856

Nbs1 can also immobilize atm at the site of the dsb via direct binding of atm to a c-terminal atm interaction motif on nbs1 . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm

SIGNOR-134508

Q99717

O00238

0

phosphorylation

up-regulates activity

0.68

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

SIGNOR-255260

P23458

P52333

2

phosphorylation

up-regulates

0.536

Il-7r signalling is initiated when il-7 crosslinks the extracellular domains of il-7ralpha and gammac, bringing together jak1 and jak3, which mutually phosphorylate each other, increasing their kinase activity.

SIGNOR-152914

Q8IYU2

P24385

1

ubiquitination

down-regulates quantity by destabilization

0.307

Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1.

SIGNOR-271405

Q9NRF2

P04629

2

binding

up-regulates

0.54

The adapter protein sh2-b has been shown to bind to activated nerve growth factor (ngf) receptor trka and has been implicated in ngf-induced neuronal differentiation and the survival of sympathetic neurons.

SIGNOR-124198

Q8WXX7

O15409

0

transcriptional regulation

up-regulates quantity by expression

0.325

By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.

SIGNOR-266832

P54727

Q96IV0

2

binding

up-regulates activity

0.82

The XPCB domain of Rad23 binds Png1, which in turn facilitates the substrate recognition of Rad23. Through interactions with Ub chains and the proteasome mediated by the UBA and UBL domains in Rad23, Rad23 facilitates substrate transfer to the proteasome.

SIGNOR-261061

P16070

P17612

0

phosphorylation

up-regulates

0.2

Pka can phosphorylate ser316 directly cd44 s291a and s316a mutants may disrupt downstream signalling events by displacing endogenous cd44 from plasma membrane microdomains.

SIGNOR-147208

Q7Z570

Q15327

1

transcriptional regulation

up-regulates quantity by expression

0.2

ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3).

SIGNOR-269461

Q96A00

Q15139

0

phosphorylation

up-regulates activity

0.2

A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.

SIGNOR-249260

P49023

O14522

0

dephosphorylation

down-regulates activity

0.462

To this end, using a phospho-proteomics approach, we identified and validated paxillin and STAT3 as the substrates of PTPRT [15, 16]|the PTPRT target site on paxillin is a previously uncharacterized tyrosine-88 residue (paxillin Y88)|In this study, we also show how pY88 paxillin transduces a signal to activate Akt

SIGNOR-263978

P22681

P16333

1

ubiquitination

down-regulates quantity by destabilization

0.644

Taken together, these results show that lysine 178 in Nck1 is the acceptor site for ubiquitin transferred by c-Cbl, and that the ubiquitination of Nck1 by c-Cbl is blocked in the presence of synaptopodin.

SIGNOR-278606

Q13191

P62993

2

binding

up-regulates activity

0.567

Here we show that in unstimulated Jurkat cells Cbl is co-immunoprecipitated with monoclonal antibody against Grb2.

SIGNOR-236051

P08254

P07585

1

cleavage

down-regulates quantity by destabilization

0.673

Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.

SIGNOR-256353

Q13224

O15409

0

transcriptional regulation

up-regulates quantity by expression

0.318

By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.

SIGNOR-266834

Q9NX09

P49815

2

binding

up-regulates activity

0.639

Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex.

SIGNOR-277469

P29350

P14618

1

dephosphorylation

down-regulates activity

0.2

SHP-1 dephosphorylates PKM2 at Y105 to inhibit nuclear function of PKM2 and determines the efficacy of targeted drugs.|SHP-1 directly dephosphorylated PKM2 at Y105 and further decreased the proliferative activity of PKM2; similar effects were found in sorafenib-treated hepatocellular carcinoma cells.|SHP-1 dephosphorylates p-PKM2Y105 and further affects the nucleus-related cell proliferation.

SIGNOR-276997

P49841

P10415

1

phosphorylation

down-regulates quantity by destabilization

0.2

A previous study has demonstrated that GSK3B triggers the degradation of BCL2 by inducing phosphorylation of BCL2 at Ser70, which induced autophagy by interrupting the interaction between BECN1 and BCL2 [32].

SIGNOR-279784

P19474

Q9UJV9

1

ubiquitination

down-regulates quantity

0.638

Furthermore, overexpression of TRIM21 in mDCs led to lower expression of DDX41 in these mDCs and up to 70% less IFN-beta production by mDCs in response to intracellular DNA (XREF_FIG).|Here we report that the E3 ligase TRIM21 negatively regulated the type I interferon response in myeloid dendritic cells (mDCs) and monocytes that had been induced by cytosolic double stranded DNA (dsDNA), mainly by promoting the ubiquitination and degradation of DDX41.

SIGNOR-278790

P61073

P11309

0

phosphorylation

up-regulates quantity

0.365

Pim-1 and Pim-3 enhance phosphorylation and cell surface expression of CXCR4.|When the in vitro phosphorylated fragments were detected with the anti-phospho (Ser339)-CXCR4 antibody, it became evident that both Pim-1 and Pim-3, but not Pim-2 can phosphorylate CXCR4 on Ser339 (XREF_FIG).

SIGNOR-278450

P12931

P08069

1

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

O95786

Q14258

0

ubiquitination

up-regulates activity

0.803

Lys63 linked polyubiquitination of RIG-I at Lys 172 catalyzed by TRIM25 is an important step for RIG-I activation.

SIGNOR-278730

O60674

P26951

2

binding

up-regulates

0.615

Indeed, only upon fibronectin adhesion is janus kinase 2 (jak2) recruited to the beta1 integrin-il-3r complex and triggers il-3r beta common phosphorylation, leading to the formation of docking sites for activated stat5a.

SIGNOR-134859

Q16649

O15534

1

transcriptional regulation

down-regulates quantity by repression

0.346

E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. All PAR proteins activate, whereas E4BP4 suppresses the mPer1 promoter through the same sequence

SIGNOR-268056

Q9ULV1

O14640

2

binding

up-regulates activity

0.598

Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin.

SIGNOR-258955

Q8NBJ5

P02462

1

glycosylation

up-regulates activity

0.402

Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.

SIGNOR-261155

Q9NQC7

Q9UQM7

0

phosphorylation

up-regulates activity

0.307

NMDA treatment of cultured hippocampal neurons causes recruitment of CYLD, as well as CaMKII, to the postsynaptic density (PSD), as shown by immunoelectron microscopy, […] Purified CaMKII phosphorylates CYLD on at least three residues (S-362, S-418, and S-772 on the human CYLD protein Q9NQC7-1) and promotes its deubiquitinase activity.

SIGNOR-266442

Q8IYD8

A8MT69

2

binding

up-regulates

0.2

We also provide biochemical evidence that mhf1 and mhf2 assemble into a heterodimer that binds dna and enhances the dna branch migration activity of fancm. These findings reveal critical roles of the mhf1-mhf2 dimer in dna damage repair and genome maintenance through fancm.

SIGNOR-164729

P15036

P21815

1

transcriptional regulation

up-regulates quantity by expression

0.2

Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin

SIGNOR-259873

Q9C0E8

Q53G59

2

binding

up-regulates activity

0.2

Lunapark Is Ubiquitylated by the CRL3KLHL12 Ubiquitin Ligase Complex. Taken together, these results demonstrate that Lunapark is ubiquitylated by the CRL3KLHL12 ubiquitin ligase, and the CRL3KLHL12-dependent ubiquitylation of Lunapark does not lead to its proteasomal degradation. Inhibition of Lunapark Ubiquitylation Affects Lysosomal Recruitment of mTORC1

SIGNOR-272197

P00519

Q8N2M8

1

phosphorylation

up-regulates activity

0.2

In biochemical assays and in Xenopus growth cones we find that Abl kinase activity enhances the association or co-localization of CLASP2 and F-actin, consistent with previous reports of CLASP binding to actin [Tsvetkov et al., ].|In vitro, Abl phosphorylates CLASP with a Km of 1.89 \u00b5M, indicating that CLASP is a bona fide substrate.

SIGNOR-280166

Q9P275

P04179

1

deubiquitination

up-regulates quantity by stabilization

0.319

Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36|Finally, USP36 was shown to be a specific deubiquitinating enzyme that reduces the ubiquitination level of SOD2 and was involved in SOD2 protein stability by extending its half-life.

SIGNOR-272280

Q8WVD3

P06493

0

phosphorylation

up-regulates activity

0.2

Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner.Altogether, our results suggest RNF138 is phosphorylated at position T27 in a CDK1- and CDK2-dependent manner.

SIGNOR-277832

O43293

O14974

1

phosphorylation

down-regulates activity

0.547

We conclude from our results Par-4 operates through a "padlock" model in which binding of Par-4 to MYPT1 activates MP by blocking access to the inhibitory phosphorylation sites, and inhibitory phosphorylation of MYPT1 by ZIPK requires "unlocking" of Par-4 by phosphorylation and displacement of Par-4 from the MP complex.|We have also demonstrated that Par-4 is required for agonist induced, ZIPK mediated inhibition of MYPT1 and thus is an important amplifier of inputs to MP.

SIGNOR-279030

Q00535

O95817

1

phosphorylation

down-regulates quantity by destabilization

0.2

CDK5-mediated phosphorylation on S297 promotes BAG3 degradation.

SIGNOR-277502

P53805

P27361

0

phosphorylation

up-regulates activity

0.38

Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin.

SIGNOR-249478

Q9Y243

P55211

1

phosphorylation

down-regulates

0.518

Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity

SIGNOR-61565

Q9ULX6

Q08211

2

binding

up-regulates activity

0.544

We report evidence for a novel nuclear export signal in HAP95 and showed that the domains involved in RHA binding and nuclear localization are required for CTE activation. Finally, we showed that HAP95 synergizes significantly with RHA on CTE-mediated reporter gene expression and promotes nuclear export of unspliced mRNA in transfected cells. Taken together, these data support the proposal that HAP95 specifically facilitates CTE-mediated gene expression by directly binding to RHA.

SIGNOR-260950

P25963

P12931

0

phosphorylation

down-regulates quantity by destabilization

0.688

C-src phosphorylates IkappaB On tyrosine 42|NF-kappaB is sequestered in the cytosol by IkappaBalpha and, in most cells, released upon serine phosphorylation of this inhibitory protein which then undergoes rapid, ubiquitin-dependent degradation.

SIGNOR-60879

P17252

Q16625

1

phosphorylation

up-regulates activity

0.363

Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X.

SIGNOR-249105

Q13950

P17844

2

binding

up-regulates

0.453

P68 (ddx5) interacts with runx2 and regulates osteoblast differentiation. / p68 is a novel co-activator for runx2

SIGNOR-236974

Q5SQI0

O43318

0

phosphorylation

up-regulates activity

0.2

Here we report TGF-beta-activated kinase 1 (TAK1) as a key activator of alphaTAT1. TAK1 directly interacts with and phosphorylates alphaTAT1 at Ser237 to critically enhance its catalytic activity

SIGNOR-272243

P49840

Q92908

1

phosphorylation

down-regulates quantity by destabilization

0.265

Through bioinformatics and cell-based experiments, we identified the AKT-repressed signal as glycogen synthase kinase 3 (GSK3)-catalyzed phosphorylation of Ser(37) on the long form of the transcription factor GATA6. Phosphorylation of GATA6 on Ser(37) promoted its degradation, thereby preventing GATA6 from repressing transcripts that are induced by TNF and attenuated by insulin

SIGNOR-253156

P61077

O95071

1

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

Q9UN36

O00141

0

phosphorylation

up-regulates

0.395

Sgk1 phosphorylated ndrg2 at thr330, ser332 and thr348 in vitro. for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, for example, the phosphorylation of thr330 or ser332 by sgk1 may prime ndrg2 for phosphorylation by gsk3 at ser326 and ser328 respectively, the phosphorylation of thr348 by sgk1 may prime for phosphorylation at ser344

SIGNOR-129676

P06493

P23443

1

phosphorylation

up-regulates

0.384

Interestingly, phosphorylation at several ser/thr residues within the c-terminal autoinhibitory tail appears to either activate or inhibit s6k1, depending on the cell cycle phase. phosphorylation of those residues (featured by the thr-421/ser-424 site) during mitosis pursued by cdk1 inactivates s6k1 we then assessed the phosphorylation status of the mitosis-specific inhibitory residue of s6k1, thr-421/ser-424, which is targeted by mitotic cdk1.

SIGNOR-111507

Q9UNW9

Q16566

0

phosphorylation

up-regulates quantity

0.255

CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. Conversely, Nova-2 with single or double mutations to alanine (2A and 1A2A) was predominantly nuclear, like the WT (Figures 5H and and5I).5I). In contrast, glutamate mutations at site 3 had no effect on Nova-2 localization (Figures 5H and and5I)5I) or on Nova-2 binding to RNA (Figure S5E). These results showed that active CaMKIV reduces Nova-2 nuclear localization by phosphorylating sites 1 and 2 (S25, T27).

SIGNOR-273521

Q9BQN1

Q8N752

2

binding

up-regulates quantity

0.2

We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.

SIGNOR-273760

Q9NR19

Q9GZQ8

1

transcriptional regulation

up-regulates quantity by expression

0.2

As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;

SIGNOR-276562

P01178-PRO_0000020495

Q9UIQ6

0

cleavage

down-regulates quantity by destabilization

0.2

It has been shown that the steady state of the mature OT form can be controlled by an oxytocinase (P-LAP) that is produced in periphery and centrally by the OT-magnocellular neurons. Noticeably, P-LAP is also expressed in parvocellular OT neurons and in other brain structures| The OT intermediate forms are produced from E16.5 (see above) but the mature amidated OT form is detected only from birth. The released mature form is then degraded by an oxytocinase (PLAP)

SIGNOR-268552

P10275

P17844

2

binding

up-regulates

0.319

P68 is a nuclear protein and interacts with ar / p68 co-occupies the active psa promoter at are regions and enhances ar transcriptional activity

SIGNOR-181456

P42224

P12931

0

phosphorylation

up-regulates activity

0.559

The tyr701 phosphorylation of signal transducer and activator of transcription 1 (stat1) induced by interferon-gamma (ifn-gamma) and 12-o-tetradecanoylphorbol 13-acetate (tpa) was inhibited by the protein kinase c (pkc) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the src kinase inhibitor pp2. An association between c-src and stat1 was increased by ifn-gamma and tpa, indicating the direct phosphorylation of stat1 by pkc-dependent c-src activation.

SIGNOR-235696

Q9UKT5

P51114

2

binding

down-regulates quantity by destabilization

0.455

Fbxo4-mediated degradation of Fxr1 suppresses tumorigenesis in head and neck squamous cell carcinomaThe Fbxo4 tumour suppressor is a component of an Skp1-Cul1-F-box E3 ligase for which two substrates are known. Here we show purification of SCFFbxo4 complexes results in the identification of fragile X protein family (FMRP, Fxr1 and Fxr2) as binding partners. Biochemical and functional analyses reveal that Fxr1 is a direct substrate of SCFFbxo4.

SIGNOR-272795

P04183

P24941

0

phosphorylation

down-regulates

0.296

Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.

SIGNOR-95578

P28482

P35398

1

phosphorylation

down-regulates

0.26

We identified the extracellular signal-regulated kinase 2 (erk-2) as roralpha4 phosphorylating kinase in vitro. The primary sequence of roralpha4 contains an erk-2 recognition motif (p-l-t(128)-p) within the hinge domain, and mutation of thr-128 to ala prevents roralpha4 phosphorylation by erk. The roralpha4-t128a mutant exhibits an increased dna-binding affinity, an increased transcriptional activity

SIGNOR-154914

P05114

P17252

0

phosphorylation

down-regulates

0.307

Protein kinases that phosphorylate hmg-14 17 at the major sites have been implicated from previous in vitro studies. Protein kinase c and a similar calcium phospholipid-dependent kinase have been reported to phosphorylate both proteins in vitro, where the phosphorylation of hmg-17 occurs predominantly at ser24 and to a lesser degree at ser28. Phosphorylation of hmg-14 at ser6 by camp- or cgmp-dependent kinases has also been reported. Thus, other kinases may contribute to phosphorylation at ser6 in response to oa. Ser88 and ser98 on hmg-14 are also phosphorylated by casein kinase ii in vitro. we conclude that the correlation we observe reflects a causal relationship, in which phosphorylation somehow facilitates the redistribution of hmg-14 and -17 toward non-nuclear pools.

SIGNOR-76286

Q99873

P35637

1

methylation

down-regulates activity

0.485

PRMT1 catalyzes the arginine methylation of Fused in Sarcoma (FUS), an RNA-binding protein that interacts with RALY. We demonstrate that RALY down-regulation decreases protein arginine N-methyltransferase 1 levels, thus reducing FUS methylation. It is known that mutations in the FUS nuclear localization signal (NLS) retain the protein to the cytosol, promote aggregate formation, and are associated with amyotrophic lateral sclerosis.

SIGNOR-262274

Q13627

O43597

1

phosphorylation

down-regulates

0.304

We identify dyrk1a as one of the protein kinases of sprouty2. We show that dyrk1a interacts with and regulates the phosphorylation status of sprouty2. Moreover, we identify thr75 on sprouty2 as a dyrk1a phosphorylation site in vitro and in vivo.

SIGNOR-179828

Q14526

P40763

2

binding

down-regulates quantity by repression

0.367

HIC1 interacts with the DNA binding domain of STAT3 and suppresses the binding of STAT3 to its target gene promoters. HIC1 C-terminal domain binds to STAT3. HIC1 mutant defective in STAT3 interaction reduced its repressive effect on STAT3 DNA binding activity, the reporter activity and gene expression of the VEGF and c-Myc genes, and cell growth in MDA-MB 231 cells.

SIGNOR-254246

P30307

P27448

0

phosphorylation

down-regulates activity

0.485

C-TAK1 protein kinase phosphorylates human Cdc25C on serine 216 and promotes 14-3-3 protein binding. Phosphorylation of serine 21 6 promotes 1 4-3-3 binding to Cdc25C and is inhibitory to Cdc25C function.

SIGNOR-250176

Q96ST3

Q12986

2

binding

up-regulates activity

0.373

we investigated the mechanism of NFX1-91 repression of the hTERT promoter and demonstrated that NFX1-91 interacts with the corepressor mSin3A/HDAC to maintain the deacetylated status at the hTERT promoter, thus providing a mechanism by which NFX1-91 represses hTERT expression.

SIGNOR-226360

P16220

Q16566

0

phosphorylation

up-regulates activity

0.708

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

SIGNOR-102722

Q9Y271

P63096

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-256740

P39905

P07949

2

binding

up-regulates

0.91

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

SIGNOR-49094

P31751

P24666

0

dephosphorylation

down-regulates activity

0.2

Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3

SIGNOR-248456

Q92914

Q14524

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-253418

Q9UKT4

P06493

0

phosphorylation

down-regulates quantity by destabilization

0.753

We find that both Emi1 phosphorylation by cyclin and Cdc2 and phosphorylation on a consensus site (DSGxxS) direct recruitment of betaTrCP and subsequent Emi1 ubiquitination and destruction.

SIGNOR-279143

P84022

P67775

0

dephosphorylation

down-regulates

0.2

Accordingly, smad3-associated pp2a activity was found under hypoxic conditions. Hypoxia attenuated the nuclear accumulation of tgf-beta-induced smad3 but did not affect smad2. Moreover, the influence of tgf-beta on a set of smad3-activated genes was attenuated by hypoxia, and this was reversed by chemical pp2a inhibition. Our data demonstrate the existence of a smad3-specific phosphatase and identify a novel role for pp2a.

SIGNOR-167480

P78527

Q00839

1

phosphorylation

up-regulates

0.375

We identify heterogeneous nuclear ribonucleoprotein u (hnrnp-u), also termed scaffold attachment factor a (saf-a), as a specific substrate for dna-pk. We show that hnrnp-u is phosphorylated at ser59 by dna-pk in vitro and in cells in response to dna double-strand breaks

SIGNOR-185058

P49915

P04637

2

binding

up-regulates

0.378

In response to genotoxic stress or nucleotide deprivation, gmps becomes nuclear and facilitates p53 stabilization by promoting its transfer from mdm2 to a gmps-usp7 deubiquitylation complex.

SIGNOR-204409

Q8NEB9

Q92622

2

binding

down-regulates

0.2

The run or cysteine-rich domain of rubicon appears to be inhibitory to the binding of rubicon to beclin 1 and vps34

SIGNOR-184547

Q93008

P06493

0

phosphorylation

up-regulates activity

0.279

Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis.

SIGNOR-275608

P55085

P07478

0

cleavage

up-regulates activity

0.2

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3

SIGNOR-263606

Q13887

Q9H0M0

0

ubiquitination

up-regulates activity

0.459

WWP1 and Smurf2 were adopted to induce ubiquitination of endogenous KLF5 protein in cells.|WWP1 or Smurf2 degrades KLF5 by ubiquitination to repress fracture healing.

SIGNOR-278683