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
P27361	Q15349	1	phosphorylation	up-regulates	0.719	Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms	SIGNOR-44949
Q9Y243	P62714	0	dephosphorylation	down-regulates activity	0.494	Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248611
P01148	P10275	2	binding	down-regulates activity	0.459	GnRH antagonizes testosterone activation of the human androgen receptor in SCL60 cells. Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5	SIGNOR-259267
P24752	P08559	1	acetylation	down-regulates activity	0.393	We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)	SIGNOR-267633
P11229	O95837	2	binding	up-regulates activity	0.402	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-257130
P09874	P55210	0	cleavage	down-regulates	0.719	Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis.	SIGNOR-83703
P08913	P09471	2	binding	up-regulates activity	0.397	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-256977
Q16612	Q05513	0	phosphorylation	down-regulates quantity by destabilization	0.2	Site-directed mutagenesis of S59A retarded P311 degradation and induced glioma cell motility. In contrast, S59D mutation resulted in the rapid degradation of P311 and reduced glioma cell migration.Taken together, our results show that the serine phosphorylation of P311 is dependent on the function of both PKCε and PKCz.	SIGNOR-273831
P21728	P19086	2	binding	up-regulates activity	0.269	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-257269
Q16665	O15054	1	transcriptional regulation	up-regulates quantity by expression	0.266	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271571
P62714	P28482	1	dephosphorylation	down-regulates activity	0.479	Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines\|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts.	SIGNOR-248590
P25116	P08311	0	cleavage	down-regulates activity	0.583	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.\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263564
Q15797	O14640	2	binding	up-regulates	0.347	These results identify a potential mechanism whereby bmp-2 antagonizes wnt signaling in osteoblast progenitors by promoting an interaction between smad1 and dvl-1 that restricts beta-catenin activation.	SIGNOR-146131
Q14CS0	O14965	2	binding	down-regulates activity	0.304	The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.\|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts	SIGNOR-265042
O75581	O14905	2	binding	up-regulates	0.618	We find that wnt9b binds to a different part of the lrp6 extracellular domain	SIGNOR-163552
O14807	P49354	0	null	up-regulates activity	0.2	Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.	SIGNOR-242553
Q8NFZ4	P58400	2	binding	up-regulates activity	0.825	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.\|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264151
P09471	P25021	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-257250
P35222	P46531	2	binding	up-regulates	0.775	Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential.	SIGNOR-236858
Q96GD4	Q9UQL6	1	phosphorylation	down-regulates	0.258	We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions	SIGNOR-198650
Q9NRW4	P06239	1	dephosphorylation	down-regulates activity	0.273	Because JKAP dephosphorylates and inactivates Lck in T cells [ xref ], we studied whether JKAP downregulation results in Lck activation in SLE T cells.	SIGNOR-277148
O15534	P78368	0	phosphorylation	down-regulates	0.394	Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1.	SIGNOR-137751
P21860	P48736	2	binding	up-regulates	0.325	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146870
Q07912	P40763	1	phosphorylation	up-regulates activity	0.286	Since STAT1 and STAT3 are structurally related [3], we also assessed if ACK1 could induce the phosphorylation of STAT3 at residue Y705 (p-STAT3).\|Our work demonstrates that catalytically active ACK1 can promote the activation of STAT1 and STAT3.\|Here we demonstrate that catalytically active ACK1 induces the tyrosine phosphorylation of STAT1 and STAT3.	SIGNOR-279312
P84022	Q92830	2	binding	up-regulates	0.526	Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo.	SIGNOR-123318
P41231	P63092	2	binding	up-regulates activity	0.385	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256759
Q96RD7	P12931	0	phosphorylation	up-regulates activity	0.379	We recently identified amino acids 198-200 (YLK) on the PANX1 intracellular loop that are critical for α1-AR-mediated vasoconstriction and PANX1 channel function. We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198	SIGNOR-277817
P19544	Q5JTC6	2	binding	up-regulates	0.437	Wtx binds wt1, a zinc-finger transcription factor that is inactivated in wilms tumor. / the ability of wtx to enhance wt1-mediated transactivation suggests a physiologically significant interaction between these 2 tumor suppressors.	SIGNOR-185644
P06239	Q06830	1	phosphorylation	down-regulates activity	0.2	Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.	SIGNOR-276277
P06493	P00533	1	phosphorylation	down-regulates	0.426	Using a synthetic peptide corresponding to the sequence surrounding ser-1002, p34cdc2 was identified as a kinase capable of phosphorylating this serine residue. phosphorylation of the egf receptor by p34cdc2 was associated with a decrease in its tyrosine protein kinase activity.	SIGNOR-38313
O75460	Q5SGD2	0	dephosphorylation	up-regulates activity	0.309	Overall, our study establishes that PP2Ce mediated IRE1 regulation in ER stress signaling is a potentially important molecular basis for its genetic contribution to metabolic syndrome.Lin et al. [36] have reported that different durations and composition of ER stress signaling pathways can dictate cell fate and the balance between survival and death.\|Recombinant wildtype PP2Ce, but not a phosphatase-dead mutant (PP2Ce-D302A), effectively dephosphorylated the phosphor-Ser724 site of IRE1\u03b1 protein (p-IRE1\u03b1) (A).	SIGNOR-277074
P08908	O75398	0	transcriptional regulation	down-regulates quantity by repression	0.437	The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription	SIGNOR-269064
O14757	P43405	1	phosphorylation	down-regulates	0.311	We found that chk1 phosphorylated the tumor suppressor spleen tyrosine kinase (l) (syk[l]) and identified the phosphorylation site at ser295. Furthermore, chk1 phosphorylation of syk(l) promoted its subsequent proteasomal degradation.	SIGNOR-197528
O95831	P98170	0	ubiquitination	down-regulates quantity by destabilization	0.434	Notably, cotransfection of XIAP along with AIF resulted in the complete inhibition of DNA degradation (21.2% degraded nuclei), suggesting that XIAP directly abrogates the ability of AIF to induce chromatin degradation.\|XIAP binds and ubiquitinates AIF, and in this study, we determined the functional consequences of XIAP-mediated AIF ubiquitination.	SIGNOR-278537
P19793	P24468	2	binding	up-regulates	0.281	Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site	SIGNOR-79446
O00429	P06493	0	phosphorylation	up-regulates activity	0.466	Drp1 is phosphorylated at the Ser616 position and activated predominantly by CDK1.	SIGNOR-279394
Q13547	P20749	2	binding	up-regulates	0.427	We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, -3, and -6	SIGNOR-129801
P17612	O00168	1	phosphorylation	up-regulates activity	0.45	PKA-dependent, alpha 1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct alpha1 subunit phosphorylation. we propose that phosphorylation of the small accessory protein phospholemman (PLM) by PKA at serine 68 is responsible for the observed isoform-specific activation of NKA.	SIGNOR-263117
P78314	P29350	0	dephosphorylation	down-regulates	0.57	Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling	SIGNOR-146508
P12755	Q9HAZ2	2	binding	up-regulates	0.326	Biochemical analysis demonstrated that mel1 interacts with ski and inhibits tgf-_ signaling by stabilizing the inactive smad3-ski complex on the promoter of tgf-_ target genes.	SIGNOR-182529
Q07820	P28482	0	phosphorylation	up-regulates	0.527	We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage.	SIGNOR-92593
P09681	P48546	2	binding	up-regulates activity	0.876	GLP-1 and GIP exert their physiological actions via stimulation of the two G protein-coupled receptors (GPCRs): the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR), respectively.	SIGNOR-278134
Q9H334	P07333	1	transcriptional regulation	down-regulates quantity by repression	0.296	Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation.	SIGNOR-269048
O95819	O43318	2	binding	up-regulates	0.582	The existence of an at least trimolecular complex consisting of nik, tak1, and ikk2, although the precise sequence of activation as well as the possible location of the kinases within the signalosome remains to be elucidated.	SIGNOR-77404
O14727	P08238	2	binding	down-regulates	0.388	The present studies demonstrate that heat shock protein 90 (hsp90) forms a cytosolic complex with apaf-1 and thereby inhibits the formation of the active complex.	SIGNOR-81043
Q14653	Q13526	2	binding	down-regulates quantity by destabilization	0.643	Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication.	SIGNOR-252256
P63000	Q6ZUM4	0	gtpase-activating protein	down-regulates activity	0.589	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-260482
O14950	Q13418	0	phosphorylation	up-regulates activity	0.314	Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19).Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activa	SIGNOR-106427
Q96GD0	Q00987	1	dephosphorylation	down-regulates activity	0.2	Considering the roles of NF2 in actin dynamics and Mdm2 regulation - , , , it is noteworthy to elucidate whether interaction of PLPP and CIN with NF2 modulates actin dynamics and Mdm2 degradation in neuronal excitability.\|Recently, we have reported that PLPP and CIN dephosphorylates Mdm2 at S166 site in activity dependent manners, which inhibits Mdm2 mediated PSD95 degradation by facilitating Mdm2 ubiquitination 38.	SIGNOR-277151
P78549	Q12899	0	ubiquitination	down-regulates quantity by destabilization	0.263	We also demonstrated that TRIM26 directly polyubiquitylates NTH1 in cells and that TRIM26 targets newly synthesized NTH1 protein for ubiquitylation dependent degradation.	SIGNOR-278733
Q9UKE5	Q9NQB0	1	phosphorylation	up-regulates	0.555	Here, we report that tnik is an activating kinase for tcf4 and essential for colorectal cancer growth. Tnik, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of tcf4.	SIGNOR-165946
Q9H2D6	P50148	2	binding	up-regulates activity	0.2	We show that the C-terminal Rho-specific DH-PH cassette of Trio is similarly activated by Galpha(q)	SIGNOR-256494
Q01664	Q13547	2	binding	up-regulates activity	0.282	We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.	SIGNOR-226590
P11137	Q9HCK8	0	transcriptional regulation	down-regulates quantity	0.2	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268916
P84243	O14757	0	phosphorylation	down-regulates activity	0.2	We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c.	SIGNOR-160557
P07101	P23246	0	transcriptional regulation	down-regulates quantity by repression	0.2	It has been reported that DJ-1 is a neuroprotective transcriptional co-activator that sequesters a transcriptional co-repressor polypyrimidine tract-binding protein-associated splicing factor (PSF) from the TH gene promoter.	SIGNOR-271697
P18433	Q86YJ5	0	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271540
Q06124	P00533	2	dephosphorylation	down-regulates activity	0.87	Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not	SIGNOR-236424
Q15109	P09429	2	binding	up-regulates activity	0.803	HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs)	SIGNOR-252059
O15111	Q04206	1	phosphorylation	up-regulates activity	0.847	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-129931
Q05655	Q13501	1	phosphorylation	up-regulates activity	0.367	Data presented here suggested that Vps34 stimulates tumor development mainly through PKC-\u03b4- activation of p62.\|In conclusion, elevation of Vps34 results in tumor progression via the PKC-\u03b4-phosphorylation of p62 at S349 and PKC-\u03b4 involved phosphorylation of Raf 1 at Y340/341.\|Vps34 induces PKC-\u03b4-dependent phosphorylation of p62.	SIGNOR-280086
P24941	Q12778	1	phosphorylation	down-regulates	0.652	Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1.	SIGNOR-150028
Q13705	P18075	2	binding	up-regulates	0.544	We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes.	SIGNOR-60240
P15514	Q9Y222	0	transcriptional regulation	up-regulates quantity by expression	0.2	Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.	SIGNOR-261582
Q8NI29	P13473	2	binding	down-regulates quantity by destabilization	0.2	Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment.We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy.	SIGNOR-272323
Q15672	P45983	0	phosphorylation	up-regulates	0.308	Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness.	SIGNOR-173417
Q15382	Q13393	2	binding	up-regulates	0.537	Rheb binds and activates pld1 in vitro in a gtp-dependent manner, strongly suggesting that pld1 is a bona fide effector for rheb.	SIGNOR-178892
P13473	Q8NI29	2	binding	down-regulates quantity by destabilization	0.2	Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment.We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy.	SIGNOR-272323
Q96RR4	Q96RR4	2	phosphorylation	up-regulates	0.2	It has been proposed that a major consequence of relief from autoinhibition is autophosphorylation of thr-482, a post-translational change that likely contributes to the increased autonomous activity of camkk2	SIGNOR-198107
Q15149	P06493	0	phosphorylation	down-regulates	0.388	Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane.	SIGNOR-41319
P41279	Q01970	1	phosphorylation	up-regulates activity	0.2	Additionally, we found that PAR1-induced Ca2+ signals are transduced through Tpl2, which activates phospholipase C\u03b23 by phosphorylation at Ser537.\|These findings raised the question whether Tpl2, which phosphorylates PLCbeta 3 at Ser537 (this report) regulates Ca 2+ signaling in thrombin stimulated cells through phosphorylation of PLCbeta 3 at this site.	SIGNOR-278519
P14635	Q14774	0	transcriptional regulation	up-regulates quantity by expression	0.2	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261619
P35568	P18031	0	dephosphorylation	down-regulates	0.779	Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein.	SIGNOR-74852
P11802	Q13761	1	phosphorylation	down-regulates	0.399	Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation.	SIGNOR-185120
O60318	P24941	0	phosphorylation	up-regulates activity	0.2	To study the inducible regulation of GANP DNA-primase during cell activation, we examined phosphorylation induced by various kinds of kinases.We observed that the cell cycle-associated kinase Cdks induced phosphorylation of GANP in vitro. Examination of immunoprecipitates of Cdk2 from B cells revealed phosphorylation of GANP-PD at a consensus sequence of Cdk phosphorylation at Ser502 (S/T-P-X-K/R) (Fig. (Fig.1C1C Left; ref. 22).	SIGNOR-262734
P55211	P00519	0	phosphorylation	up-regulates	0.513	C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9.	SIGNOR-133260
P55957	P19784	0	phosphorylation	up-regulates activity	0.286	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. \| These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250978
P06400	Q14209	2	binding	down-regulates	0.914	Cyclin-dependent kinase (cdk) phosphorylation of the retinoblastoma protein (rb) drives cell proliferation through rb complexes with e2f transcription factors and other regulatory proteins.	SIGNOR-197328
Q05D32	Q8N165	1	dephosphorylation	up-regulates quantity by stabilization	0.356	We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D).	SIGNOR-273773
P46937	Q15797	2	binding	up-regulates	0.575	Yap binds to the phosphorylated smad1 to activate gene transcription.	SIGNOR-201462
P15311	P41743	0	phosphorylation	up-regulates	0.342	Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation.	SIGNOR-160855
Q96J02	P21580	2	binding	up-regulates activity	0.28	Here we demonstrate that the regulatory molecule tax1bp1 recruited the e3 ligase itch to a20 via two 'ppxy' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling a20-mediated recruitment and inactivation of rip1. (abstract)	SIGNOR-160621
Q9BXM7	Q16891	2	binding	up-regulates activity	0.4	MIC60 Is Crucial for Parkin Recruitment and Transiently Interacts with PINK1	SIGNOR-266301
Q8N2C7	Q8IZF0	2	binding	up-regulates activity	0.809	The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80.	SIGNOR-265184
P35222	P18031	0	dephosphorylation	up-regulates activity	0.66	PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.\|The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin.\|Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function.	SIGNOR-277121
P09471	P32249	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-256994
P68400	P07910	1	phosphorylation	down-regulates activity	0.357	In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C.	SIGNOR-133540
Q9BV73	P51955	0	phosphorylation	down-regulates	0.774	C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro.	SIGNOR-204837
Q9H8V3	P06493	0	phosphorylation	down-regulates	0.577	We show that phosphorylation of ect2 at threonine-341 (t341) affects the autoregulatory mechanism of ect2. In g2/m phase, ect2 was phosphorylated at t341 most likely by cyclin b/cyclin-dependent kinase 1 (cdk1) ect2 is biologically active even when it is not phosphorylated at t341	SIGNOR-140549
Q8TCY5	P32245	2	binding	down-regulates activity	0.489	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252362
O15516	Q00535	0	phosphorylation	up-regulates	0.328	Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock.	SIGNOR-203227
Q13315	P67775	0	dephosphorylation	down-regulates activity	0.333	Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro.	SIGNOR-248644
Q8WWM7	P40238	2	binding	down-regulates	0.353	A2d binds to cytokine receptors mpl and epo-r. A2d is associated with these unoccupied receptorsin vivo,and stimulation with tpo or epo causes the rapid dissociation of a2d from the activated receptor.	SIGNOR-113891
Q9UQL6	Q14012	0	phosphorylation	down-regulates	0.419	Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.	SIGNOR-85022
Q12879	P78352	0	relocalization	up-regulates activity	0.811	The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses.	SIGNOR-264194
O75385	P17252	0	phosphorylation	down-regulates activity	0.2	ULK1 is phosphorylated by PKCalpha at S423 in vivo and in vitro.\|PKC\u03b1 phosphorylation of ULK1 does not change its kinase activity	SIGNOR-279558
P50591	O14763	2	binding	up-regulates	0.934	Tumour necrosis factor-related apoptosis inducing ligand (trail) receptor 2 (trail-r2) also known as tnfrsf10b (tumour necrosis factor receptor (tnfr) super family 10b) or killer/dr5, a member of the tnfr family, is a promising candidate tumour suppressor gene at 8p21-22.	SIGNOR-134524
Q12778	Q99576	0	relocalization	down-regulates activity	0.301	GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells.	SIGNOR-256146
Q9NW38	Q9NPD8	2	ubiquitination	down-regulates quantity	0.901	Monoubiquitination of UBE2T was enhanced by FANCL introduction, suggesting that FANCL feeds back to UBE2T and can downregulate its activity.Although the FA pathway has been extensively studied, the E2 enzyme cooperating with the FA core complex for monoubiquitination of FANCD2 has not been discovered.\|This monoubiquitination is stimulated by the presence of the FANCL protein and inactivates UBE2T.	SIGNOR-278809
Q96FW1	P03372	1	deubiquitination	down-regulates activity	0.546	OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.\|We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells.	SIGNOR-276529

P27361

Q15349

1

phosphorylation

up-regulates

0.719

Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms

SIGNOR-44949

Q9Y243

P62714

0

dephosphorylation

down-regulates activity

0.494

Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.

SIGNOR-248611

P01148

P10275

2

binding

down-regulates activity

0.459

GnRH antagonizes testosterone activation of the human androgen receptor in SCL60 cells. Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5

SIGNOR-259267

P24752

P08559

1

acetylation

down-regulates activity

0.393

We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)

SIGNOR-267633

P11229

O95837

2

binding

up-regulates activity

0.402

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-257130

P09874

P55210

0

cleavage

down-regulates

0.719

Caspase-7 cleaves parp;redundancy exists between the caspase-3 and -7 at the level of parp proteolysis.

SIGNOR-83703

P08913

P09471

2

binding

up-regulates activity

0.397

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-256977

Q16612

Q05513

0

phosphorylation

down-regulates quantity by destabilization

0.2

Site-directed mutagenesis of S59A retarded P311 degradation and induced glioma cell motility. In contrast, S59D mutation resulted in the rapid degradation of P311 and reduced glioma cell migration.Taken together, our results show that the serine phosphorylation of P311 is dependent on the function of both PKCε and PKCz.

SIGNOR-273831

P21728

P19086

2

binding

up-regulates activity

0.269

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-257269

Q16665

O15054

1

transcriptional regulation

up-regulates quantity by expression

0.266

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271571

P62714

P28482

1

dephosphorylation

down-regulates activity

0.479

Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines|Protein phosphatase-2A was the only vanadate-insensitive phosphatase acting on Thr 183 of p42mapk or on MAPKK to be detected in PC12 cell extracts.

SIGNOR-248590

P25116

P08311

0

cleavage

down-regulates activity

0.583

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.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.

SIGNOR-263564

Q15797

O14640

2

binding

up-regulates

0.347

These results identify a potential mechanism whereby bmp-2 antagonizes wnt signaling in osteoblast progenitors by promoting an interaction between smad1 and dvl-1 that restricts beta-catenin activation.

SIGNOR-146131

Q14CS0

O14965

2

binding

down-regulates activity

0.304

The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.|We found that UBXN-2 and CDC-48 coimmunoprecipitated with AIR-1 from embryonic extracts

SIGNOR-265042

O75581

O14905

2

binding

up-regulates

0.618

We find that wnt9b binds to a different part of the lrp6 extracellular domain

SIGNOR-163552

O14807

P49354

0

null

up-regulates activity

0.2

Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.

SIGNOR-242553

Q8NFZ4

P58400

2

binding

up-regulates activity

0.825

Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)

SIGNOR-264151

P09471

P25021

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-257250

P35222

P46531

2

binding

up-regulates

0.775

Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential.

SIGNOR-236858

Q96GD4

Q9UQL6

1

phosphorylation

down-regulates

0.258

We define the precise site of aurb-mediated phosphorylation as a conserved serine within the nuclear localization signals of hdac4, hdac5, and hdac9 at ser265, ser278, and ser242, respectivelyduring mitosis, aurb-mediated phosphorylation may localize class iia hdacs to a phosphorylation gradient at the spindle midzone, permitting temporal and spatial regulatory mechanisms altering hdac protein interactions

SIGNOR-198650

Q9NRW4

P06239

1

dephosphorylation

down-regulates activity

0.273

Because JKAP dephosphorylates and inactivates Lck in T cells [ xref ], we studied whether JKAP downregulation results in Lck activation in SLE T cells.

SIGNOR-277148

O15534

P78368

0

phosphorylation

down-regulates

0.394

Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1.

SIGNOR-137751

P21860

P48736

2

binding

up-regulates

0.325

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

SIGNOR-146870

Q07912

P40763

1

phosphorylation

up-regulates activity

0.286

Since STAT1 and STAT3 are structurally related [3], we also assessed if ACK1 could induce the phosphorylation of STAT3 at residue Y705 (p-STAT3).|Our work demonstrates that catalytically active ACK1 can promote the activation of STAT1 and STAT3.|Here we demonstrate that catalytically active ACK1 induces the tyrosine phosphorylation of STAT1 and STAT3.

SIGNOR-279312

P84022

Q92830

2

binding

up-regulates

0.526

Gcn5 functions like pcaf, in that it binds to tgf-beta-specific r-smads, and enhances transcriptional activity induced by tgf-beta. In addition, gcn5, but not pcaf, interacts with r-smads for bone morphogenetic protein (bmp) signalling pathways, and enhances bmp-induced transcriptional activity, suggesting that gcn5 and pcaf have distinct physiological functions in vivo.

SIGNOR-123318

P41231

P63092

2

binding

up-regulates activity

0.385

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

SIGNOR-256759

Q96RD7

P12931

0

phosphorylation

up-regulates activity

0.379

We recently identified amino acids 198-200 (YLK) on the PANX1 intracellular loop that are critical for α1-AR-mediated vasoconstriction and PANX1 channel function. We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198

SIGNOR-277817

P19544

Q5JTC6

2

binding

up-regulates

0.437

Wtx binds wt1, a zinc-finger transcription factor that is inactivated in wilms tumor. / the ability of wtx to enhance wt1-mediated transactivation suggests a physiologically significant interaction between these 2 tumor suppressors.

SIGNOR-185644

P06239

Q06830

1

phosphorylation

down-regulates activity

0.2

Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.

SIGNOR-276277

P06493

P00533

1

phosphorylation

down-regulates

0.426

Using a synthetic peptide corresponding to the sequence surrounding ser-1002, p34cdc2 was identified as a kinase capable of phosphorylating this serine residue. phosphorylation of the egf receptor by p34cdc2 was associated with a decrease in its tyrosine protein kinase activity.

SIGNOR-38313

O75460

Q5SGD2

0

dephosphorylation

up-regulates activity

0.309

Overall, our study establishes that PP2Ce mediated IRE1 regulation in ER stress signaling is a potentially important molecular basis for its genetic contribution to metabolic syndrome.Lin et al. [36] have reported that different durations and composition of ER stress signaling pathways can dictate cell fate and the balance between survival and death.|Recombinant wildtype PP2Ce, but not a phosphatase-dead mutant (PP2Ce-D302A), effectively dephosphorylated the phosphor-Ser724 site of IRE1\u03b1 protein (p-IRE1\u03b1) (A).

SIGNOR-277074

P08908

O75398

0

transcriptional regulation

down-regulates quantity by repression

0.437

The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription

SIGNOR-269064

O14757

P43405

1

phosphorylation

down-regulates

0.311

We found that chk1 phosphorylated the tumor suppressor spleen tyrosine kinase (l) (syk[l]) and identified the phosphorylation site at ser295. Furthermore, chk1 phosphorylation of syk(l) promoted its subsequent proteasomal degradation.

SIGNOR-197528

O95831

P98170

0

ubiquitination

down-regulates quantity by destabilization

0.434

Notably, cotransfection of XIAP along with AIF resulted in the complete inhibition of DNA degradation (21.2% degraded nuclei), suggesting that XIAP directly abrogates the ability of AIF to induce chromatin degradation.|XIAP binds and ubiquitinates AIF, and in this study, we determined the functional consequences of XIAP-mediated AIF ubiquitination.

SIGNOR-278537

P19793

P24468

2

binding

up-regulates

0.281

Arp-1/rxr, coup-tfi/rxr, and arp-1/coup-tfi heterodimers bound the fp330-3' site

SIGNOR-79446

O00429

P06493

0

phosphorylation

up-regulates activity

0.466

Drp1 is phosphorylated at the Ser616 position and activated predominantly by CDK1.

SIGNOR-279394

Q13547

P20749

2

binding

up-regulates

0.427

We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, -3, and -6

SIGNOR-129801

P17612

O00168

1

phosphorylation

up-regulates activity

0.45

PKA-dependent, alpha 1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct alpha1 subunit phosphorylation. we propose that phosphorylation of the small accessory protein phospholemman (PLM) by PKA at serine 68 is responsible for the observed isoform-specific activation of NKA.

SIGNOR-263117

P78314

P29350

0

dephosphorylation

down-regulates

0.57

Shp-1 dephosphorylates 3bp2 and potentially downregulates 3bp2-mediated t cell antigen receptor signaling

SIGNOR-146508

P12755

Q9HAZ2

2

binding

up-regulates

0.326

Biochemical analysis demonstrated that mel1 interacts with ski and inhibits tgf-_ signaling by stabilizing the inactive smad3-ski complex on the promoter of tgf-_ target genes.

SIGNOR-182529

Q07820

P28482

0

phosphorylation

up-regulates

0.527

We found that jnk phosphorylated ser-121 and thr-163 of mcl-1 in response to stimulation with h(2)o(2) and that transfection of unphosphorylatable mcl-1 resulted in an enhanced anti-apoptotic activity in response to stimulation with h(2)o(2). Jnk-dependent phosphorylation and thus inactivation of mcl-1 may be one of the mechanisms through which oxidative stress induces cellular damage.

SIGNOR-92593

P09681

P48546

2

binding

up-regulates activity

0.876

GLP-1 and GIP exert their physiological actions via stimulation of the two G protein-coupled receptors (GPCRs): the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR), respectively.

SIGNOR-278134

Q9H334

P07333

1

transcriptional regulation

down-regulates quantity by repression

0.296

Overexpression of MFH/Foxp1 markedly attenuated phorbol ester-induced expression of c-fms, which encodes the M-CSF receptor and is obligatory for macrophage differentiation.

SIGNOR-269048

O95819

O43318

2

binding

up-regulates

0.582

The existence of an at least trimolecular complex consisting of nik, tak1, and ikk2, although the precise sequence of activation as well as the possible location of the kinases within the signalosome remains to be elucidated.

SIGNOR-77404

O14727

P08238

2

binding

down-regulates

0.388

The present studies demonstrate that heat shock protein 90 (hsp90) forms a cytosolic complex with apaf-1 and thereby inhibits the formation of the active complex.

SIGNOR-81043

Q14653

Q13526

2

binding

down-regulates quantity by destabilization

0.643

Here we report that activation of IRF3 is negatively regulated by the peptidyl-prolyl isomerase Pin1. After stimulation by double-stranded RNA, induced phosphorylation of the Ser339–Pro340 motif of IRF3 led to its interaction with Pin1 and finally polyubiquitination and then proteasome-dependent degradation of IRF3. Suppression of Pin1 by RNA interference or genetic deletion resulted in enhanced IRF-3-dependent production of interferon-beta, with consequent reduction of virus replication.

SIGNOR-252256

P63000

Q6ZUM4

0

gtpase-activating protein

down-regulates activity

0.589

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-260482

O14950

Q13418

0

phosphorylation

up-regulates activity

0.314

Integrin-linked kinase cdna was cloned, sequenced, expressed in e. coli, and shown to phosphorylate myosin light chain in the absence of ca(2+) at ser(19) and thr(18). Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activation of myosin light chain kinase, and phosphorylation of the 20-kDa light chain of myosin at Ser(19).Smooth muscle contraction follows an increase in cytosolic Ca(2+) concentration, activa

SIGNOR-106427

Q96GD0

Q00987

1

dephosphorylation

down-regulates activity

0.2

Considering the roles of NF2 in actin dynamics and Mdm2 regulation - , , , it is noteworthy to elucidate whether interaction of PLPP and CIN with NF2 modulates actin dynamics and Mdm2 degradation in neuronal excitability.|Recently, we have reported that PLPP and CIN dephosphorylates Mdm2 at S166 site in activity dependent manners, which inhibits Mdm2 mediated PSD95 degradation by facilitating Mdm2 ubiquitination 38.

SIGNOR-277151

P78549

Q12899

0

ubiquitination

down-regulates quantity by destabilization

0.263

We also demonstrated that TRIM26 directly polyubiquitylates NTH1 in cells and that TRIM26 targets newly synthesized NTH1 protein for ubiquitylation dependent degradation.

SIGNOR-278733

Q9UKE5

Q9NQB0

1

phosphorylation

up-regulates

0.555

Here, we report that tnik is an activating kinase for tcf4 and essential for colorectal cancer growth. Tnik, but not its catalytically inactive mutant, phosphorylated the conserved serine 154 residue of tcf4.

SIGNOR-165946

Q9H2D6

P50148

2

binding

up-regulates activity

0.2

We show that the C-terminal Rho-specific DH-PH cassette of Trio is similarly activated by Galpha(q)

SIGNOR-256494

Q01664

Q13547

2

binding

up-regulates activity

0.282

We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.

SIGNOR-226590

P11137

Q9HCK8

0

transcriptional regulation

down-regulates quantity

0.2

Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells

SIGNOR-268916

P84243

O14757

0

phosphorylation

down-regulates activity

0.2

We identify chk1 as the kinase responsible for h3-t11 phosphorylation. H3-t11 phosphorylation occurs throughout the cell cycle and is chk1 dependent in vivo.Phosphorylation at thr-12 (h3t11ph) by pkn1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of lys-10 (h3k9me) by kdm4c/jmjd2c.

SIGNOR-160557

P07101

P23246

0

transcriptional regulation

down-regulates quantity by repression

0.2

It has been reported that DJ-1 is a neuroprotective transcriptional co-activator that sequesters a transcriptional co-repressor polypyrimidine tract-binding protein-associated splicing factor (PSF) from the TH gene promoter.

SIGNOR-271697

P18433

Q86YJ5

0

ubiquitination

down-regulates quantity by destabilization

0.2

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

SIGNOR-271540

Q06124

P00533

2

dephosphorylation

down-regulates activity

0.87

Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not

SIGNOR-236424

Q15109

P09429

2

binding

up-regulates activity

0.803

HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs)

SIGNOR-252059

O15111

Q04206

1

phosphorylation

up-regulates activity

0.847

Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.

SIGNOR-129931

Q05655

Q13501

1

phosphorylation

up-regulates activity

0.367

Data presented here suggested that Vps34 stimulates tumor development mainly through PKC-\u03b4- activation of p62.|In conclusion, elevation of Vps34 results in tumor progression via the PKC-\u03b4-phosphorylation of p62 at S349 and PKC-\u03b4 involved phosphorylation of Raf 1 at Y340/341.|Vps34 induces PKC-\u03b4-dependent phosphorylation of p62.

SIGNOR-280086

P24941

Q12778

1

phosphorylation

down-regulates

0.652

Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1.

SIGNOR-150028

Q13705

P18075

2

binding

up-regulates

0.544

We show that bmp7 and activin bind to the same type ii receptors, actrii and iib, but recruit distinct type i receptors into heteromeric receptor complexes.

SIGNOR-60240

P15514

Q9Y222

0

transcriptional regulation

up-regulates quantity by expression

0.2

Notably, amphiregulin (Areg), thrombospondin-1 (Tsp-1), JunB, Egr1, adrenomedullin (Adm), Bcl-3 and methyl-CpG binding domain protein 1 (Mbd1) were downregulated in the lungs from Dmp1-null mice while Gas1 and Ect2 genes were upregulated.

SIGNOR-261582

Q8NI29

P13473

2

binding

down-regulates quantity by destabilization

0.2

Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment.We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy.

SIGNOR-272323

Q15672

P45983

0

phosphorylation

up-regulates

0.308

Phosphorylation of serine 68 of twist1 by mapks stabilizes twist1 protein and promotes breast cancer cell invasiveness.

SIGNOR-173417

Q15382

Q13393

2

binding

up-regulates

0.537

Rheb binds and activates pld1 in vitro in a gtp-dependent manner, strongly suggesting that pld1 is a bona fide effector for rheb.

SIGNOR-178892

P13473

Q8NI29

2

binding

down-regulates quantity by destabilization

0.2

Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment.We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy.

SIGNOR-272323

Q96RR4

2

phosphorylation

up-regulates

0.2

It has been proposed that a major consequence of relief from autoinhibition is autophosphorylation of thr-482, a post-translational change that likely contributes to the increased autonomous activity of camkk2

SIGNOR-198107

Q15149

P06493

0

phosphorylation

down-regulates

0.388

Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site. threonine 4542 was identified as the major target for the kinase. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin b (cdk1/cycb) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of hela cells by adding activated cdk1/cycb kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane.

SIGNOR-41319

P41279

Q01970

1

phosphorylation

up-regulates activity

0.2

Additionally, we found that PAR1-induced Ca2+ signals are transduced through Tpl2, which activates phospholipase C\u03b23 by phosphorylation at Ser537.|These findings raised the question whether Tpl2, which phosphorylates PLCbeta 3 at Ser537 (this report) regulates Ca 2+ signaling in thrombin stimulated cells through phosphorylation of PLCbeta 3 at this site.

SIGNOR-278519

P14635

Q14774

0

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-261619

P35568

P18031

0

dephosphorylation

down-regulates

0.779

Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein.

SIGNOR-74852

P11802

Q13761

1

phosphorylation

down-regulates

0.399

Our findings demonstrate that the cell cycle proteins cyclin d1 and cdk4 induce runx2 and runx3 phosphorylation, ubiquitylation and proteasomal degradation.

SIGNOR-185120

O60318

P24941

0

phosphorylation

up-regulates activity

0.2

To study the inducible regulation of GANP DNA-primase during cell activation, we examined phosphorylation induced by various kinds of kinases.We observed that the cell cycle-associated kinase Cdks induced phosphorylation of GANP in vitro. Examination of immunoprecipitates of Cdk2 from B cells revealed phosphorylation of GANP-PD at a consensus sequence of Cdk phosphorylation at Ser502 (S/T-P-X-K/R) (Fig. (Fig.1C1C Left; ref. 22).

SIGNOR-262734

P55211

P00519

0

phosphorylation

up-regulates

0.513

C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9.

SIGNOR-133260

P55957

P19784

0

phosphorylation

up-regulates activity

0.286

Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.

SIGNOR-250978

P06400

Q14209

2

binding

down-regulates

0.914

Cyclin-dependent kinase (cdk) phosphorylation of the retinoblastoma protein (rb) drives cell proliferation through rb complexes with e2f transcription factors and other regulatory proteins.

SIGNOR-197328

Q05D32

Q8N165

1

dephosphorylation

up-regulates quantity by stabilization

0.356

We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D).

SIGNOR-273773

P46937

Q15797

2

binding

up-regulates

0.575

Yap binds to the phosphorylated smad1 to activate gene transcription.

SIGNOR-201462

P15311

P41743

0

phosphorylation

up-regulates

0.342

Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation.

SIGNOR-160855

Q96J02

P21580

2

binding

up-regulates activity

0.28

Here we demonstrate that the regulatory molecule tax1bp1 recruited the e3 ligase itch to a20 via two 'ppxy' motifs. Itch was essential for the termination of tumor necrosis factor receptor signaling by controlling a20-mediated recruitment and inactivation of rip1. (abstract)

SIGNOR-160621

Q9BXM7

Q16891

2

binding

up-regulates activity

0.4

MIC60 Is Crucial for Parkin Recruitment and Transiently Interacts with PINK1

SIGNOR-266301

Q8N2C7

Q8IZF0

2

binding

up-regulates activity

0.809

The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80.

SIGNOR-265184

P35222

P18031

0

dephosphorylation

up-regulates activity

0.66

PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site.|The nonreceptor tyrosine phosphatase PTP1B associates with the cytoplasmic domain of N-cadherin and may regulate cadherin function through dephosphorylation of beta-catenin.|Thus, interaction of PTP1B with N-cadherin is essential for its association with beta-catenin, stable expression at the cell surface, and consequently, cadherin function.

SIGNOR-277121

P09471

P32249

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-256994

P68400

P07910

1

phosphorylation

down-regulates activity

0.357

In contrast, hnRNP-C1 that was also modified at the CK1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that CK1alpha-mediated phosphorylation modulates the mRNA binding ability of hnRNP-C.

SIGNOR-133540

Q9BV73

P51955

0

phosphorylation

down-regulates

0.774

C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro.

SIGNOR-204837

Q9H8V3

P06493

0

phosphorylation

down-regulates

0.577

We show that phosphorylation of ect2 at threonine-341 (t341) affects the autoregulatory mechanism of ect2. In g2/m phase, ect2 was phosphorylated at t341 most likely by cyclin b/cyclin-dependent kinase 1 (cdk1) ect2 is biologically active even when it is not phosphorylated at t341

SIGNOR-140549

Q8TCY5

P32245

2

binding

down-regulates activity

0.489

We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.

SIGNOR-252362

O15516

Q00535

0

phosphorylation

up-regulates

0.328

Cdk5 phosphorylates clock at the thr-451 and thr-461 residues in association with transcriptional activation of clock.

SIGNOR-203227

Q13315

P67775

0

dephosphorylation

down-regulates activity

0.333

Ionizing radiation induces autophosphorylation of the ataxia-telangiectasia mutated (ATM) protein kinase on serine 1981; however, the precise mechanisms that regulate ATM activation are not fully understood. Here, we show that the protein phosphatase inhibitor okadaic acid (OA) induces autophosphorylation of ATM on serine 1981 in unirradiated cells at concentrations that inhibit protein phosphatase 2A-like activity in vitro.

SIGNOR-248644

Q8WWM7

P40238

2

binding

down-regulates

0.353

A2d binds to cytokine receptors mpl and epo-r. A2d is associated with these unoccupied receptorsin vivo,and stimulation with tpo or epo causes the rapid dissociation of a2d from the activated receptor.

SIGNOR-113891

Q9UQL6

Q14012

0

phosphorylation

down-regulates

0.419

Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.

SIGNOR-85022

Q12879

P78352

0

relocalization

up-regulates activity

0.811

The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses.

SIGNOR-264194

O75385

P17252

0

phosphorylation

down-regulates activity

0.2

ULK1 is phosphorylated by PKCalpha at S423 in vivo and in vitro.|PKC\u03b1 phosphorylation of ULK1 does not change its kinase activity

SIGNOR-279558

P50591

O14763

2

binding

up-regulates

0.934

Tumour necrosis factor-related apoptosis inducing ligand (trail) receptor 2 (trail-r2) also known as tnfrsf10b (tumour necrosis factor receptor (tnfr) super family 10b) or killer/dr5, a member of the tnfr family, is a promising candidate tumour suppressor gene at 8p21-22.

SIGNOR-134524

Q12778

Q99576

0

relocalization

down-regulates activity

0.301

GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells.

SIGNOR-256146

Q9NW38

Q9NPD8

2

ubiquitination

down-regulates quantity

0.901

Monoubiquitination of UBE2T was enhanced by FANCL introduction, suggesting that FANCL feeds back to UBE2T and can downregulate its activity.Although the FA pathway has been extensively studied, the E2 enzyme cooperating with the FA core complex for monoubiquitination of FANCD2 has not been discovered.|This monoubiquitination is stimulated by the presence of the FANCL protein and inactivates UBE2T.

SIGNOR-278809

Q96FW1

P03372

1

deubiquitination

down-regulates activity

0.546

OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.|We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells.

SIGNOR-276529