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
Q03113	P34995	2	binding	up-regulates activity	0.263	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-257278
O96017	P00441	1	phosphorylation	up-regulates activity	0.376	ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes.	SIGNOR-262794
P98082	O75581	2	binding	down-regulates	0.495	Wnt stimulation induces the casein kinase 2 (ck2)-dependent phosphorylation of lrp6 at s1579, promoting its binding to dab2 and internalization with clathrin.	SIGNOR-196925
P12931	O60331	1	phosphorylation	up-regulates	0.285	Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation.	SIGNOR-134459
Q9Y266	P53350	0	phosphorylation	up-regulates activity	0.73	Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites.	SIGNOR-103403
Q00535	Q14194	1	phosphorylation	up-regulates	0.622	These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness.	SIGNOR-159314
P15311	Q15475	0	transcriptional regulation	up-regulates quantity	0.342	We now show that the gene encoding Ezrin is a direct transcriptional target of Six1.	SIGNOR-259374
P11831	P35354	1	null	up-regulates	0.252	Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy.	SIGNOR-255965
Q9ULV8	O15357	2	binding	down-regulates	0.2	This association between ship2 and cbl could sequester cbl from the egfr, thereby regulating the kinetics of egfr-cbl association and subsequent internalization and degradation of the receptor.	SIGNOR-133388
P29317	P07947	1	phosphorylation	up-regulates activity	0.423	EphA2 interacts with YES1 and phosphorylates YES1 at Tyr426 site.	SIGNOR-277556
P58400	Q8NFZ3	2	binding	up-regulates activity	0.2	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-264148
P08754	Q9Y5N1	2	binding	up-regulates activity	0.437	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-256832
P36888	P62993	2	binding	up-regulates activity	0.604	FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc	SIGNOR-245060
P35222	P23471	0	dephosphorylation	up-regulates activity	0.378	PTPRZ1 constitutively promotes the tyrosine dephosphorylation of \u03b2-catenin, and thus \u03b2-catenin participation in TCF-mediated transcription.	SIGNOR-277044
P35790	Q9H6E5	1	phosphorylation	up-regulates activity	0.2	Our data indicate that the kinase activities of both the isoforms of CKI -- alpha and epsilon modulate Star-PAP polyadenylation activity and target mRNAs.\|Taken together, these data suggest that phosphorylation of Star-PAP by CKI modulates the Star-PAP polyadenylation activity downstream of stimulation by oxidant stress and phosphorylation primes Star-PAP, so that it can be stimulated by PI4,5 P 2.	SIGNOR-279162
P09471	P41145	2	binding	up-regulates activity	0.347	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-256989
Q86TM6	Q15011	2	binding	up-regulates activity	0.574	FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp	SIGNOR-261349
Q13315	Q8WVD3	1	phosphorylation	up-regulates activity	0.2	We further confirm that RNF138 is phosphorylated by ATM at Ser124.	SIGNOR-279505
P60484	Q8IZP0	1	dephosphorylation	down-regulates quantity by destabilization	0.241	After dephosphorylation by PTEN, Abi1 is degraded by calpains.\|We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway.	SIGNOR-276948
Q9BXM7	P60484	1	phosphorylation	down-regulates activity	0.47	PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import.	SIGNOR-277915
Q14721	O95292	1	relocalization	up-regulates quantity	0.2	Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.\|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.	SIGNOR-262121
Q13043	P45983	0	phosphorylation	up-regulates	0.268	C-jun n-terminal kinase enhances mst1-mediated pro-apoptotic signaling through phosphorylation at serine 82.	SIGNOR-162327
Q14493	P68431	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265413
Q00987	Q9NXV6	1	ubiquitination	down-regulates	0.37	Carf interacts with hdm2 and is ubiquitinated and negatively regulated by hdm2 by proteasome-dependent degradation.	SIGNOR-160974
O94925	Q02156	0	phosphorylation	up-regulates activity	0.2	PKCε is the kinase that phosphorylates GAC at Ser314.	SIGNOR-277387
P31270	O15550	0	transcriptional regulation	up-regulates quantity by expression	0.263	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260021
Q92956	O00463	2	binding	up-regulates activity	0.625	ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5\|synergistic activation of NF-κB by ATAR and TRAF5 293 cells	SIGNOR-262592
Q969S3	Q99683	0	phosphorylation	up-regulates	0.487	Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis.	SIGNOR-175113
P07954	P15336	2	binding	up-regulates activity	0.2	Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes.	SIGNOR-266314
P30622	Q14203	2	binding	up-regulates activity	0.782	MT-unbound CLIP-170 can adopt a folded conformation through an intramolecular interaction of its terminal domains. Binding to MTs correlates with the unfolding of CLIP-170, which allows the interaction of the COOH-terminal domain with its binding partners, such as dynactin, resulting in their recruitment to the MT tip. The NH2 terminus of p150Glued binds directly to the COOH terminus of CLIP-170 through its second metal-binding motif.	SIGNOR-252164
P54725	Q05086	0	polyubiquitination	down-regulates quantity by destabilization	0.486	Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP. E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B.	SIGNOR-272550
Q9UN71	Q9Y5I2	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265701
P26651	Q16539	0	phosphorylation	down-regulates activity	0.357	TTP appears to be a p38Î±/Î² MAPK target and pretreating skeletal muscle with a p38Î±/Î² MAPK inhibitor reduces TTP phosphorylation.	SIGNOR-253596
P06744	O15297	0	dephosphorylation	down-regulates activity	0.24	The WIP1 mediated inhibition of NLK activity markedly decreased the phosphorylation of lymphoid enhancer binding factor 1 (LEF1), enhancing its interaction with beta-catenin.\|Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development.	SIGNOR-277155
Q86UW7	P63027	2	binding	up-regulates activity	0.255	CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly.	SIGNOR-264341
P25963	Q9Y6K9	0	phosphorylation	down-regulates activity	0.848	IκB components are phosphorylated on two amino-terminal serine residues by the IκB kinase (IKK) complex, composed of two catalytic proteins, IKKα and IKKβ, and the regulatory subunit IKKγ (NEMO, IKBKG). This modification targets IκB for degradation by the proteasome, allowing the release and nuclear translocation of NF-κB.	SIGNOR-280462
Q06187	P40763	1	phosphorylation	down-regulates activity	0.382	Phosphorylation of STAT-3 by BTK may also alter the conformation of STAT-3 in such a way as to make it inaccessible as a substrate of activating kinases such as JAK3.\|The ability of BTK to negatively regulate STAT-3 activity suggests several possible models for a mechanism of BTK action.	SIGNOR-279011
P55055	P19793	2	binding	up-regulates	0.694	We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.	SIGNOR-123091
P46937	Q99594	2	binding	up-regulates	0.85	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201471
Q99835	P62879	2	binding	up-regulates	0.2	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-199177
O00141	P42345	0	phosphorylation	up-regulates	0.849	Mtor phosphorylated sgk1, but not sgk1-s422a, in vitro. Sgk1 phosphorylated p27 in vitro. These data implicate sgk1 as an mtorc1 (mtor-raptor) substrate. mtor may promote g1 progression in part through sgk1 activation	SIGNOR-179113
P53779	O60282	1	phosphorylation	down-regulates activity	0.32	Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. JNK3 phosphorylates kinesin-1 at Ser176	SIGNOR-262950
P98171	P63000	1	gtpase-activating protein	down-regulates activity	0.479	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-260460
P68400	Q9UER7	1	phosphorylation	up-regulates	0.327	Daxx-sim is phosphorylated by ck2 kinase at residues s737 and s739. Phosphorylation promotes daxx-sim binding affinity toward sumo-1 over sumo-2/3, causing daxx preference for sumo-1 conjugation and interaction with sumo-1-modified factors.	SIGNOR-173105
O95990	Q9Y243	2	binding	up-regulates	0.2	Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation	SIGNOR-81800
Q13131	Q14524	1	phosphorylation	down-regulates quantity by destabilization	0.2	AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule-associated protein 1 light chain 3 (LC3), by exposing the LC3-interacting region adjacent to T101 in Nav1.5.	SIGNOR-277432
Q8IXL6	P04275	1	phosphorylation	up-regulates activity	0.2	In vitro phosphorylation of von Willebrand factor by FAM20c enhances its ability to support platelet adhesion.	SIGNOR-279331
P19793	Q14994	2	binding	up-regulates	0.468	Therefore, both car-rxr heterodimers and car monomers can contribute to the gene activating function of pbrems in car target genes.	SIGNOR-104441
P52333	P23458	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-152917
O75553	Q8WXH5	2	binding	down-regulates quantity by destabilization	0.2	SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1.	SIGNOR-272139
P41236	P49841	0	phosphorylation	up-regulates activity	0.412	Protein phosphatase 1 (PP1) is complexed with inhibitor 2 (I-2) in the cytosol. In rabbit muscle extract PP1.I-2 is activated upon preincubation with ATP/Mg. This activation is caused by phosphorylation of I-2 on Thr(72) by glycogen synthase kinase 3 (GSK3).	SIGNOR-251257
Q99683	P53041	0	dephosphorylation	down-regulates activity	0.597	After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845.	SIGNOR-248540
Q92974	P27448	0	phosphorylation	up-regulates activity	0.382	Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules.	SIGNOR-277368
O15169	Q9Y6R4	2	binding	up-regulates	0.42	Mekk4, also binds to axin in vivo and mediates axin-induced jnk activation.	SIGNOR-104003
Q12933	Q13489	2	binding	up-regulates	0.892	A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution.	SIGNOR-182124
Q5H8A3	Q9GZQ4	2	binding	up-regulates	0.631	Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus.	SIGNOR-133131
P38936	P01106	0	transcriptional regulation	down-regulates quantity by repression	0.779	C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a	SIGNOR-102740
Q13145	O14641	2	binding	up-regulates	0.516	Bmp-2 mediates phosphorylated smad1 (psmad1) or, with loss of bmprii, psmad3-dependent recruitment of disheveled (dvl) to promote rhoa-rac1 signaling necessary for motility.	SIGNOR-23037
P24723	P28482	1	phosphorylation	up-regulates activity	0.506	Protein kinase C-eta regulates Mcl-1 level via ERK1. knockdown of PKCη but not PKCα, -δ or -ε caused a significant decrease in ERK (extracellular signal-regulated kinase) phosphorylation. Knockdown of ERK1 but not ERK2 decreased Mcl-1 level, and the decrease in Mcl-1 caused by PKCη knockdown was restored by ERK1 overexpression. These results suggest that PKCη utilizes the ERK signaling pathway to protect against ubiquitin-mediated proteasomal degradation of Mcl-1.	SIGNOR-261910
Q4ZG55	Q14686	0	transcriptional regulation	up-regulates quantity by expression	0.2	Herein, using growth-regulating estrogen receptor binding 1 (GREB1) as an ERα target gene in Ishikawa cells, we demonstrate that nuclear receptor co-activator 6 (NCOA6) is essential for estradiol (E2)/ERα-activated GREB1 transcription. We found that NCOA6 associates with the GREB1 promoter and enhancer in an E2-independent manner and that NCOA6 knockout reduces chromatin looping, enhancer-promoter interactions, and basal GREB1 expression in the absence of E2.	SIGNOR-265883
Q9UQM7	P15036	1	phosphorylation	down-regulates	0.2	Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters	SIGNOR-183596
P11021	O75460	2	binding	down-regulates activity	0.82	Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain	SIGNOR-260176
P17612	P12931	1	phosphorylation	up-regulates activity	0.361	PKA activated Src both in vitro and in vivo by phosphorylating Src on serine 17 within its amino terminus	SIGNOR-247988
P01178-PRO_0000020496	P01178-PRO_0000020495	2	binding	up-regulates quantity	0.2	Neurophysins I and II (NPI and NPII) serve in the neurosecretory granules of the posterior pituitary as carrier proteins for the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively, until the latter are released into blood.	SIGNOR-270351
Q13286	P06493	0	phosphorylation	down-regulates activity	0.257	(D) Phosphorylation of Cln3 by Cdk1 is independent of Ssa1 T36.\|Thereby, both Cdk1 and Pho85can promote Cln3 degradation, though under distinct circumstances.	SIGNOR-279013
P28482	Q05469	1	phosphorylation	up-regulates activity	0.368	Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL.	SIGNOR-249413
Q14118	Q9ULB1	2	binding	up-regulates activity	0.426	The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM.	SIGNOR-265458
O75298	Q9C037	0	ubiquitination	down-regulates quantity	0.2	2: TRIM4 ubiquitinates and degrades the NSP2 protein.\|Mechanistic studies showed that TRIM4 ubiquitinated modified NSP2 and down-regulated NSP2 expression.	SIGNOR-278793
P28482	O95997	1	phosphorylation	up-regulates	0.353	Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function.	SIGNOR-79515
P00533	P16333	2	binding	up-regulates activity	0.576	We show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues	SIGNOR-252089
Q16611	Q92843	2	binding	down-regulates	0.467	Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax.	SIGNOR-152989
P18846	Q13362	0	dephosphorylation	up-regulates	0.2	We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf5	SIGNOR-167564
O60229	Q16659	0	phosphorylation	up-regulates activity	0.406	The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements.	SIGNOR-263094
Q92633	Q03113	2	binding	up-regulates	0.46	Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription.	SIGNOR-198507
P84243	O75582	0	phosphorylation	down-regulates activity	0.2	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-119233
Q16584	Q08378	1	phosphorylation	up-regulates activity	0.361	In vitro kinase assays demonstrated that MLK3 directly phosphorylates golgin-160 in the N-terminal head region between residues 96 and 259.	SIGNOR-279065
P56706	Q9ULW2	2	binding	up-regulates	0.646	Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling	SIGNOR-137934
Q9UQM7	Q04760	1	phosphorylation	up-regulates activity	0.2	This study is able to show that a phosphorylation of threonine-107 (T107) in the (rate-limiting) Glyoxalase 1 (Glo1) protein, mediated by Ca2+/calmodulin-dependent kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1 (lower KM; higher Vmax).	SIGNOR-273553
P01009	P00748	2	binding	down-regulates activity	0.33	C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1).	SIGNOR-263515
P35228	P27361	0	phosphorylation	up-regulates	0.354	Erk phosphorylated inos on ser745. Mutation of ser745 to ala did not affect basal inos activity but eliminated inos phosphorylation and activation in response to b1r agonist.	SIGNOR-157711
P29803	P24752	0	acetylation	down-regulates activity	0.2	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-267634
P17612	P42858	1	phosphorylation	down-regulates quantity by destabilization	0.2	Moreover, phosphorylation of C-HEAT Ser2550 by cAMP-dependent protein kinase (PKA), the top hit in kinase activity screens, was found to hasten huntingtin degradation, such that levels of the catalytic subunit (PRKACA) were inversely related to huntingtin levels.	SIGNOR-277625
P16885	P07333	0	null	up-regulates	0.369	Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway	SIGNOR-255570
Q96CN5	Q5TZA2	2	binding	up-regulates activity	0.44	Here, we show that LRRC45 is a centrosome linker that localizes at the proximal ends of the centrioles and forms fiber-like structures between them. Depletion of LRRC45 results in centrosome splitting during interphase. LRRC45 interacts with C-Nap1 and rootletin	SIGNOR-273704
O15085	Q14344	2	binding	up-regulates activity	0.635	This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho	SIGNOR-256517
P56945	P84022	2	binding	down-regulates	0.277	In this study, we show that, after tyrosine phosphorylation of p130cas mediated by integrin signaling, the phosphorylated p130cas is able to interact with phosphorylated smad3 and in turn prevent transcriptional activation by smad3	SIGNOR-161265
P06493	Q16635	1	phosphorylation	down-regulates quantity by destabilization	0.266	Our studies suggest that phosphorylation and degradation of TAZ by Cdk1 may play important roles in apoptosis induced by antitubulin drugs.	SIGNOR-278240
P50552	Q15418	0	phosphorylation	down-regulates	0.45	Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin.	SIGNOR-172899
P49768	P35222	2	binding	down-regulates	0.808	Importantly, our data show that binding of ps1 to cadherin mediates the effects of ps1 on the phosphorylation, ubiquitination, and destabilization of beta-catenin. Thus, cadherins mediate both the association of ps1 and beta-catenin and the effects of ps1 on the cellular levels of beta-catenin	SIGNOR-22837
Q9BZS1	P26358	0	transcriptional regulation	down-regulates quantity by repression	0.488	Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35)	SIGNOR-269053
P21580	Q96J02	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
P15336	Q16539	0	phosphorylation	up-regulates	0.793	On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.	SIGNOR-65597
P27361	P04637	1	phosphorylation	up-regulates	0.704	Mutant p53 is constitutively phosphorylated at serine 15 in uv-induced mouse skin tumors: involvement of erk1/2 map kinase.	SIGNOR-100270
Q15077	P63092	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 ‚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-256804
P01137	P27986	2	binding	up-regulates activity	0.258	While association of the TGF_RI receptor with p85 requires TGF-_ stimulation.	SIGNOR-217960
Q14994	Q15466	2	binding	down-regulates	0.508	The short heterodimer partner (shp), an orphan nuclear receptor that lacks a conventional dna binding domain, was initially identified by its interaction with car. We have examined the role of shp in car-mediated transactivation of the cyp2b gene. Coexpression of shp inhibited the transactivation of the cyp2b gene by car in cultured hepatoma cells and the p160 coactivator grip1 reversed the inhibition.	SIGNOR-123154
P35222	P19784	0	phosphorylation	up-regulates quantity by stabilization	0.471	We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.	SIGNOR-275993
Q9H211	Q9H211	2	binding	up-regulates activity	0.2	We further show that Cdc6 physically associates with Cdt1 via its N-terminal noncatalytic domain, a region we had previously shown to be essential for Cdc6 function.	SIGNOR-261682
Q12947	Q9H1B7	1	transcriptional regulation	up-regulates quantity by expression	0.253	FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation.	SIGNOR-267152
P78536	P07359	1	cleavage	down-regulates activity	0.284	GPIbα is shed by metalloproteases such as ADAM17, a process that releases a soluble GPIbα fragment termed glycocalicin. ADAM17 cleaves within the GPIbα-based peptide (LRGV465LK) through a mechanism that is only partially understood [42]. GPIbα shedding has been shown to be constitutive but it can be increased by activation of protein kinases C (PKC) or inhibition of calmodulin [42, 43]. Shedding leads to decreased receptor density	SIGNOR-261861

Q03113

P34995

2

binding

up-regulates activity

0.263

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-257278

O96017

P00441

1

phosphorylation

up-regulates activity

0.376

ROS signaling is mediated by Mec1/ATM and its effector Dun1/Cds1 kinase, through Dun1 interaction with Sod1 and regulation of Sod1 by phosphorylation at S60, 99. In the nucleus, Sod1 binds to the promoters and regulates the expression of oxidative resistance and repair genes.

SIGNOR-262794

P98082

O75581

2

binding

down-regulates

0.495

Wnt stimulation induces the casein kinase 2 (ck2)-dependent phosphorylation of lrp6 at s1579, promoting its binding to dab2 and internalization with clathrin.

SIGNOR-196925

P12931

O60331

1

phosphorylation

up-regulates

0.285

Phosphorylation by src of the tyrosine adjacent to s650 (y649 in human pipki gamma) was shown to enhance pipki gamma targeting to focal adhesions. We find that y649 phosphorylation does not stimulate directly pipki gamma binding to talin, but may do so indirectly by inhibiting s650 phosphorylation.

SIGNOR-134459

Q9Y266

P53350

0

phosphorylation

up-regulates activity

0.73

Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites.

SIGNOR-103403

Q00535

Q14194

1

phosphorylation

up-regulates

0.622

These findings suggest that sema3a-induced spine development is regulated by phosphorylation of crmp1 by cdk5. Introduction of crmp1-wt, but not crmp1-t509a/s522a, a crmp1 mutant that cannot be phosphorylated by cdk5, rescued the defect in sema3a responsiveness.

SIGNOR-159314

P15311

Q15475

0

transcriptional regulation

up-regulates quantity

0.342

We now show that the gene encoding Ezrin is a direct transcriptional target of Six1.

SIGNOR-259374

P11831

P35354

1

null

up-regulates

0.252

Srf within myofibers modulates Il6 and Cox2/Il4 expressions and, therefore, exerts a paracrine control of satellite cell proliferation and fusion, respectively, which in turn support skeletal muscle hypertrophy.

SIGNOR-255965

Q9ULV8

O15357

2

binding

down-regulates

0.2

This association between ship2 and cbl could sequester cbl from the egfr, thereby regulating the kinetics of egfr-cbl association and subsequent internalization and degradation of the receptor.

SIGNOR-133388

P29317

P07947

1

phosphorylation

up-regulates activity

0.423

EphA2 interacts with YES1 and phosphorylates YES1 at Tyr426 site.

SIGNOR-277556

P58400

Q8NFZ3

2

binding

up-regulates activity

0.2

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-264148

P08754

Q9Y5N1

2

binding

up-regulates activity

0.437

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-256832

P36888

P62993

2

binding

up-regulates activity

0.604

FL stimulation induces association of Grb2 with Flt3, SHP-2,and Shc

SIGNOR-245060

P35222

P23471

0

dephosphorylation

up-regulates activity

0.378

PTPRZ1 constitutively promotes the tyrosine dephosphorylation of \u03b2-catenin, and thus \u03b2-catenin participation in TCF-mediated transcription.

SIGNOR-277044

P35790

Q9H6E5

1

phosphorylation

up-regulates activity

0.2

Our data indicate that the kinase activities of both the isoforms of CKI -- alpha and epsilon modulate Star-PAP polyadenylation activity and target mRNAs.|Taken together, these data suggest that phosphorylation of Star-PAP by CKI modulates the Star-PAP polyadenylation activity downstream of stimulation by oxidant stress and phosphorylation primes Star-PAP, so that it can be stimulated by PI4,5 P 2.

SIGNOR-279162

P09471

P41145

2

binding

up-regulates activity

0.347

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-256989

Q86TM6

Q15011

2

binding

up-regulates activity

0.574

FAM8A1 enhances binding of Herp to Hrd1, an interaction that is required for ERAD. Our findings support a model of Hrd1 complex formation, where the Hrd1 cytoplasmic domain and FAM8A1 have a central role in the assembly and activity of this ERAD machinery. A conserved Hrd1 cytoplasmic domain interacts with FAM8A1 and Herp

SIGNOR-261349

Q13315

Q8WVD3

1

phosphorylation

up-regulates activity

0.2

We further confirm that RNF138 is phosphorylated by ATM at Ser124.

SIGNOR-279505

P60484

Q8IZP0

1

dephosphorylation

down-regulates quantity by destabilization

0.241

After dephosphorylation by PTEN, Abi1 is degraded by calpains.|We demonstrate that PTEN dephosphorylation of Abi1 at Y213 and S216 results in Abi1 degradation through the calpain pathway.

SIGNOR-276948

Q9BXM7

P60484

1

phosphorylation

down-regulates activity

0.47

PINK1 interacts with and phosphorylates PTEN at Serine179, resulting in the activation of AKT and the inhibition of PTEN nuclear import.

SIGNOR-277915

Q14721

O95292

1

relocalization

up-regulates quantity

0.2

Confirmation that Kv2.1 and -2.2 bind VAPA and VAPB employed colocalization/redistribution, siRNA knockdown, and Förster resonance energy transfer (FRET)-based assays.|As Kv2.1 accumulates on the surface it begins to bind ER VAPs and form the large and stable membrane junctions.

SIGNOR-262121

Q13043

P45983

0

phosphorylation

up-regulates

0.268

C-jun n-terminal kinase enhances mst1-mediated pro-apoptotic signaling through phosphorylation at serine 82.

SIGNOR-162327

Q14493

P68431

1

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265413

Q00987

Q9NXV6

1

ubiquitination

down-regulates

0.37

Carf interacts with hdm2 and is ubiquitinated and negatively regulated by hdm2 by proteasome-dependent degradation.

SIGNOR-160974

O94925

Q02156

0

phosphorylation

up-regulates activity

0.2

PKCε is the kinase that phosphorylates GAC at Ser314.

SIGNOR-277387

P31270

O15550

0

transcriptional regulation

up-regulates quantity by expression

0.263

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

SIGNOR-260021

Q92956

O00463

2

binding

up-regulates activity

0.625

ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5|synergistic activation of NF-κB by ATAR and TRAF5 293 cells

SIGNOR-262592

Q969S3

Q99683

0

phosphorylation

up-regulates

0.487

Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis.

SIGNOR-175113

P07954

P15336

2

binding

up-regulates activity

0.2

Glucose deficiency induces AMPK activation, which phosphorylates FH at Ser75 and promotes its binding to ATF2 and the enrichment of the FH–ATF2 complex on the promoter regions of ATF2-targeted genes.

SIGNOR-266314

P30622

Q14203

2

binding

up-regulates activity

0.782

MT-unbound CLIP-170 can adopt a folded conformation through an intramolecular interaction of its terminal domains. Binding to MTs correlates with the unfolding of CLIP-170, which allows the interaction of the COOH-terminal domain with its binding partners, such as dynactin, resulting in their recruitment to the MT tip. The NH2 terminus of p150Glued binds directly to the COOH terminus of CLIP-170 through its second metal-binding motif.

SIGNOR-252164

P54725

Q05086

0

polyubiquitination

down-regulates quantity by destabilization

0.486

Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP. E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B.

SIGNOR-272550

Q9UN71

Q9Y5I2

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265701

P26651

Q16539

0

phosphorylation

down-regulates activity

0.357

TTP appears to be a p38Î±/Î² MAPK target and pretreating skeletal muscle with a p38Î±/Î² MAPK inhibitor reduces TTP phosphorylation.

SIGNOR-253596

P06744

O15297

0

dephosphorylation

down-regulates activity

0.24

The WIP1 mediated inhibition of NLK activity markedly decreased the phosphorylation of lymphoid enhancer binding factor 1 (LEF1), enhancing its interaction with beta-catenin.|Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development.

SIGNOR-277155

Q86UW7

P63027

2

binding

up-regulates activity

0.255

CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly.

SIGNOR-264341

P25963

Q9Y6K9

0

phosphorylation

down-regulates activity

0.848

IκB components are phosphorylated on two amino-terminal serine residues by the IκB kinase (IKK) complex, composed of two catalytic proteins, IKKα and IKKβ, and the regulatory subunit IKKγ (NEMO, IKBKG). This modification targets IκB for degradation by the proteasome, allowing the release and nuclear translocation of NF-κB.

SIGNOR-280462

Q06187

P40763

1

phosphorylation

down-regulates activity

0.382

Phosphorylation of STAT-3 by BTK may also alter the conformation of STAT-3 in such a way as to make it inaccessible as a substrate of activating kinases such as JAK3.|The ability of BTK to negatively regulate STAT-3 activity suggests several possible models for a mechanism of BTK action.

SIGNOR-279011

P55055

P19793

2

binding

up-regulates

0.694

We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.

SIGNOR-123091

P46937

Q99594

2

binding

up-regulates

0.85

When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.

SIGNOR-201471

Q99835

P62879

2

binding

up-regulates

0.2

Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.

SIGNOR-199177

O00141

P42345

0

phosphorylation

up-regulates

0.849

Mtor phosphorylated sgk1, but not sgk1-s422a, in vitro. Sgk1 phosphorylated p27 in vitro. These data implicate sgk1 as an mtorc1 (mtor-raptor) substrate. mtor may promote g1 progression in part through sgk1 activation

SIGNOR-179113

P53779

O60282

1

phosphorylation

down-regulates activity

0.32

Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. JNK3 phosphorylates kinesin-1 at Ser176

SIGNOR-262950

P98171

P63000

1

gtpase-activating protein

down-regulates activity

0.479

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-260460

P68400

Q9UER7

1

phosphorylation

up-regulates

0.327

Daxx-sim is phosphorylated by ck2 kinase at residues s737 and s739. Phosphorylation promotes daxx-sim binding affinity toward sumo-1 over sumo-2/3, causing daxx preference for sumo-1 conjugation and interaction with sumo-1-modified factors.

SIGNOR-173105

O95990

Q9Y243

2

binding

up-regulates

0.2

Full-length tcl1 and its isoforms bind to akt / in in vitro kinase assays using gsk-3_ as a substrate, we found that the presence of any of the tcl1 family proteins (tcl1, mtcp1, or tcl1b) as gst fusion proteins significantly enhanced akt-induced gsk-3_ phosphorylation

SIGNOR-81800

Q13131

Q14524

1

phosphorylation

down-regulates quantity by destabilization

0.2

AMPK was found to phosphorylate Nav1.5 at threonine (T) 101, which then regulates the interaction between Nav1.5 and the autophagic adaptor protein, microtubule-associated protein 1 light chain 3 (LC3), by exposing the LC3-interacting region adjacent to T101 in Nav1.5.

SIGNOR-277432

Q8IXL6

P04275

1

phosphorylation

up-regulates activity

0.2

In vitro phosphorylation of von Willebrand factor by FAM20c enhances its ability to support platelet adhesion.

SIGNOR-279331

P19793

Q14994

2

binding

up-regulates

0.468

Therefore, both car-rxr heterodimers and car monomers can contribute to the gene activating function of pbrems in car target genes.

SIGNOR-104441

P52333

P23458

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-152917

O75553

Q8WXH5

2

binding

down-regulates quantity by destabilization

0.2

SOCS7 promotes Dab1 polyubiquitylation and degradation. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1.

SIGNOR-272139

P41236

P49841

0

phosphorylation

up-regulates activity

0.412

Protein phosphatase 1 (PP1) is complexed with inhibitor 2 (I-2) in the cytosol. In rabbit muscle extract PP1.I-2 is activated upon preincubation with ATP/Mg. This activation is caused by phosphorylation of I-2 on Thr(72) by glycogen synthase kinase 3 (GSK3).

SIGNOR-251257

Q99683

P53041

0

dephosphorylation

down-regulates activity

0.597

After exposure of cells to H2O2, ASK1 is transiently activated by autophosphorylation at Thr845. The protein then associates with PP5 (protein serine/threonine phosphatase 5), which inactivates ASK1 by dephosphorylation of Thr845.

SIGNOR-248540

Q92974

P27448

0

phosphorylation

up-regulates activity

0.382

Rho-Rac guanine nucleotide exchange factor 2 (ARHGEF2), which activates Ras homolog family member A (RHOA), is anchored to the microtubule network and sequestered in an inhibited state through binding to dynein light chain Tctex-1 type 1 (DYNLT1). We showed in mammalian cells that liver kinase B1 (LKB1) activated the microtubule affinity-regulating kinase 3 (MARK3), which in turn phosphorylated ARHGEF2 at Ser151 This modification disrupted the interaction between ARHGEF2 and DYNLT1 by generating a 14-3-3 binding site in ARHGEF2, thus causing ARHGEF2 to dissociate from microtubules.

SIGNOR-277368

O15169

Q9Y6R4

2

binding

up-regulates

0.42

Mekk4, also binds to axin in vivo and mediates axin-induced jnk activation.

SIGNOR-104003

Q12933

Q13489

2

binding

up-regulates

0.892

A traf2 trimer interacts with one ciap2 both in the crystal and in solution through its death domain and amino-terminal region, tradd recruits rip1 (receptor-interacting protein), traf2, and through its interaction with traf2, c-iap1 and c-iap2 (13). Traf2 recruit ciap1 and ciap2. A traf2 trimer interacts with one ciap2 both in the crystal and in solution.

SIGNOR-182124

Q5H8A3

Q9GZQ4

2

binding

up-regulates

0.631

Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus.

SIGNOR-133131

P38936

P01106

0

transcriptional regulation

down-regulates quantity by repression

0.779

C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a

SIGNOR-102740

Q13145

O14641

2

binding

up-regulates

0.516

Bmp-2 mediates phosphorylated smad1 (psmad1) or, with loss of bmprii, psmad3-dependent recruitment of disheveled (dvl) to promote rhoa-rac1 signaling necessary for motility.

SIGNOR-23037

P24723

P28482

1

phosphorylation

up-regulates activity

0.506

Protein kinase C-eta regulates Mcl-1 level via ERK1. knockdown of PKCη but not PKCα, -δ or -ε caused a significant decrease in ERK (extracellular signal-regulated kinase) phosphorylation. Knockdown of ERK1 but not ERK2 decreased Mcl-1 level, and the decrease in Mcl-1 caused by PKCη knockdown was restored by ERK1 overexpression. These results suggest that PKCη utilizes the ERK signaling pathway to protect against ubiquitin-mediated proteasomal degradation of Mcl-1.

SIGNOR-261910

Q4ZG55

Q14686

0

transcriptional regulation

up-regulates quantity by expression

0.2

Herein, using growth-regulating estrogen receptor binding 1 (GREB1) as an ERα target gene in Ishikawa cells, we demonstrate that nuclear receptor co-activator 6 (NCOA6) is essential for estradiol (E2)/ERα-activated GREB1 transcription. We found that NCOA6 associates with the GREB1 promoter and enhancer in an E2-independent manner and that NCOA6 knockout reduces chromatin looping, enhancer-promoter interactions, and basal GREB1 expression in the absence of E2.

SIGNOR-265883

Q9UQM7

P15036

1

phosphorylation

down-regulates

0.2

Camkii caused ets-2 phosphorylation.Serine 246, 310, and 313 were the targets. Camkii to phosphorylates ets-2, thus altering ets-2 binding to its downstream promoters

SIGNOR-183596

P11021

O75460

2

binding

down-regulates activity

0.82

Besides being activated like PERK via dissociation of GRP78, IRE1 is also activated by direct binding of the unfolded protein to its N-terminal luminal domain

SIGNOR-260176

P17612

P12931

1

phosphorylation

up-regulates activity

0.361

PKA activated Src both in vitro and in vivo by phosphorylating Src on serine 17 within its amino terminus

SIGNOR-247988

P01178-PRO_0000020496

P01178-PRO_0000020495

2

binding

up-regulates quantity

0.2

Neurophysins I and II (NPI and NPII) serve in the neurosecretory granules of the posterior pituitary as carrier proteins for the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively, until the latter are released into blood.

SIGNOR-270351

Q13286

P06493

0

phosphorylation

down-regulates activity

0.257

(D) Phosphorylation of Cln3 by Cdk1 is independent of Ssa1 T36.|Thereby, both Cdk1 and Pho85can promote Cln3 degradation, though under distinct circumstances.

SIGNOR-279013

P28482

Q05469

1

phosphorylation

up-regulates activity

0.368

Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL.

SIGNOR-249413

Q14118

Q9ULB1

2

binding

up-regulates activity

0.426

The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM.

SIGNOR-265458

O75298

Q9C037

0

ubiquitination

down-regulates quantity

0.2

2: TRIM4 ubiquitinates and degrades the NSP2 protein.|Mechanistic studies showed that TRIM4 ubiquitinated modified NSP2 and down-regulated NSP2 expression.

SIGNOR-278793

P28482

O95997

1

phosphorylation

up-regulates

0.353

Pttg is phosphorylated in vitro on ser(162) by map kinase and this phosphorylation site plays an essential role in pttg transactivation function.

SIGNOR-79515

P00533

P16333

2

binding

up-regulates activity

0.576

We show that epidermal growth factor or platelet-derived growth factor stimulation of intact human or murine cells leads to phosphorylation of Nck protein on tyrosine, serine, and threonine residues

SIGNOR-252089

Q16611

Q92843

2

binding

down-regulates

0.467

Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax.

SIGNOR-152989

P18846

Q13362

0

dephosphorylation

up-regulates

0.2

We propose that constitutive hyperphosphorylation by ck1/ck2 maintains atf1 in an inactive state that promotes transcriptional repression. Pp2a/b56c antagonizes phosphorylation of atm sites in both creb and atf5

SIGNOR-167564

O60229

Q16659

0

phosphorylation

up-regulates activity

0.406

The brain-specific nucleotide exchange factor kalirin-7 (Kal7) was identified as an MK5 interaction partner and substrate protein. The MK5 substrate Kal7, a Rho GEF and known activator of Rac GTPases, further contributes to PAK activation and actin filament reorganization. Thus, the coordinated phosphorylation of Borg proteins and Kal7 by ERK3 and MK5 constitute a novel signaling cascade involving feed-forward circuits, multiple GTPases, and cytoskeletal elements.

SIGNOR-263094

Q92633

Q03113

2

binding

up-regulates

0.46

Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription.

SIGNOR-198507

P84243

O75582

0

phosphorylation

down-regulates activity

0.2

Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.

SIGNOR-119233

Q16584

Q08378

1

phosphorylation

up-regulates activity

0.361

In vitro kinase assays demonstrated that MLK3 directly phosphorylates golgin-160 in the N-terminal head region between residues 96 and 259.

SIGNOR-279065

P56706

Q9ULW2

2

binding

up-regulates

0.646

Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling

SIGNOR-137934

Q9UQM7

Q04760

1

phosphorylation

up-regulates activity

0.2

This study is able to show that a phosphorylation of threonine-107 (T107) in the (rate-limiting) Glyoxalase 1 (Glo1) protein, mediated by Ca2+/calmodulin-dependent kinase II delta (CamKIIδ), is associated with elevated catalytic efficiency of Glo1 (lower KM; higher Vmax).

SIGNOR-273553

P01009

P00748

2

binding

down-regulates activity

0.33

C1INH is a serine protease inhibitor (serpin) that acts on both the complement pathway and the contact system and is the main inhibitor of the contact system by targeting both FXIIa and PK 9. Additionally, FXIIa can be inhibited by α1‐antitrypsin and plasminogen activator inhibitor‐1 (PAI‐1).

SIGNOR-263515

P35228

P27361

0

phosphorylation

up-regulates

0.354

Erk phosphorylated inos on ser745. Mutation of ser745 to ala did not affect basal inos activity but eliminated inos phosphorylation and activation in response to b1r agonist.

SIGNOR-157711

P29803

P24752

0

acetylation

down-regulates activity

0.2

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-267634

P17612

P42858

1

phosphorylation

down-regulates quantity by destabilization

0.2

Moreover, phosphorylation of C-HEAT Ser2550 by cAMP-dependent protein kinase (PKA), the top hit in kinase activity screens, was found to hasten huntingtin degradation, such that levels of the catalytic subunit (PRKACA) were inversely related to huntingtin levels.

SIGNOR-277625

P16885

P07333

0

null

up-regulates

0.369

Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway

SIGNOR-255570

Q96CN5

Q5TZA2

2

binding

up-regulates activity

0.44

Here, we show that LRRC45 is a centrosome linker that localizes at the proximal ends of the centrioles and forms fiber-like structures between them. Depletion of LRRC45 results in centrosome splitting during interphase. LRRC45 interacts with C-Nap1 and rootletin

SIGNOR-273704

O15085

Q14344

2

binding

up-regulates activity

0.635

This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho

SIGNOR-256517

P56945

P84022

2

binding

down-regulates

0.277

In this study, we show that, after tyrosine phosphorylation of p130cas mediated by integrin signaling, the phosphorylated p130cas is able to interact with phosphorylated smad3 and in turn prevent transcriptional activation by smad3

SIGNOR-161265

P06493

Q16635

1

phosphorylation

down-regulates quantity by destabilization

0.266

Our studies suggest that phosphorylation and degradation of TAZ by Cdk1 may play important roles in apoptosis induced by antitubulin drugs.

SIGNOR-278240

P50552

Q15418

0

phosphorylation

down-regulates

0.45

Rsk1 phosphorylated vasp on t278, a site regulating its binding to actin.

SIGNOR-172899

P49768

P35222

2

binding

down-regulates

0.808

Importantly, our data show that binding of ps1 to cadherin mediates the effects of ps1 on the phosphorylation, ubiquitination, and destabilization of beta-catenin. Thus, cadherins mediate both the association of ps1 and beta-catenin and the effects of ps1 on the cellular levels of beta-catenin

SIGNOR-22837

Q9BZS1

P26358

0

transcriptional regulation

down-regulates quantity by repression

0.488

Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35)

SIGNOR-269053

P21580

Q96J02

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

P15336

Q16539

0

phosphorylation

up-regulates

0.793

On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.

SIGNOR-65597

P27361

P04637

1

phosphorylation

up-regulates

0.704

Mutant p53 is constitutively phosphorylated at serine 15 in uv-induced mouse skin tumors: involvement of erk1/2 map kinase.

SIGNOR-100270

Q15077

P63092

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 ‚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-256804

P01137

P27986

2

binding

up-regulates activity

0.258

While association of the TGF_RI receptor with p85 requires TGF-_ stimulation.

SIGNOR-217960

Q14994

Q15466

2

binding

down-regulates

0.508

The short heterodimer partner (shp), an orphan nuclear receptor that lacks a conventional dna binding domain, was initially identified by its interaction with car. We have examined the role of shp in car-mediated transactivation of the cyp2b gene. Coexpression of shp inhibited the transactivation of the cyp2b gene by car in cultured hepatoma cells and the p160 coactivator grip1 reversed the inhibition.

SIGNOR-123154

P35222

P19784

0

phosphorylation

up-regulates quantity by stabilization

0.471

We show that CKII phosphorylates the N-terminal region of beta-catenin and we identified Ser29, Thr102, and Thr112 as substrates for the enzyme. We provide evidence that CKII regulates the cytoplasmic stability of beta-catenin and acts synergistically with GSK-3beta in the multi-protein complex that controls the degradation of beta-catenin.

SIGNOR-275993

Q9H211

2

binding

up-regulates activity

0.2

We further show that Cdc6 physically associates with Cdt1 via its N-terminal noncatalytic domain, a region we had previously shown to be essential for Cdc6 function.

SIGNOR-261682

Q12947

Q9H1B7

1

transcriptional regulation

up-regulates quantity by expression

0.253

FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation.

SIGNOR-267152

P78536

P07359

1

cleavage

down-regulates activity

0.284

GPIbα is shed by metalloproteases such as ADAM17, a process that releases a soluble GPIbα fragment termed glycocalicin. ADAM17 cleaves within the GPIbα-based peptide (LRGV465LK) through a mechanism that is only partially understood [42]. GPIbα shedding has been shown to be constitutive but it can be increased by activation of protein kinases C (PKC) or inhibition of calmodulin [42, 43]. Shedding leads to decreased receptor density

SIGNOR-261861