GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 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
Q96FA3	P51617	2	ubiquitination	up-regulates quantity by expression	0.767	These results were consistent with the observations made in vitro, namely that pellino isoforms are activated by irak1-catalysed phosphorylation and that, once activated, can ubiquitinate irak1 in cells.	SIGNOR-159055
P45974	P0CG47	1	cleavage	up-regulates quantity	0.767	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270821
P08949	P28336	1	binding	up-regulates	0.767	These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins.	SIGNOR-107022
Q8N0W4	Q9HDB5	1	binding	up-regulates activity	0.767	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-264170
P42345	P35568	1	phosphorylation	down-regulates activity	0.766	Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten	SIGNOR-106590
P06241	P56945	1	phosphorylation	up-regulates activity	0.766	Taken together, these results suggest that p130Cas is directly phosphorylated by Fyn kinase in the cytoplasm of oligodendrocytes.	SIGNOR-279372
Q13164	Q06413	1	phosphorylation	up-regulates	0.766	Bmk1 dramatically enhances the transactivation activity of mef2c by phosphorylating a serine residue at amino acid position 387 in this transcription factor.	SIGNOR-53545
P01189	Q01726	1	binding	up-regulates activity	0.766	Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses.	SIGNOR-252370
Q9NZJ5	P05198	1	phosphorylation	down-regulates activity	0.766	We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK).	SIGNOR-260874
P41221	Q14332	1	binding	down-regulates	0.766	Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway.	SIGNOR-23441
P55317	P10275	1	transcriptional regulation	down-regulates quantity by repression	0.766	FOXA1 directly inhibits AR expression and thus the transcription of its target genes. FOXA1 inhibits AR gene expression in prostate cancer. oss of FOXA1 may lead to androgen-independent AR signaling and thus castration-resistant prostate cancer progression. Indeed, we have recently reported that FOXA1 is downregulated in CRPC	SIGNOR-251541
Q13309	P46527	1	ubiquitination	down-regulates	0.766	Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3).	SIGNOR-154194
P01106	P42771	1	transcriptional regulation	down-regulates quantity by repression	0.766	C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a	SIGNOR-102743
O60674	P10912	1	phosphorylation	up-regulates activity	0.766	Jak2 is then phosphorylated and, in turn, phosphorylates the GHR and the signal transducers and activators of transcription (STAT) protein.	SIGNOR-279198
P53671	P23528	1	phosphorylation	down-regulates activity	0.766	We report here that limk1 and limk2 phosphorylate both cofilin and actin-depolymerizing factor (adf) specifically at ser-3 and exhibit partially distinct substrate specificity when tested using site-directed cofilin mutants as substrates	SIGNOR-105098
P04626	P35222	1	phosphorylation	down-regulates activity	0.766	Second, ErbB2 phosphorylates \u03b2-catenin at Tyr 654, leading to dissociation of the E-cadherin-\u03b2-catenin membrane complex and increased signaling to Wnt target genes such as cyclin D1 ( ).	SIGNOR-279041
Q6UXX9	Q9BXB1	1	binding	up-regulates	0.766	Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation.	SIGNOR-174486
P09919	Q99062	1	binding	up-regulates	0.766	The gcsf:gcsf-r complex formed a 2:2 stoichiometry by means of a cross-over interaction between the ig-like domains of gcsf-r and gcsf. the ig-like domain cross-over structure necessary for gcsf-r activation is consistent with previously reported thermodynamic and mutational analyses.	SIGNOR-144743
P01189	P33032	1	binding	up-regulates activity	0.766	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268715
P31749	P03372	1	phosphorylation	up-regulates	0.765	Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.	SIGNOR-84963
Q03113	Q9NZN5	1	binding	up-regulates activity	0.765	P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation.	SIGNOR-256522
Q9UNA0	P16112	1	cleavage	down-regulates quantity by destabilization	0.765	Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints\|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374	SIGNOR-266985
P15498	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.765	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-260581
P38936	P12004	1	binding	down-regulates	0.765	P21 exerts its effect on the cell cycle not only by inhibiting cyclin/cdk complexes, but also by inhibiting proliferating cell nuclear antigen (pcna)	SIGNOR-191939
Q8N726	Q00987	1	relocalization	down-regulates activity	0.765	We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53.	SIGNOR-192697
P23458	P42226	1	phosphorylation	up-regulates activity	0.765	IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes	SIGNOR-249531
Q9HC29	O43353	1	binding	up-regulates activity	0.765	The function of NOD2 could be to recruit RICK at the plasma membrane to form an active complex able to activate part of the NF-κB pathway. NOD2 induces a membrane recruitment of RICK that is dependent on a CARD-CARD interaction.	SIGNOR-252402
O14920	Q15653	1	phosphorylation	down-regulates	0.765	We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation	SIGNOR-52932
P17693	Q99706	1	binding	up-regulates	0.764	Recombinant soluble kir2dl4 binds to cells expressing hla-g but not to cells expressing other hla class i molecules.	SIGNOR-66132
P06239	P20963	1	phosphorylation	up-regulates	0.764	During tcr signaling, lck interacts with numerous molecules, including tcr-zeta. The binding of lck to the tyrosine-phosphorylated zeta chain of the tcr would serve to strengthen the interaction of the associated cd4 and the tcr complex, leading to increased avidity for the antigen-major histocompatibility protein complex.	SIGNOR-41361
P31749	O60343	1	phosphorylation	down-regulates	0.764	Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt	SIGNOR-252594
O43318	P52564	1	phosphorylation	up-regulates activity	0.764	The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination	SIGNOR-109497
P11488	P18545	1	binding	down-regulates activity	0.764	In the dark, PDE6 activity is suppressed by its inhibitory γ-subunit (Pγ). Rhodopsin-catalyzed activation of the G protein, transducin, relieves this inhibition and enhances PDE6 catalysis.	SIGNOR-260008
P12931	Q03135	1	phosphorylation	down-regulates activity	0.764	Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn	SIGNOR-118007
Q8IUD6	O95786	1	ubiquitination	up-regulates activity	0.764	Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region.	SIGNOR-265569
P18075	P27037	1	binding	up-regulates	0.764	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-60237
Q00535	P10636	1	phosphorylation	down-regulates activity	0.763	We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.	SIGNOR-249321
P31749	P98177	1	phosphorylation	down-regulates	0.763	Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression	SIGNOR-252486
P07900	P10275	1	binding	up-regulates activity	0.763	The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes.	SIGNOR-251536
P56704	P34925	1	binding	up-regulates	0.763	Here, we report that ryk directly binds wnt-1 and wnt-3a via its wif domain and is required for the tcf.	SIGNOR-129580
Q14563	Q9HCM2	1	binding	up-regulates activity	0.763	We provide evidence suggesting that, in endothelial cells and glioblastoma cells, plexin-A4 is a required component of both Sema3A and Sema3B receptor complexes and inhibition of its expression nullifies both Sema3A and Sema3B signaling. The specificity for Sema3A or Sema3B is determined by the presence of plexin-A1 in Sema3A receptors and plexin-A2 in Sema3B receptors, and silencing each abrogates signaling by the appropriate semaphorin.	SIGNOR-261811
Q96A98	P49190	1	binding	up-regulates	0.763	Subsequent efforts led to the isolation and definition of the primary structure of a novel peptide, referred to as tip39, from bovine hypothalamus and the synthetic peptide was shown to efficiently activate human, rat, and zebrafish pth2 receptors	SIGNOR-115124
Q969H0	P01106	1	ubiquitination	down-regulates quantity	0.762	We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it.	SIGNOR-243545
Q00653	Q01201	1	binding	up-regulates activity	0.762	The map3k14-activated chuk/ikka homodimer phosphorylates nfkb2/p100 associated with relb, inducing its proteolytic processing to nfkb2/p52 and the formation of nf-kappa-b relb-p52 complexes. The nf-kappa-b heterodimeric relb-p52 complex is a transcriptional activator.	SIGNOR-182835
P06493	Q08050	1	phosphorylation	up-regulates	0.762	A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity	SIGNOR-187880
Q13115	P28482	1	dephosphorylation	down-regulates activity	0.762	Dephosphorylation and Inactivation of ERKs\|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185	SIGNOR-248718
Q14393	Q12866	1	binding	up-regulates	0.762	We also found that gas6 stimulated tyrosine phosphorylation of axl, sky, and mer receptors ectopically expressed in chinese hamster ovary cells. Taken together, these findings suggest that gas6 is a common ligand for axl, sky, and mer, all known members of an axl/sky receptor subfamily.	SIGNOR-44953
Q9Y2U5	Q13163	1	phosphorylation	up-regulates	0.762	Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.	SIGNOR-104634
P30086	P04049	1	binding	down-regulates	0.762	Suppression of raf-1 kinase activity and map kinase by rkip. Rkip binds to raf-1, mek and erk, but not to ras.	SIGNOR-70838
P43405	P29353	1	phosphorylation	up-regulates	0.762	The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2).	SIGNOR-59635
P98172	P54753	1	binding	up-regulates	0.762	The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion.	SIGNOR-52517
P20396	P34981	1	binding	up-regulates activity	0.762	When TRH reaches the pars distalis of the pituitary, it regulates cells that express TRH receptor-1 (TRH-R1), such as the thyrotrophs. These cell types are subject to a multifactorial regulation that determines the extent and specificity of their response to TRH.	SIGNOR-267200
Q5T4W7	O60609	1	binding	up-regulates	0.762	Here, we report the identification of artemin, a novel member of the gdnf family, and demonstrate that it is the ligand for the former orphan receptor gfralpha3-ret. Artemin can also activate the gfralpha1-ret complex.	SIGNOR-63009
Q9UQ26	P20336	1	relocalization	up-regulates activity	0.762	N-terminal interactions of RIMs with RAB3 and MUNC13 regulate DCV fusion. Through N-terminal interactions, RIMs position MUNC13 and recruit DCVs via RAB3, which is located on the vesicle	SIGNOR-264377
P53350	O95235	1	phosphorylation	up-regulates activity	0.761	MKlp2 treated with Plk1 did not form the regular microtubule bundles seen with MKlp2 only; many single microtubules were seen instead, and the bundles that were formed were loose parallel arrays rather than the dense bundles seen with untreated MKlp2.\|We propose that phosphorylation of MKlp2 by Plk1 is necessary for the spatial restriction of Plk1 to the central spindle during anaphase and telophase, and the complex of these two proteins is required for cytokinesis.	SIGNOR-278201
P12272	Q03431	1	binding	up-regulates activity	0.761	Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.\|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production.	SIGNOR-270549
Q9UBX5	P15502	1	binding	up-regulates activity	0.761	The binding of tropoelastin fragments to fibulin-5 was directly proportional to their propensity to coacervate. Furthermore, the addition of fibulin-5 to tropoelastin facilitated coacervation. Taken together, the present study shows that fibulin-5 enhances elastic fiber formation in part by improving the self-association properties of tropoelastin.	SIGNOR-252137
Q14449	P06213	1	binding	down-regulates activity	0.761	Growth factor receptor-bound protein 14 (Grb14) interacts with insulin receptor (IR) through the between PH and SH2 (BPS) domain. Grb14-IR complex formation is initiated by insulin stimulation, and the binding event results in the inhibition of insulin signalling.	SIGNOR-264873
P52735	P63000	1	guanine nucleotide exchange factor	up-regulates	0.761	Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases.	SIGNOR-81645
P12931	P35222	1	phosphorylation	down-regulates activity	0.761	beta-catenin is a good substrate of pp60c- srctyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation.	SIGNOR-106458
O94782	Q9BXW9	1	deubiquitination	down-regulates activity	0.761	The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2\|The level of monoubiquitinated FANCD2 protein increases in response to various types of DNA damage in mammalian cells	SIGNOR-263273
Q9UM11	Q16763	1	binding	up-regulates activity	0.761	Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity	SIGNOR-265081
Q9ULV8	P00533	1	polyubiquitination	down-regulates quantity by destabilization	0.761	In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.	SIGNOR-272605
Q9BXH1	Q07817	1	binding	down-regulates activity	0.761	Only bimbh3 and bbc3 had comparable strong affinities for all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.	SIGNOR-133811
P18031	P00533	2	dephosphorylation	down-regulates activity	0.76	We have shown previously that amino acid residues flanking the phosphotyrosine are important for efficient PTP1 catalysis (Table 1 and Refs. 9, 10, and 17). For example, the kcat/Km value for the undecapeptide, EGFR988-989 (epidermal growth factor autophosphorylation site Tyr992, residues 988-998) (Asp-Ala-Asp-Glu-pTyr-Leu-Ile-Pro-Gln-Gln-Gly) is 3220-fold higher than that of phosphotyrosine (Table 1). We further demonstrated that a minimum of six amino acid residues are required for the most efficient PTP1 binding and catalysis.	SIGNOR-248407
P15018	P42702	1	binding	up-regulates	0.76	Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44).	SIGNOR-139102
Q9UBE8	Q9UJU2	1	phosphorylation	down-regulates	0.76	Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk.	SIGNOR-97812
P00533	Q13480	1	phosphorylation	up-regulates	0.76	Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689).	SIGNOR-236400
Q8IW41	P04637	1	phosphorylation	up-regulates	0.76	Furthermore, we show that prak activates p53 by direct phosphorylation. prak phosphorylates p53 at ser37	SIGNOR-152847
P07900	P29474	1	binding	up-regulates	0.76	The binding of hsp90 to enos enhances the activation of enos.	SIGNOR-57211
O60346	P31749	1	dephosphorylation	down-regulates	0.76	Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth.	SIGNOR-252601
P12931	P18206	1	phosphorylation	down-regulates activity	0.76	The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail.	SIGNOR-247424
Q13191	P00533	1	polyubiquitination	down-regulates quantity by destabilization	0.76	Here we describe that overexpression of cbl-b, a homologue of the c-cbl protooncogene, inhibits EGFR-induced apoptosis in MDA-MB-468 breast cancer cells. Overexpression of cbl-b results in a shortened duration of EGFR activation upon EGF stimulation. This is demonstrated by decreased amounts of phosphorylated EGFR as well as by inhibition of multiple downstream signaling pathways. The inhibition of signaling by cbl-b results from increased ubiquitination and degradation of the activated EGFR.	SIGNOR-272934
Q13489	P55211	1	binding	down-regulates	0.76	Xiap, birc2 and birc3 were shown to bind pro-casp9. Iaps may suppress casp9 by direct auto-activation of pro-caspase-11	SIGNOR-56481
Q16690	P27361	1	dephosphorylation	down-regulates	0.76	Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway	SIGNOR-67358
P61586	P15311	1	phosphorylation	up-regulates activity	0.76	Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies.	SIGNOR-268429
P33151	P35222	1	binding	up-regulates activity	0.76	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265867
P04090	Q9HBX9	1	binding	up-regulates	0.76	Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway	SIGNOR-114549
Q9H257	O95999	1	binding	up-regulates quantity by stabilization	0.76	To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB.	SIGNOR-257602
P12931	P10275	1	phosphorylation	up-regulates activity	0.76	In addition to the ability of Src to promotes castration resistant progression and AR activation, Src is involved in regulating prostate cancer cell migration, invasion, and metastasis and affects bone remodeling.\|These data suggest that downstream of cell surface receptors, Ack1 mediates AR tyrosine phosphorylation at Tyr 267 and Src mediates AR tyrosine phosphorylation at Tyr 534.	SIGNOR-278168
P00533	P18031	2	phosphorylation	up-regulates	0.76	After binding to egfr, ptp1b becomes tyrosine-phosphorylated at tyr-66 phosphorylation of ptp1b by egfr enhances its catalytic activity	SIGNOR-52950
P00519	P46108	1	phosphorylation	down-regulates activity	0.76	Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl	SIGNOR-175135
Q96S44	P04637	1	phosphorylation	up-regulates	0.76	The intrinsic transcriptional activity of p53 was up-regulated by a transient transfection of prpk to cos-7 cells. Prpk was shown to bind to p53 and to phosphorylate p53 at ser-15.	SIGNOR-157471
P0DP23	P29474	1	binding	up-regulates activity	0.76	Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer	SIGNOR-251615
P28482	P42229	1	phosphorylation	up-regulates	0.76	Gh treatment of chinese hamster ovary cells stably transfected with the gh receptor (choa cells) led to rapid and transient activation of both stat5a and erk1 and erk2. these observations show, for the first time, direct physical interaction between erk and stat5a and also clearly identify serine 780 as a target for erk.	SIGNOR-66239
Q8TCY5	Q01718	1	binding	up-regulates activity	0.76	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor.	SIGNOR-252360
P28482	Q15418	1	phosphorylation	up-regulates activity	0.759	Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.	SIGNOR-219308
Q04771	Q99717	1	phosphorylation	up-regulates	0.759	Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2	SIGNOR-60171
P45983	O43521	1	phosphorylation	down-regulates quantity by destabilization	0.759	Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination.	SIGNOR-250132
P06493	Q9NQS7	1	phosphorylation	up-regulates	0.759	Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase.	SIGNOR-143387
Q8NFZ4	P78352	1	relocalization	up-regulates activity	0.759	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264193
P12931	O00401	1	phosphorylation	up-regulates activity	0.759	An Src family tyrosine kinase, v-Src, phosphorylates and activates N-WASP.	SIGNOR-279487
P48357	P40763	1	binding	up-regulates activity	0.759	LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2.	SIGNOR-263495
P01189	P41968	1	binding	up-regulates activity	0.759	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268705
Q9BYF1	P01019	1	cleavage	up-regulates activity	0.759	The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus.	SIGNOR-256315
P35222	P36402	1	binding	up-regulates	0.759	Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1	SIGNOR-134282
P33076	P48382	1	binding	up-regulates activity	0.759	RFX5 can activate transcription only in cooperation with CIITA. RFX5 and CIITA associate to form a complex capable of activating transcription from class II major histocompatibility complex promoters. In this complex, promoter specificity is determined by the DNA binding domain of RFX5 and the general transcription apparatus is recruited by the acidic activation domain of CIITA.	SIGNOR-240980
P01112	P42338	1	binding	up-regulates activity	0.759	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner.	SIGNOR-175189
O95886	P78352	1	binding	up-regulates activity	0.758	SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.	SIGNOR-264211
P06239	O43561	1	phosphorylation	up-regulates	0.758	Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation.	SIGNOR-149182

Q96FA3

P51617

2

ubiquitination

up-regulates quantity by expression

0.767

These results were consistent with the observations made in vitro, namely that pellino isoforms are activated by irak1-catalysed phosphorylation and that, once activated, can ubiquitinate irak1 in cells.

SIGNOR-159055

P45974

P0CG47

1

cleavage

up-regulates quantity

0.767

Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.

SIGNOR-270821

P08949

P28336

1

binding

up-regulates

0.767

These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins.

SIGNOR-107022

Q8N0W4

Q9HDB5

1

binding

up-regulates activity

0.767

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-264170

P42345

P35568

1

phosphorylation

down-regulates activity

0.766

Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten

SIGNOR-106590

P06241

P56945

1

phosphorylation

up-regulates activity

0.766

Taken together, these results suggest that p130Cas is directly phosphorylated by Fyn kinase in the cytoplasm of oligodendrocytes.

SIGNOR-279372

Q13164

Q06413

1

phosphorylation

up-regulates

0.766

Bmk1 dramatically enhances the transactivation activity of mef2c by phosphorylating a serine residue at amino acid position 387 in this transcription factor.

SIGNOR-53545

P01189

Q01726

1

binding

up-regulates activity

0.766

Alpha-melanocyte stimulating hormone (alpha-MSH) binds to melanocortin-1 receptor (MC1R) on melanocytes to stimulate pigmentation and modulate various cutaneous inflammatory responses.

SIGNOR-252370

Q9NZJ5

P05198

1

phosphorylation

down-regulates activity

0.766

We now demonstrate a major role for Rheb in inhibiting protein synthesis by enhancing the phosphorylation of eIF2α by protein kinase-like ER kinase (PERK).

SIGNOR-260874

P41221

Q14332

1

binding

down-regulates

0.766

Fz2 was also required for the wnt3a-dependent accumulation of beta-catenin, and wnt5a competed with wnt3a for binding to fz2 in vitro and in intact cells, thereby inhibiting the beta-catenin pathway.

SIGNOR-23441

P55317

P10275

1

transcriptional regulation

down-regulates quantity by repression

0.766

FOXA1 directly inhibits AR expression and thus the transcription of its target genes. FOXA1 inhibits AR gene expression in prostate cancer. oss of FOXA1 may lead to androgen-independent AR signaling and thus castration-resistant prostate cancer progression. Indeed, we have recently reported that FOXA1 is downregulated in CRPC

SIGNOR-251541

Q13309

P46527

1

ubiquitination

down-regulates

0.766

Up-regulation of skp2 by notch signaling enhances proteasome-mediated degradation of the ckis, p27 kip1 and p21 cip1, and causes premature entry into s phase. ;the recognition of p27 by skp2/cks1 of the scfskp2 complex is dictated by cycline/cdk2, providing a high affinity binding site and the phosphorylation of p27 at t187, serving here we provide evidence suggesting that both cdk2/e and phosphorylation of thr(187) on p27 are essential for the recognition of p27 by the scf(skp2/cks1) complex, the ubiquitin-protein isopeptide ligase (e3).

SIGNOR-154194

P01106

P42771

1

transcriptional regulation

down-regulates quantity by repression

0.766

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

SIGNOR-102743

O60674

P10912

1

phosphorylation

up-regulates activity

0.766

Jak2 is then phosphorylated and, in turn, phosphorylates the GHR and the signal transducers and activators of transcription (STAT) protein.

SIGNOR-279198

P53671

P23528

1

phosphorylation

down-regulates activity

0.766

We report here that limk1 and limk2 phosphorylate both cofilin and actin-depolymerizing factor (adf) specifically at ser-3 and exhibit partially distinct substrate specificity when tested using site-directed cofilin mutants as substrates

SIGNOR-105098

P04626

P35222

1

phosphorylation

down-regulates activity

0.766

Second, ErbB2 phosphorylates \u03b2-catenin at Tyr 654, leading to dissociation of the E-cadherin-\u03b2-catenin membrane complex and increased signaling to Wnt target genes such as cyclin D1 ( ).

SIGNOR-279041

Q6UXX9

Q9BXB1

1

binding

up-regulates

0.766

Here we demonstrate that lgr4 and lgr5 bind the r-spondins with high affinity and mediate the potentiation of wnt/betBeta-catenin signaling by enhancing wnt-induced lrp6 phosphorylation.

SIGNOR-174486

P09919

Q99062

1

binding

up-regulates

0.766

The gcsf:gcsf-r complex formed a 2:2 stoichiometry by means of a cross-over interaction between the ig-like domains of gcsf-r and gcsf. the ig-like domain cross-over structure necessary for gcsf-r activation is consistent with previously reported thermodynamic and mutational analyses.

SIGNOR-144743

P01189

P33032

1

binding

up-regulates activity

0.766

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

SIGNOR-268715

P31749

P03372

1

phosphorylation

up-regulates

0.765

Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.

SIGNOR-84963

Q03113

Q9NZN5

1

binding

up-regulates activity

0.765

P115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of G alpha 12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation.

SIGNOR-256522

Q9UNA0

P16112

1

cleavage

down-regulates quantity by destabilization

0.765

Aggrecan Degradation in Human Cartilage Evidence for both Matrix Metalloproteinase and Aggrecanase Activity in Normal, Osteoarthritic, and Rheumatoid Joints|Stromelysin-1 (MMP-3), as well as other MMPs, cleave aggrecan in the interglobular domain between Asn341 and Phe342 to generate a G1 fragment with the COOH terminus VDIPEN341 (11–13). This fragment has been isolated and identified by NH2-terminal sequence analysis from human OA cartilage (11). A second proteolytic activity identified as “aggrecanase” also cleaves aggrecan in the interglobular domain, but between Glu373 and Ala374 (19–24), generating a G1 fragment with a COOH terminus of NITEGE374

SIGNOR-266985

P15498

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.765

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-260581

P38936

P12004

1

binding

down-regulates

0.765

P21 exerts its effect on the cell cycle not only by inhibiting cyclin/cdk complexes, but also by inhibiting proliferating cell nuclear antigen (pcna)

SIGNOR-191939

Q8N726

Q00987

1

relocalization

down-regulates activity

0.765

We propose that p14(arf) increases the binding of p53-mdm2 complexes to chromatin, thereby limiting the access of protein deacetylases to p53.

SIGNOR-192697

P23458

P42226

1

phosphorylation

up-regulates activity

0.765

IL-4-stimulated Stat6 activation is mediated by Jak1 whereas Tyk2 is required for Stat6 activation in IL-13-treated monocytes

SIGNOR-249531

Q9HC29

O43353

1

binding

up-regulates activity

0.765

The function of NOD2 could be to recruit RICK at the plasma membrane to form an active complex able to activate part of the NF-κB pathway. NOD2 induces a membrane recruitment of RICK that is dependent on a CARD-CARD interaction.

SIGNOR-252402

O14920

Q15653

1

phosphorylation

down-regulates

0.765

We described the purification of a 900 kda protein kinase complex, the ikb kinase (ikk), that phosphorylates ikbalfa and ikbbeta at the sites that mediate their ubiquitination and degradation

SIGNOR-52932

P17693

Q99706

1

binding

up-regulates

0.764

Recombinant soluble kir2dl4 binds to cells expressing hla-g but not to cells expressing other hla class i molecules.

SIGNOR-66132

P06239

P20963

1

phosphorylation

up-regulates

0.764

During tcr signaling, lck interacts with numerous molecules, including tcr-zeta. The binding of lck to the tyrosine-phosphorylated zeta chain of the tcr would serve to strengthen the interaction of the associated cd4 and the tcr complex, leading to increased avidity for the antigen-major histocompatibility protein complex.

SIGNOR-41361

P31749

O60343

1

phosphorylation

down-regulates

0.764

Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt

SIGNOR-252594

O43318

P52564

1

phosphorylation

up-regulates activity

0.764

The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination

SIGNOR-109497

P11488

P18545

1

binding

down-regulates activity

0.764

In the dark, PDE6 activity is suppressed by its inhibitory γ-subunit (Pγ). Rhodopsin-catalyzed activation of the G protein, transducin, relieves this inhibition and enhances PDE6 catalysis.

SIGNOR-260008

P12931

Q03135

1

phosphorylation

down-regulates activity

0.764

Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn

SIGNOR-118007

Q8IUD6

O95786

1

ubiquitination

up-regulates activity

0.764

Our data suggest that Riplet/RNF135 is a novel factor of the RIG-I pathway that is involved in the evoking of human innate immunity against RNA virus infection, and activates RIG-I through ubiquitination of its C-terminal region.

SIGNOR-265569

P18075

P27037

1

binding

up-regulates

0.764

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-60237

Q00535

P10636

1

phosphorylation

down-regulates activity

0.763

We found that cdk5 phosphorylated tau(441) at Thr-181, Ser-199, Ser-202, Thr-205, Thr-212, Ser-214, Thr-217, Thr-231, Ser-235, Ser-396, and Ser-404, but not at Ser-262, Ser-400, Thr-403, Ser-409, Ser-413, or Ser-422. GSK-3beta phosphorylated all the cdk5-catalyzed sites above except Ser-235.

SIGNOR-249321

P31749

P98177

1

phosphorylation

down-regulates

0.763

Foxo4 transcription factor, also referred to afx, contains three putative phosphorylation motif sites for protein kinase b (pkb), thr32, ser197, and ser262, and it is proposed that phosphorylated foxo4 stays in the cytosol and is imported to the nucleus through dephosphorylation to induce target gene expression

SIGNOR-252486

P07900

P10275

1

binding

up-regulates activity

0.763

The unliganded AR resides predominately in the cytoplasm as a heteromeric complex with hsp90 and other chaperone proteins. These chaperone proteins maintain AR in a form that is receptive to ligand binding. Regulation of gene expression by androgen-activated AR occurs through receptor nuclear translocation, dimerization, and binding to androgen response elements (AREs) in the DNA of target genes.

SIGNOR-251536

P56704

P34925

1

binding

up-regulates

0.763

Here, we report that ryk directly binds wnt-1 and wnt-3a via its wif domain and is required for the tcf.

SIGNOR-129580

Q14563

Q9HCM2

1

binding

up-regulates activity

0.763

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

SIGNOR-261811

Q96A98

P49190

1

binding

up-regulates

0.763

Subsequent efforts led to the isolation and definition of the primary structure of a novel peptide, referred to as tip39, from bovine hypothalamus and the synthetic peptide was shown to efficiently activate human, rat, and zebrafish pth2 receptors

SIGNOR-115124

Q969H0

P01106

1

ubiquitination

down-regulates quantity

0.762

We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it.

SIGNOR-243545

Q00653

Q01201

1

binding

up-regulates activity

0.762

The map3k14-activated chuk/ikka homodimer phosphorylates nfkb2/p100 associated with relb, inducing its proteolytic processing to nfkb2/p52 and the formation of nf-kappa-b relb-p52 complexes. The nf-kappa-b heterodimeric relb-p52 complex is a transcriptional activator.

SIGNOR-182835

P06493

Q08050

1

phosphorylation

up-regulates

0.762

A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity

SIGNOR-187880

Q13115

P28482

1

dephosphorylation

down-regulates activity

0.762

Dephosphorylation and Inactivation of ERKs|A single protein kinase, MEK, activates ERK2 by phosphorylating threonine 183 and tyrosine 185

SIGNOR-248718

Q14393

Q12866

1

binding

up-regulates

0.762

We also found that gas6 stimulated tyrosine phosphorylation of axl, sky, and mer receptors ectopically expressed in chinese hamster ovary cells. Taken together, these findings suggest that gas6 is a common ligand for axl, sky, and mer, all known members of an axl/sky receptor subfamily.

SIGNOR-44953

Q9Y2U5

Q13163

1

phosphorylation

up-regulates

0.762

Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.

SIGNOR-104634

P30086

P04049

1

binding

down-regulates

0.762

Suppression of raf-1 kinase activity and map kinase by rkip. Rkip binds to raf-1, mek and erk, but not to ras.

SIGNOR-70838

P43405

P29353

1

phosphorylation

up-regulates

0.762

The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2).

SIGNOR-59635

P98172

P54753

1

binding

up-regulates

0.762

The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion.

SIGNOR-52517

P20396

P34981

1

binding

up-regulates activity

0.762

When TRH reaches the pars distalis of the pituitary, it regulates cells that express TRH receptor-1 (TRH-R1), such as the thyrotrophs. These cell types are subject to a multifactorial regulation that determines the extent and specificity of their response to TRH.

SIGNOR-267200

Q5T4W7

O60609

1

binding

up-regulates

0.762

Here, we report the identification of artemin, a novel member of the gdnf family, and demonstrate that it is the ligand for the former orphan receptor gfralpha3-ret. Artemin can also activate the gfralpha1-ret complex.

SIGNOR-63009

Q9UQ26

P20336

1

relocalization

up-regulates activity

0.762

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

SIGNOR-264377

P53350

O95235

1

phosphorylation

up-regulates activity

0.761

MKlp2 treated with Plk1 did not form the regular microtubule bundles seen with MKlp2 only; many single microtubules were seen instead, and the bundles that were formed were loose parallel arrays rather than the dense bundles seen with untreated MKlp2.|We propose that phosphorylation of MKlp2 by Plk1 is necessary for the spatial restriction of Plk1 to the central spindle during anaphase and telophase, and the complex of these two proteins is required for cytokinesis.

SIGNOR-278201

P12272

Q03431

1

binding

up-regulates activity

0.761

Prostate-specific antigen was found to specifically cleave PTHrP 1-141 in a time- and dose-dependent manner.|The preferred PSA cleavage site of PTHrP 1-141 was determined to be at the carboxyl-terminus of phenylalanine 23, consistent with chymotryptic-like enzymatic activity of PSA. Cleavage of PTHrP by PSA completely abolished the ability of PTHrP to stimulate cAMP production.

SIGNOR-270549

Q9UBX5

P15502

1

binding

up-regulates activity

0.761

The binding of tropoelastin fragments to fibulin-5 was directly proportional to their propensity to coacervate. Furthermore, the addition of fibulin-5 to tropoelastin facilitated coacervation. Taken together, the present study shows that fibulin-5 enhances elastic fiber formation in part by improving the self-association properties of tropoelastin.

SIGNOR-252137

Q14449

P06213

1

binding

down-regulates activity

0.761

Growth factor receptor-bound protein 14 (Grb14) interacts with insulin receptor (IR) through the between PH and SH2 (BPS) domain. Grb14-IR complex formation is initiated by insulin stimulation, and the binding event results in the inhibition of insulin signalling.

SIGNOR-264873

P52735

P63000

1

guanine nucleotide exchange factor

up-regulates

0.761

Vav2 activates rac1 / vav2 is an exchange factor for rho family gtpases.

SIGNOR-81645

P12931

P35222

1

phosphorylation

down-regulates activity

0.761

beta-catenin is a good substrate of pp60c- srctyrosine kinase in vitro;this kinase modifies specifically tyr-86 and tyr-654although consistently detected, this negative effect of tyr-86 phosphorylation on tbp binding was clearly less important than the positive effect observed after tyr-654 phosphorylation.

SIGNOR-106458

O94782

Q9BXW9

1

deubiquitination

down-regulates activity

0.761

The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2|The level of monoubiquitinated FANCD2 protein increases in response to various types of DNA damage in mammalian cells

SIGNOR-263273

Q9UM11

Q16763

1

binding

up-regulates activity

0.761

Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity

SIGNOR-265081

Q9ULV8

P00533

1

polyubiquitination

down-regulates quantity by destabilization

0.761

In summary, we have shown that CBLC and AIP4 can interact and that these two E3 ligases could contribute to down-regulate EGFR signaling by ubiquitination.

SIGNOR-272605

Q9BXH1

Q07817

1

binding

down-regulates activity

0.761

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

SIGNOR-133811

P18031

P00533

2

dephosphorylation

down-regulates activity

0.76

We have shown previously that amino acid residues flanking the phosphotyrosine are important for efficient PTP1 catalysis (Table 1 and Refs. 9, 10, and 17). For example, the kcat/Km value for the undecapeptide, EGFR988-989 (epidermal growth factor autophosphorylation site Tyr992, residues 988-998) (Asp-Ala-Asp-Glu-pTyr-Leu-Ile-Pro-Gln-Gln-Gly) is 3220-fold higher than that of phosphotyrosine (Table 1). We further demonstrated that a minimum of six amino acid residues are required for the most efficient PTP1 binding and catalysis.

SIGNOR-248407

P15018

P42702

1

binding

up-regulates

0.76

Lif binds at low-affinity to lifr, the structure of which is closely related to that of gp130 (42). Lifr then becomes heterodimerized with gp130 to form the high-affinity and signaling-competent complex (43). Osm utilizes this type of heterodimer, i.e. the lifr/gp130 complex (43, 44).

SIGNOR-139102

Q9UBE8

Q9UJU2

1

phosphorylation

down-regulates

0.76

Regulation of lymphoid enhancer factor 1/t-cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in wnt/beta-catenin signaling.Nlk phosphorylates lef-1/tcf on two serine/threonine residues located in its central region. Mutation of both residues to alanine enhanced lef-1 transcriptional activity and rendered it resistant to inhibition by nlk.

SIGNOR-97812

P00533

Q13480

1

phosphorylation

up-regulates

0.76

Gab-1 is a multisubstrate docking protein downstream in the signaling pathways of different receptor tyrosine kinases, including the epidermal growth factor receptor (egfr)the entire protein was phosphorylated by regfr at eight tyrosine residues (y285, y373, y406, y447, y472, y619, y657, and y689).

SIGNOR-236400

Q8IW41

P04637

1

phosphorylation

up-regulates

0.76

Furthermore, we show that prak activates p53 by direct phosphorylation. prak phosphorylates p53 at ser37

SIGNOR-152847

P07900

P29474

1

binding

up-regulates

0.76

The binding of hsp90 to enos enhances the activation of enos.

SIGNOR-57211

O60346

P31749

1

dephosphorylation

down-regulates

0.76

Here, we identify a protein_ phosphatase, ph domain leucine-rich repeat protein_ phosphatase_ (phlpp), that specifically_ dephosphorylates_ the hydrophobic motif of_ akt_ (ser473 in akt1), triggering_ apoptosis_ and suppressing_ tumor_ growth.

SIGNOR-252601

P12931

P18206

1

phosphorylation

down-regulates activity

0.76

The phosphorylation of vinculin on tyrosine residues 100 and 1065, mediated by SRC kinases, affects cell spreadingWhen phosphorylated, the vinculin tail exhibited significantly less binding to the vinculin head domain than the unphosphorylated tail.

SIGNOR-247424

Q13191

P00533

1

polyubiquitination

down-regulates quantity by destabilization

0.76

Here we describe that overexpression of cbl-b, a homologue of the c-cbl protooncogene, inhibits EGFR-induced apoptosis in MDA-MB-468 breast cancer cells. Overexpression of cbl-b results in a shortened duration of EGFR activation upon EGF stimulation. This is demonstrated by decreased amounts of phosphorylated EGFR as well as by inhibition of multiple downstream signaling pathways. The inhibition of signaling by cbl-b results from increased ubiquitination and degradation of the activated EGFR.

SIGNOR-272934

Q13489

P55211

1

binding

down-regulates

0.76

Xiap, birc2 and birc3 were shown to bind pro-casp9. Iaps may suppress casp9 by direct auto-activation of pro-caspase-11

SIGNOR-56481

Q16690

P27361

1

dephosphorylation

down-regulates

0.76

Extracellular regulated kinases (erk) 1 and erk2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase vhr. A novel role in down-regulating the erk pathway

SIGNOR-67358

P61586

P15311

1

phosphorylation

up-regulates activity

0.76

Rev-erbα interacted with OPHN-1, promoted RhoA activity and phosphorylation of ERM. etection of phosphorylated ezrin (Thr567)/radixin (Thr564)/moesin (Thr558)(p-ERM) in Rev-erbαfl/flCre− and Rev-erbαfl/flPF4Cre+ platelets using phospho-specific antibodies.

SIGNOR-268429

P33151

P35222

1

binding

up-regulates activity

0.76

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265867

P04090

Q9HBX9

1

binding

up-regulates

0.76

Lgr7 and lgr8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (camp)-dependent pathway

SIGNOR-114549

Q9H257

O95999

1

binding

up-regulates quantity by stabilization

0.76

To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB.

SIGNOR-257602

P12931

P10275

1

phosphorylation

up-regulates activity

0.76

In addition to the ability of Src to promotes castration resistant progression and AR activation, Src is involved in regulating prostate cancer cell migration, invasion, and metastasis and affects bone remodeling.|These data suggest that downstream of cell surface receptors, Ack1 mediates AR tyrosine phosphorylation at Tyr 267 and Src mediates AR tyrosine phosphorylation at Tyr 534.

SIGNOR-278168

P00533

P18031

2

phosphorylation

up-regulates

0.76

After binding to egfr, ptp1b becomes tyrosine-phosphorylated at tyr-66 phosphorylation of ptp1b by egfr enhances its catalytic activity

SIGNOR-52950

P00519

P46108

1

phosphorylation

down-regulates activity

0.76

Negative regulation of crk by abl is essential for the antitumorigenic effects of ephrinb2,similar pathways may operate for crkl

SIGNOR-175135

Q96S44

P04637

1

phosphorylation

up-regulates

0.76

The intrinsic transcriptional activity of p53 was up-regulated by a transient transfection of prpk to cos-7 cells. Prpk was shown to bind to p53 and to phosphorylate p53 at ser-15.

SIGNOR-157471

P0DP23

P29474

1

binding

up-regulates activity

0.76

Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer

SIGNOR-251615

P28482

P42229

1

phosphorylation

up-regulates

0.76

Gh treatment of chinese hamster ovary cells stably transfected with the gh receptor (choa cells) led to rapid and transient activation of both stat5a and erk1 and erk2. these observations show, for the first time, direct physical interaction between erk and stat5a and also clearly identify serine 780 as a target for erk.

SIGNOR-66239

Q8TCY5

Q01718

1

binding

up-regulates activity

0.76

We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling.We have previously identified MRAP as an accessory protein for MC2R, required for receptor trafficking to the cell surface and the formation of a functional MC2R. Here we have identified MRAP2 as a homologue of MRAP. Like MRAP, MRAP2 is able to support MC2R cell-surface expression, producing a functional ACTH-responsive receptor.

SIGNOR-252360

P28482

Q15418

1

phosphorylation

up-regulates activity

0.759

Several lines of evidence indicate that the mapkap-k1 isoforms are also activated by mapks in vivo via the ras-dependent protein kinase cascade that is triggered by growth factors or tumor-promoting phorbol esters, such as phorbol 12-myristate 13-acetate (pma). here we identify six sites in mapkap-k1a that become phosphorylated in transfected cos-1 cells. The inactive form of mapkap-k1a in unstimulated cells is partially phosphorylated at ser222 and ser733. Stimulation with phorbol 12-myristate 13-acetate induces the phosphorylation of thr360, ser364, thr574, and ser381 and increases the phosphorylation of ser222 and ser733.

SIGNOR-219308

Q04771

Q99717

1

phosphorylation

up-regulates

0.759

Bmp7 stimulated phosphorylation of endogenous smad1 and 5, formation of complexes with smad4 and induced the promoter for the homeobox gene, tlx2

SIGNOR-60171

P45983

O43521

1

phosphorylation

down-regulates quantity by destabilization

0.759

Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination.

SIGNOR-250132

P06493

Q9NQS7

1

phosphorylation

up-regulates

0.759

Here, we report that cdk1 phosphorylates thr 59 and thr 388 on inner centromere protein (incenp), which regulates the localization and kinase activity of aurora-b from prophase to metaphase. The replacement of endogenous incenp with t388a resulted in the delay of progression from metaphase to anaphase.

SIGNOR-143387

Q8NFZ4

P78352

1

relocalization

up-regulates activity

0.759

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

SIGNOR-264193

P12931

O00401

1

phosphorylation

up-regulates activity

0.759

An Src family tyrosine kinase, v-Src, phosphorylates and activates N-WASP.

SIGNOR-279487

P48357

P40763

1

binding

up-regulates activity

0.759

LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2.

SIGNOR-263495

P01189

P41968

1

binding

up-regulates activity

0.759

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

SIGNOR-268705

Q9BYF1

P01019

1

cleavage

up-regulates activity

0.759

The ACE2 hydrolytic activity is dependent on the C terminus sequence of the substrate, which is evident from the data with the angiotensin peptides. After 2 h, ACE2 hydrolyzes Ang I partially and Ang II completely, although there is no hydrolysis of angiotensin 1–9, angiotensin 1–7, and angiotensin 1–5, which possess the same N terminus.

SIGNOR-256315

P35222

P36402

1

binding

up-regulates

0.759

Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation (fig 2?2),), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1

SIGNOR-134282

P33076

P48382

1

binding

up-regulates activity

0.759

RFX5 can activate transcription only in cooperation with CIITA. RFX5 and CIITA associate to form a complex capable of activating transcription from class II major histocompatibility complex promoters. In this complex, promoter specificity is determined by the DNA binding domain of RFX5 and the general transcription apparatus is recruited by the acidic activation domain of CIITA.

SIGNOR-240980

P01112

P42338

1

binding

up-regulates activity

0.759

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner.

SIGNOR-175189

O95886

P78352

1

binding

up-regulates activity

0.758

SAPAPs are specifically expressed in neuronal cells and enriched in the PSD fraction. SAPAPs induce the enrichment of PSD-95/SAP90 to the plasma membrane in transfected cells. Thus, SAPAPs may have a potential activity to maintain the structure of PSD by concentrating its components to the membrane area.

SIGNOR-264211

P06239

O43561

1

phosphorylation

up-regulates

0.758

Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation.

SIGNOR-149182