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
P41159	P48357	1	binding	up-regulates	0.814	Both ob-ra and ob-rb bind leptin with the same affinity, whereas only ob-rb can elicit intracellular response	SIGNOR-55656
Q14145	Q16236	1	ubiquitination	down-regulates quantity	0.813	Keap1 is a substrate receptor of a Cul3-RING ubiquitin ligase (CRL3) that, in physiological conditions, constitutively binds and targets Nrf2 for degradation	SIGNOR-259335
Q9H211	P49736	1	binding	up-regulates activity	0.813	Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1.	SIGNOR-261681
P35568	P27986	1	binding	up-regulates activity	0.813	Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2).	SIGNOR-175668
Q7Z4H7	Q8NHV4	1	binding	up-regulates activity	0.813	FAM29A recruits NEDD1 to spindle MTs. Ectopically expressed NEDD1 and FAM29A interact with each other.	SIGNOR-261421
P18509	P32241	1	binding	up-regulates	0.813	Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip).	SIGNOR-116066
P21359	P01112	1	gtpase-activating protein	down-regulates activity	0.813	Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation	SIGNOR-204357
Q92878	Q13315	1	binding	up-regulates	0.813	One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase.	SIGNOR-175053
O60674	P19235	1	phosphorylation	up-regulates activity	0.812	JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2	SIGNOR-251351
P53350	Q99661	1	phosphorylation	up-regulates activity	0.812	Active PLK1, in turn, phosphorylates MCAK at Ser715 which promotes its microtubule depolymerase activity essential for faithful chromosome segregation.	SIGNOR-276931
P35236	P28482	2	dephosphorylation	down-regulates activity	0.812	HePTP efficiently dephosphorylated active ERK2 on the tyrosine residue in the activation loop in vitro. Together, these data identify ERK2 as a specific and direct target of HePTP and are consistent with a model in which HePTP negatively regulates ERK2 activity as part of a feedback mechanism	SIGNOR-248484
P28482	P35236	2	phosphorylation	up-regulates activity	0.812	First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.\|	SIGNOR-249436
Q9BXW9	P51587	1	binding	up-regulates activity	0.812	Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction	SIGNOR-263238
P06241	P22681	1	phosphorylation	up-regulates activity	0.812	Fyn associates with cbl and phosphorylates tyrosine 731 in cbl, a binding site for phosphatidylinositol 3-kinasecbl represents a substrate for src-like kinases that are activated in response to the engagement of cell surface receptors, and that src-like kinases are responsible for the phosphorylation of a tyrosine residue in cbl that may regulate activation of phosphatidylinositol 3-kinase	SIGNOR-63968
Q9Y5X1	P50570	1	binding	up-regulates	0.812	Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes.	SIGNOR-133976
P36897	P84022	1	phosphorylation	up-regulates activity	0.812	A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus	SIGNOR-235380
P20827	Q15375	1	binding	up-regulates	0.812	The best known function is their role in the guidance of migration of axons and cells in the nervous system through repulsive interactions	SIGNOR-56965
P46940	P60953	1	binding	down-regulates activity	0.811	Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.	SIGNOR-261888
P52798	P54756	1	binding	up-regulates	0.811	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52430
P52565	P63000	1	guanine nucleotide exchange factor	down-regulates activity	0.811	Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma.	SIGNOR-268436
Q8WZA2	P61224	1	guanine nucleotide exchange factor	up-regulates activity	0.811	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263955
P31749	Q00987	1	phosphorylation	up-regulates quantity by stabilization	0.811	Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.	SIGNOR-116270
Q15303	P42229	1	phosphorylation	up-regulates activity	0.811	ERBB4 directly activates STAT5A, in part, through phosphorylation of STAT5A at the regulatory Tyr-694.\|ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events.	SIGNOR-279711
P20827	Q9UF33	1	binding	up-regulates	0.811	Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity	SIGNOR-56962
P78352	Q12879	1	relocalization	up-regulates activity	0.811	The PDZ domains of PSD-95 and related proteins interact with the COOH-terminal sequences of K+channels and NMDA2 receptors (3). By these interactions, PSD-95 may mediate the clustering of K+ channels and NMDA receptors at synapses.	SIGNOR-264194
P20827	P54756	1	binding	up-regulates	0.811	Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity	SIGNOR-56910
Q9BXM7	O95140	1	phosphorylation	down-regulates quantity	0.81	If PINK1 is responsible for the degradation of Mfn2, then silencing PINK1 should induce mitochondrial fusion by upregulating Mfn2 expression.\|We show that downregulation of Mfn2 is induced by proteasomal degradation triggered by PINK1, which phosphorylates Mfn2 at S442.	SIGNOR-278208
P00533	P27986	1	binding	up-regulates	0.81	The egf-r coimmunoprecipitated with p85 alpha	SIGNOR-121959
Q96EB6	Q12778	1	deacetylation	down-regulates quantity by destabilization	0.81	SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3	SIGNOR-217975
P61586	Q13464	1	binding	up-regulates activity	0.81	Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization.	SIGNOR-199542
Q13253	P12643	1	binding	down-regulates	0.81	Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides	SIGNOR-100657
P48061	P61073	1	binding	up-regulates	0.809	To study the role of the sdf-1/cxcr4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cdna encoding sdf-1 of the lower vertebrate xenopus laevis (xsdf-1). Recombinant xsdf-1 was produced in insect cells, purified, and functionally characterized. Although xsdf-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)sdf-1alpha in terms of activating both x. laevis cxcr4 and hcxcr4. Thus, both xsdf-1 and hsdf-1alpha promoted cxcr4-mediated activation of heterotrimeric g(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells.	SIGNOR-115029
P49137	P04792	1	phosphorylation	down-regulates	0.809	Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.	SIGNOR-94021
P23458	Q13651	2	phosphorylation	up-regulates activity	0.809	Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3).	SIGNOR-251338
Q96AX9	Q9Y219	1	ubiquitination	up-regulates	0.809	Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2.	SIGNOR-137922
Q8N2C7	Q8IZF0	1	binding	up-regulates activity	0.809	The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80.	SIGNOR-265184
Q13315	P15927	1	phosphorylation	up-regulates	0.809	Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro.	SIGNOR-121861
Q13651	P23458	2	binding	up-regulates activity	0.809	Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5.	SIGNOR-68010
Q9P2Y5	Q8NEB9	1	binding	up-regulates activity	0.809	Although both human atg14 and uvrag interact with beclin 1 and vps34.	SIGNOR-181554
P12931	P49023	1	phosphorylation	up-regulates activity	0.808	Here, we demonstrate that Src kinase directly phosphorylates Y88 paxillin\|In this study, we also show how pY88 paxillin transduces a signal to activate Akt	SIGNOR-263977
P78527	P49917	1	phosphorylation	down-regulates	0.808	Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability.	SIGNOR-125877
P49768	P35222	1	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
Q92585	Q04721	1	binding	up-regulates	0.808	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1.	SIGNOR-84835
Q13323	Q07817	1	binding	down-regulates	0.808	We have identified a novel cellular protein, bik, that interacts with the cellular survival-promoting proteins, bcl-2 and bcl-xl in transient transfection assays, bik promotes cell death in a manner similar to the death-promoting members of the bcl-2 family, bax and bak.	SIGNOR-26453
P28482	Q9BY84	1	phosphorylation	up-regulates quantity by stabilization	0.808	Phosphorylation of Ser-446 determines stability of MKP-7.\|We also determined that MKP-7 phosphorylated at Ser-446 has a longer half-life than unphosphorylated form of the wild type protein, as does a phospho-mimic mutant of MKP-7. These results indicate that activation of the ERK pathway strongly blocks JNK activation through stabilization of MKP-7 mediated by phosphorylation.	SIGNOR-249389
Q9GZV5	Q15562	1	binding	up-regulates	0.808	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201382
Q92854	O43157	1	binding	up-regulates	0.808	Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors.	SIGNOR-92201
Q66GS9	Q9HC77	1	binding	up-regulates activity	0.808	In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation.	SIGNOR-269677
O43561	P19174	1	binding	up-regulates activity	0.808	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-246060
P40424	P14653	1	binding	up-regulates activity	0.807	Pbx1 and exd act as cofactors that enhance the DNA binding specificity of Hox proteins. The structure of the HoxB1Pbx1DNA ternary complex shows that HoxB1 and Pbx1 bind to overlapping binding sites located on opposite faces of the DNA.	SIGNOR-241219
P48730	O15534	1	phosphorylation	down-regulates quantity by destabilization	0.807	Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2).	SIGNOR-268001
P11802	P28749	1	phosphorylation	up-regulates activity	0.807	Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.	SIGNOR-250764
P08069	Q92569	1	binding	up-regulates	0.807	Moreover, we found that the insulin-like growth factor-1 receptor (igf-ir) bound to p55pik;the interaction occurred at the receptor tyrosine 1316 and involved both p55pik sh2 domains.	SIGNOR-52683
P01033	P14780	1	binding	down-regulates activity	0.807	Tissue inhibitor of metalloproteinase (TIMP-1) is an inhibitor of MMP-9 that binds to MMP-9 precursors and to the active form.	SIGNOR-278116
P18075	Q04771	1	binding	up-regulates	0.807	Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2	SIGNOR-236913
P04626	P29353	1	binding	up-regulates	0.807	Shc interacts with and is an excellent substrate for erbb2 and appears to play an important role in mitogenic signaling through this receptor tyrosine kinase	SIGNOR-65579
Q9NRD5	P42262	1	binding	up-regulates activity	0.807	RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above.	SIGNOR-264046
Q92793	P10242	1	binding	up-regulates activity	0.807	the nuclear co-activator CREB binding protein (CBP). This protein interacts directly with both c-Myb and v-Myb and potentiates Myb-specific transcription	SIGNOR-240994
P43405	Q8WV28	1	phosphorylation	up-regulates	0.806	The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex.	SIGNOR-96044
Q92974	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.806	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-260529
O43921	Q15375	1	binding	up-regulates	0.806	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-52206
P15923	P15172	1	binding	up-regulates activity	0.806	In addition we demonstrate that myod, in conjunction with e12/e47-like proteins, is functioning as a regulatory nodal point for activation of several other downstream muscle regulators.	SIGNOR-20540
Q15726	Q969F8	1	binding	up-regulates	0.806	Here we show that kiss-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan g-protein-coupled receptor (hot7t175) and have named 'metastin'	SIGNOR-108480
O14640	P35222	1	binding	up-regulates activity	0.806	Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation 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-134285
O60674	P42224	1	phosphorylation	up-regulates	0.806	Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation.	SIGNOR-235709
Q9NS23	Q13043	1	binding	up-regulates	0.806	Rassf1a and mst1 co-exist as a complex localizing at microtubules throughout the cell cycle, of which the rassf1a mst1 interaction is stimulatory to the mst1 kinase activity.	SIGNOR-197744
P03971	Q16671	1	binding	up-regulates	0.806	The results point to anti-m?llerian Hormone (amh) being the most likely candidate ligand for c14.	SIGNOR-36215
Q9BXL7	Q9UDY8	1	binding	up-regulates	0.805	The carboxy-terminal part of the bcl10 card and a short stretch of 13 amino acids following the card are required for constitutive binding to malt1.	SIGNOR-167393
P28562	Q16539	2	dephosphorylation	down-regulates activity	0.805	The activity of MAPKs can be also regulated by a family of DUSPs (dual-specificity phosphatases)/MKPs (MAPK phosphatases), which dephosphorylate both phosphotyrosine and phosphothreonine residues MKPs 1, 4, 5 and 7 can dephosphorylate p38_ and p38_ in addition to JNK MAPKs. Importantly, some MKPs are transcriptionally up-regulated by stimuli that activate MAPK signalling, and are thought to play an important role limiting the extent of MAPK activation	SIGNOR-166571
P28562	P28482	2	dephosphorylation	down-regulates activity	0.805	We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively	SIGNOR-248465
P19438	Q15628	1	binding	up-regulates activity	0.805	We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed.	SIGNOR-32739
P04114	P01130	1	binding	up-regulates	0.805	In the case of ldl, binding of apolipoprotein b (apob) to the ldl-r18-20 and proteoglycans17 21 initiates plasma clearance and lipoprotein degradation	SIGNOR-87035
Q96PU5	P84022	1	ubiquitination	down-regulates activity	0.805	Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation	SIGNOR-232104
P28482	P28562	2	phosphorylation	down-regulates	0.805	The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain	SIGNOR-141593
P31749	P35222	1	phosphorylation	up-regulates	0.805	Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity\|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo.	SIGNOR-252499
Q86UR5	P20336	1	relocalization	up-regulates activity	0.805	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-264381
O15444	P51686	1	binding	up-regulates	0.805	Ccr9 is a specific receptor for the beta-chemokine teck/ccl25.	SIGNOR-104902
Q9BY84	Q16539	1	dephosphorylation	down-regulates	0.805	Mkp-7 binds to and inactivates p38 mapk and jnk/sapk, but not erk inhibited by dual specificity phosphatases, such as dusp1, dusp10, and dusp16(uniprot)	SIGNOR-108233
P11940	P06730	1	binding	up-regulates activity	0.805	The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling	SIGNOR-260968
Q16539	P28562	2	binding	up-regulates activity	0.805	Here we have shown that mkp-1 associates directly with p38 map kinase both in vivo and in vitro, and that this interaction enhances the catalytic activity of mkp-1. The point mutation asp-316-->asn in the c-terminus of p38, analogous to the erk2 (extracellular-signal-regulated kinase 2) sevenmaker mutation, dramatically decreases its binding to mkp-1 and substantially compromises its stimulatory effect on the catalytic activity of this phosphatase.	SIGNOR-83752
P00746	P00751	1	cleavage	up-regulates activity	0.804	The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb	SIGNOR-263488
P18075	Q13873	1	binding	up-regulates	0.804	In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7.	SIGNOR-30512
O43561	P62993	1	binding	up-regulates	0.804	Phosphorylated tyrosines 171, 191, and 226 [in LAT] bind to the SH2 domains of the Grb2 family of adaptor proteins and must be present for optimal signalling	SIGNOR-251520
P43403	Q13094	1	phosphorylation	up-regulates	0.804	Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient.	SIGNOR-46859
P53350	P30307	1	phosphorylation	up-regulates	0.804	The nuclear accumulation of active m-phase promoting factor (mpf) during prophase is thought to be essential for coordinating m-phase events in vertebrate cells. The protein phosphatase cdc25c, an activator of mpf, enters the nucleus to keep mpf active in the nucleus during prophase. these results suggest that plk1 phosphorylates cdc25c on ser198 and regulates nuclear translocation of cdc25c during prophase.	SIGNOR-115993
P52797	P29320	1	binding	up-regulates	0.804	The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells.	SIGNOR-52312
P12931	P56945	1	phosphorylation	up-regulates activity	0.803	Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src\|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs	SIGNOR-246393
Q14258	O95786	1	ubiquitination	up-regulates activity	0.803	Lys63 linked polyubiquitination of RIG-I at Lys 172 catalyzed by TRIM25 is an important step for RIG-I activation.	SIGNOR-278730
Q9Y4P1	Q9GZQ8	1	cleavage	up-regulates	0.803	Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.	SIGNOR-125449
O95271	P54274	1	ADP-ribosylation	down-regulates activity	0.803	Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA.	SIGNOR-263377
P35568	P62993	1	binding	up-regulates activity	0.803	Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis.	SIGNOR-236614
Q9Y2H0	P78352	1	binding	up-regulates activity	0.803	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-264212
Q2MKA7	Q9ULT6	1	relocalization	down-regulates quantity	0.803	Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3.	SIGNOR-260113
Q96EB6	P04637	1	deacetylation	down-regulates	0.803	Sirt1 has been shown to regulate cell fate in part by deacetylating the p53 protein at lysine 382 and inhibiting p53-mediated transcriptional activation and apoptosis.	SIGNOR-182515
Q8N2C7	Q9P2D8	1	binding	up-regulates activity	0.803	The NALCN complex in the brain consists of NALCN, UNC80 and UNC79. UNC80 directly associates with NALCN and UNC79 forms part of the complex by its interaction with UNC80.	SIGNOR-265183
Q15465	Q9Y6C5	1	binding	down-regulates activity	0.803	Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.	SIGNOR-217776
P09429	Q15109	1	binding	up-regulates activity	0.803	HMGB1 is known to influence cellular responses within the nervous system via two distinct receptor families; the Receptor for Advanced Glycation End-products (RAGE) and Toll-like receptors (TLRs)	SIGNOR-252059
Q9UQB8	Q9Y6W5	1	binding	up-regulates activity	0.802	Here we demonstrate that IRSp53, a substrate for insulin receptor with unknown function, is the 'missing link' between Rac and WAVE. Activated Rac binds to the amino terminus of IRSp53, and carboxy-terminal Src-homology-3 domain of IRSp53 binds to WAVE to form a trimolecular complex. From studies of ectopic expression, we found that IRSp53 is essential for Rac to induce membrane ruffling, probably because it recruits WAVE, which stimulates actin polymerization mediated by the Arp2/3 complex.	SIGNOR-265556
P36896	Q15796	1	phosphorylation	up-regulates activity	0.802	ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway	SIGNOR-235157
P09429	O00206	1	binding	up-regulates activity	0.802	Here we show that Toll-like receptor 4 (TLR4), a pivotal receptor for activation of innate immunity and cytokine release, is required for HMGB1-dependent activation of macrophage TNF release.	SIGNOR-252057

P41159

P48357

1

binding

up-regulates

0.814

Both ob-ra and ob-rb bind leptin with the same affinity, whereas only ob-rb can elicit intracellular response

SIGNOR-55656

Q14145

Q16236

1

ubiquitination

down-regulates quantity

0.813

Keap1 is a substrate receptor of a Cul3-RING ubiquitin ligase (CRL3) that, in physiological conditions, constitutively binds and targets Nrf2 for degradation

SIGNOR-259335

Q9H211

P49736

1

binding

up-regulates activity

0.813

Chromosomal DNA replication requires the recruitment of the six-subunit minichromosome maintenance (Mcm) complex to chromatin through the action of Cdc6 and Cdt1.

SIGNOR-261681

P35568

P27986

1

binding

up-regulates activity

0.813

Phosphorylated irs then acts as docking site to recruit and activate phosphatidylinositol-3-kinase (pi3k) which phosphorylates membrane phospholipids, generating phosphoinositide-3,4,5-triphosphate (pip3) from phosphoinositide-4,5-biphosphate (pip2).

SIGNOR-175668

Q7Z4H7

Q8NHV4

1

binding

up-regulates activity

0.813

FAM29A recruits NEDD1 to spindle MTs. Ectopically expressed NEDD1 and FAM29A interact with each other.

SIGNOR-261421

P18509

P32241

1

binding

up-regulates

0.813

Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip).

SIGNOR-116066

P21359

P01112

1

gtpase-activating protein

down-regulates activity

0.813

Nf1encodes neurofibromin, a protein with multiple functions including ras inactivation (ras gtpase-activating protein or rasgap) and adenylyl cyclase (ac) activation

SIGNOR-204357

Q92878

Q13315

1

binding

up-regulates

0.813

One of the earliest events is recruitment and activation of the atm at the damaged dna sites through the mre11rad50nbs1 (mrn) sensor complex. . the mre11/rad50/nbs1 (mrn) complex maintains genomic stability by bridging dna ends and initiating dna damage signaling through activation of the atm kinase.

SIGNOR-175053

O60674

P19235

1

phosphorylation

up-regulates activity

0.812

JAK2 in turn phosphorylates several tyrosine residues on the EpoR-cytosolic domain and probably on JAK2 itself that serve as docking sites for SH2 or protein tyrosine binding domains of downstream signal transduction proteins such as STAT5, phosphatidylinositol 3-kinase, Shc, and tyrosine phosphatases SHP1 and SHP2

SIGNOR-251351

P53350

Q99661

1

phosphorylation

up-regulates activity

0.812

Active PLK1, in turn, phosphorylates MCAK at Ser715 which promotes its microtubule depolymerase activity essential for faithful chromosome segregation.

SIGNOR-276931

P35236

P28482

2

dephosphorylation

down-regulates activity

0.812

HePTP efficiently dephosphorylated active ERK2 on the tyrosine residue in the activation loop in vitro. Together, these data identify ERK2 as a specific and direct target of HePTP and are consistent with a model in which HePTP negatively regulates ERK2 activity as part of a feedback mechanism

SIGNOR-248484

P28482

P35236

2

phosphorylation

up-regulates activity

0.812

First, Erk phosphorylates HePTP at residues Thr45 and Ser72. Second, HePTP dephosphorylates Erk at PTyr185.|

SIGNOR-249436

Q9BXW9

P51587

1

binding

up-regulates activity

0.812

Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction

SIGNOR-263238

P06241

P22681

1

phosphorylation

up-regulates activity

0.812

Fyn associates with cbl and phosphorylates tyrosine 731 in cbl, a binding site for phosphatidylinositol 3-kinasecbl represents a substrate for src-like kinases that are activated in response to the engagement of cell surface receptors, and that src-like kinases are responsible for the phosphorylation of a tyrosine residue in cbl that may regulate activation of phosphatidylinositol 3-kinase

SIGNOR-63968

Q9Y5X1

P50570

1

binding

up-regulates

0.812

Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes.

SIGNOR-133976

P36897

P84022

1

phosphorylation

up-regulates activity

0.812

A major event leading to Smad3 activation is the TGF-beta-induced, TbetaRI-mediated phosphorylation at two C-terminal serine residues, Ser-423 and Ser-425, which triggers dissociation of Smad3 from its receptors to form a complex with Smad4 and accumulate in the nucleus

SIGNOR-235380

P20827

Q15375

1

binding

up-regulates

0.812

The best known function is their role in the guidance of migration of axons and cells in the nervous system through repulsive interactions

SIGNOR-56965

P46940

P60953

1

binding

down-regulates activity

0.811

Although the name implies that it functions as a GTPase-activating protein, IQGAP1 actually stabilizes Cdc42 and Rac1 in the active, GTP-bound form (5, 8, 17). Thus, IQGAP1 acts as an “anti-GTPase-activating protein” for Cdc42 and Rac1, with marked effects on the cytoskeleton.

SIGNOR-261888

P52798

P54756

1

binding

up-regulates

0.811

Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor

SIGNOR-52430

P52565

P63000

1

guanine nucleotide exchange factor

down-regulates activity

0.811

Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma.

SIGNOR-268436

Q8WZA2

P61224

1

guanine nucleotide exchange factor

up-regulates activity

0.811

Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.

SIGNOR-263955

P31749

Q00987

1

phosphorylation

up-regulates quantity by stabilization

0.811

Mitogen-induced activation of phosphatidylinositol 3-kinase (pi3-kinase) and its downstream target, the akt/pkb serine-threonine kinase, results in phosphorylation of mdm2 on serine 166 and serine 186. Phosphorylation on these sites is necessary for translocation of mdm2 from the cytoplasm into the nucleus.Both akt expression and serum treatment induced phosphorylation of mdm2 at ser186.

SIGNOR-116270

Q15303

P42229

1

phosphorylation

up-regulates activity

0.811

ERBB4 directly activates STAT5A, in part, through phosphorylation of STAT5A at the regulatory Tyr-694.|ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events.

SIGNOR-279711

P20827

Q9UF33

1

binding

up-regulates

0.811

Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity

SIGNOR-56962

P78352

Q12879

1

relocalization

up-regulates activity

0.811

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

SIGNOR-264194

P20827

P54756

1

binding

up-regulates

0.811

Ephrin-a1 binds and activates the tyrosine kinase activity of eph-a2, and has a dissociation constant of 20_30 nm. ephrin-a1 interacts with all the other epha subclass receptors as well, although with different affinity

SIGNOR-56910

Q9BXM7

O95140

1

phosphorylation

down-regulates quantity

0.81

If PINK1 is responsible for the degradation of Mfn2, then silencing PINK1 should induce mitochondrial fusion by upregulating Mfn2 expression.|We show that downregulation of Mfn2 is induced by proteasomal degradation triggered by PINK1, which phosphorylates Mfn2 at S442.

SIGNOR-278208

P00533

P27986

1

binding

up-regulates

0.81

The egf-r coimmunoprecipitated with p85 alpha

SIGNOR-121959

Q96EB6

Q12778

1

deacetylation

down-regulates quantity by destabilization

0.81

SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3

SIGNOR-217975

P61586

Q13464

1

binding

up-regulates activity

0.81

Planar cell polarity (pcp) signalling triggers activation of the small gtpases rhoa and rac1, which in turn activate rho kinase (rock) and jun-n-terminal kinase (jnk), respectively, leading to actin polymerization and microtubule stabilization.

SIGNOR-199542

Q13253

P12643

1

binding

down-regulates

0.81

Noggin acts by binding bmps, thus preventing them from binding to their receptors (180). Noggin binds with various degrees of affinity bmp-2, -4, -5, -6, and -7, gdf-5, gdf-6, and vg1, but not other members of the tgf- family of peptides

SIGNOR-100657

P48061

P61073

1

binding

up-regulates

0.809

To study the role of the sdf-1/cxcr4-chemokine/receptor system as a regulator of vertebrate development, we isolated and characterized a cdna encoding sdf-1 of the lower vertebrate xenopus laevis (xsdf-1). Recombinant xsdf-1 was produced in insect cells, purified, and functionally characterized. Although xsdf-1 is only 64-66% identical with its mammalian counterparts, it is indistinguishable from human (h)sdf-1alpha in terms of activating both x. laevis cxcr4 and hcxcr4. Thus, both xsdf-1 and hsdf-1alpha promoted cxcr4-mediated activation of heterotrimeric g(i2) in a cell-free system and induced release of intracellular calcium ions in and chemotaxis of intact lymphoblastic cells.

SIGNOR-115029

P49137

P04792

1

phosphorylation

down-regulates

0.809

Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.

SIGNOR-94021

P23458

Q13651

2

phosphorylation

up-regulates activity

0.809

Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3).

SIGNOR-251338

Q96AX9

Q9Y219

1

ubiquitination

up-regulates

0.809

Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2.

SIGNOR-137922

Q8N2C7

Q8IZF0

1

binding

up-regulates activity

0.809

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

SIGNOR-265184

Q13315

P15927

1

phosphorylation

up-regulates

0.809

Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro.

SIGNOR-121861

Q13651

P23458

2

binding

up-regulates activity

0.809

Specifically, il-10 effects the activation of jak1 (associated with the il-10 receptor alpha Chain) and tyk2 (associated with the il-10 receptor beta Chain) and induces the activation of stat1, stat3, and, in some cells, stat5.

SIGNOR-68010

Q9P2Y5

Q8NEB9

1

binding

up-regulates activity

0.809

Although both human atg14 and uvrag interact with beclin 1 and vps34.

SIGNOR-181554

P12931

P49023

1

phosphorylation

up-regulates activity

0.808

Here, we demonstrate that Src kinase directly phosphorylates Y88 paxillin|In this study, we also show how pY88 paxillin transduces a signal to activate Akt

SIGNOR-263977

P78527

P49917

1

phosphorylation

down-regulates

0.808

Using tandem mass spectrometry, we identified a dna-pk phosphorylation site at thr-650 in human lig4 and a potential second phosphorylation site at ser-668 or ser-672. Phosphorylation of lig4 per se was not required for lig4 dna end joining activity. Substitution of these amino acids with alanine, individually or in combination, led to changes in lig4 protein stability of mouse lig4. The phosphomimetic mutation s650d returned lig4 stability to that of the wild-type protein. Furthermore dna-pk was found to negatively regulate lig4 protein stability.

SIGNOR-125877

P49768

P35222

1

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

Q92585

Q04721

1

binding

up-regulates

0.808

Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes1.

SIGNOR-84835

Q13323

Q07817

1

binding

down-regulates

0.808

We have identified a novel cellular protein, bik, that interacts with the cellular survival-promoting proteins, bcl-2 and bcl-xl in transient transfection assays, bik promotes cell death in a manner similar to the death-promoting members of the bcl-2 family, bax and bak.

SIGNOR-26453

P28482

Q9BY84

1

phosphorylation

up-regulates quantity by stabilization

0.808

Phosphorylation of Ser-446 determines stability of MKP-7.|We also determined that MKP-7 phosphorylated at Ser-446 has a longer half-life than unphosphorylated form of the wild type protein, as does a phospho-mimic mutant of MKP-7. These results indicate that activation of the ERK pathway strongly blocks JNK activation through stabilization of MKP-7 mediated by phosphorylation.

SIGNOR-249389

Q9GZV5

Q15562

1

binding

up-regulates

0.808

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

SIGNOR-201382

Q92854

O43157

1

binding

up-regulates

0.808

Binding of sema 4d to plexin b1 stimulates the tyrosine kinase activity of met, resulting in tyrosine phosphorylation of both receptors.

SIGNOR-92201

Q66GS9

Q9HC77

1

binding

up-regulates activity

0.808

In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation.

SIGNOR-269677

O43561

P19174

1

binding

up-regulates activity

0.808

By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.

SIGNOR-246060

P40424

P14653

1

binding

up-regulates activity

0.807

Pbx1 and exd act as cofactors that enhance the DNA binding specificity of Hox proteins. The structure of the HoxB1Pbx1DNA ternary complex shows that HoxB1 and Pbx1 bind to overlapping binding sites located on opposite faces of the DNA.

SIGNOR-241219

P48730

O15534

1

phosphorylation

down-regulates quantity by destabilization

0.807

Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2).

SIGNOR-268001

P11802

P28749

1

phosphorylation

up-regulates activity

0.807

Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression.

SIGNOR-250764

P08069

Q92569

1

binding

up-regulates

0.807

Moreover, we found that the insulin-like growth factor-1 receptor (igf-ir) bound to p55pik;the interaction occurred at the receptor tyrosine 1316 and involved both p55pik sh2 domains.

SIGNOR-52683

P01033

P14780

1

binding

down-regulates activity

0.807

Tissue inhibitor of metalloproteinase (TIMP-1) is an inhibitor of MMP-9 that binds to MMP-9 precursors and to the active form.

SIGNOR-278116

P18075

Q04771

1

binding

up-regulates

0.807

Bmp-4 and gdf-5 are known to bind to activin receptor-like kinase 3 (alk-3) and/or alk-6 (also termed bmp type ia and type ib receptors, respectively), whereas bmp-6 and bmp-7 preferentially bind to alk-2

SIGNOR-236913

P04626

P29353

1

binding

up-regulates

0.807

Shc interacts with and is an excellent substrate for erbb2 and appears to play an important role in mitogenic signaling through this receptor tyrosine kinase

SIGNOR-65579

Q9NRD5

P42262

1

binding

up-regulates activity

0.807

RAB39B directs GluA2 trafficking in neurons. GTP-bound RAB39B interacts with PICK1. In line with evidence that PICK1 can dimerize, the structural model suggests that dimerization of PICK1 is a prerequisite for simultaneous recognition of both RAB39B and GluA2 each by one of the PICK1 molecules in the PICK1 dimer (Fig. 6a–c). The existence of such complex is supported by our co-immunoprecipitation experiments shown above.

SIGNOR-264046

Q92793

P10242

1

binding

up-regulates activity

0.807

the nuclear co-activator CREB binding protein (CBP). This protein interacts directly with both c-Myb and v-Myb and potentiates Myb-specific transcription

SIGNOR-240994

P43405

Q8WV28

1

phosphorylation

up-regulates

0.806

The phosphorylation of multiple tyrosine residues not only amplifies plcgamma-mediated signaling but also supports 'cis'-mediated interaction between distinct signaling effectors within a large molecular complex.

SIGNOR-96044

Q92974

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.806

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-260529

O43921

Q15375

1

binding

up-regulates

0.806

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-52206

P15923

P15172

1

binding

up-regulates activity

0.806

In addition we demonstrate that myod, in conjunction with e12/e47-like proteins, is functioning as a regulatory nodal point for activation of several other downstream muscle regulators.

SIGNOR-20540

Q15726

Q969F8

1

binding

up-regulates

0.806

Here we show that kiss-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan g-protein-coupled receptor (hot7t175) and have named 'metastin'

SIGNOR-108480

O14640

P35222

1

binding

up-regulates activity

0.806

Activated DVL binds and inhibits the phosphorylation of beta-catenin by GSK3B, blocking beta-catenin degradation 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-134285

O60674

P42224

1

phosphorylation

up-regulates

0.806

Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation.

SIGNOR-235709

Q9NS23

Q13043

1

binding

up-regulates

0.806

Rassf1a and mst1 co-exist as a complex localizing at microtubules throughout the cell cycle, of which the rassf1a mst1 interaction is stimulatory to the mst1 kinase activity.

SIGNOR-197744

P03971

Q16671

1

binding

up-regulates

0.806

The results point to anti-m?llerian Hormone (amh) being the most likely candidate ligand for c14.

SIGNOR-36215

Q9BXL7

Q9UDY8

1

binding

up-regulates

0.805

The carboxy-terminal part of the bcl10 card and a short stretch of 13 amino acids following the card are required for constitutive binding to malt1.

SIGNOR-167393

P28562

Q16539

2

dephosphorylation

down-regulates activity

0.805

The activity of MAPKs can be also regulated by a family of DUSPs (dual-specificity phosphatases)/MKPs (MAPK phosphatases), which dephosphorylate both phosphotyrosine and phosphothreonine residues MKPs 1, 4, 5 and 7 can dephosphorylate p38_ and p38_ in addition to JNK MAPKs. Importantly, some MKPs are transcriptionally up-regulated by stimuli that activate MAPK signalling, and are thought to play an important role limiting the extent of MAPK activation

SIGNOR-166571

P28562

P28482

2

dephosphorylation

down-regulates activity

0.805

We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively

SIGNOR-248465

P19438

Q15628

1

binding

up-regulates activity

0.805

We have identified a novel 34 kda protein, designated tradd, that specifically interacts with an intracellular domain of tnfr1 tradd interacts with the death domain of tnfrsf1a to initiate distinct signaling cascades for two of the most important biological activities of tnf, nf-kb activation and programmed cell death tradd, a novel protein that specifically interacts with the death domain of tnfr1 and activates signaling pathways for both of these activities when overexpressed.

SIGNOR-32739

P04114

P01130

1

binding

up-regulates

0.805

In the case of ldl, binding of apolipoprotein b (apob) to the ldl-r18-20 and proteoglycans17 21 initiates plasma clearance and lipoprotein degradation

SIGNOR-87035

Q96PU5

P84022

1

ubiquitination

down-regulates activity

0.805

Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation

SIGNOR-232104

P28482

P28562

2

phosphorylation

down-regulates

0.805

The dual-specificity mapk phosphatase mkp-1/cl100/dusp1 is an inducible nuclear protein controlled by p44/42 mapk (erk1/2) in a negative feedback mechanism to inhibit kinase activity. Here, we report on the molecular basis for a novel positive feedback mechanism to sustain erk activation by triggering mkp-1 proteolysis. Active erk2 docking to the def motif (fxfp, residues 339-342) of n-terminally truncated mkp-1 in vitro initiated phosphorylation at the ser(296)/ser(323) domain

SIGNOR-141593

P31749

P35222

1

phosphorylation

up-regulates

0.805

Phosphorylation of beta-catenin by akt promotes beta-catenin transcriptional activity|we have demonstrated that akt phosphorylates beta-catenin at ser552 in vitro and in vivo.

SIGNOR-252499

Q86UR5

P20336

1

relocalization

up-regulates activity

0.805

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-264381

O15444

P51686

1

binding

up-regulates

0.805

Ccr9 is a specific receptor for the beta-chemokine teck/ccl25.

SIGNOR-104902

Q9BY84

Q16539

1

dephosphorylation

down-regulates

0.805

Mkp-7 binds to and inactivates p38 mapk and jnk/sapk, but not erk inhibited by dual specificity phosphatases, such as dusp1, dusp10, and dusp16(uniprot)

SIGNOR-108233

P11940

P06730

1

binding

up-regulates activity

0.805

The binding of PABP to mRNA poly(A) tails is followed by interactions with eukaryotic initiation factor (eIF4G) and other translation factors, including eIF4E, to constitute a translation initiation complex, which mediates cellular mRNA circularization and enhances cap-dependent translation by facilitating ribosome recycling

SIGNOR-260968

Q16539

P28562

2

binding

up-regulates activity

0.805

Here we have shown that mkp-1 associates directly with p38 map kinase both in vivo and in vitro, and that this interaction enhances the catalytic activity of mkp-1. The point mutation asp-316-->asn in the c-terminus of p38, analogous to the erk2 (extracellular-signal-regulated kinase 2) sevenmaker mutation, dramatically decreases its binding to mkp-1 and substantially compromises its stimulatory effect on the catalytic activity of this phosphatase.

SIGNOR-83752

P00746

P00751

1

cleavage

up-regulates activity

0.804

The resulting proconvertase C3bB is subsequently cleaved by factor D (FD), generating the AP C3 convertase C3bBb

SIGNOR-263488

P18075

Q13873

1

binding

up-regulates

0.804

In transfected cos-1 cells, osteogenic protein (op)-1/bmp-7, and less efficiently bmp-4, bound to bmpr-ii. Bmpr-ii bound ligands only weakly alone, but the binding was facilitated by the presence of previously identified type i receptors for bmps. Binding of op-1/bmp-7 to bmpr-ii was also observed in nontransfected cell lines. Moreover, a transcriptional activation signal was transduced by bmpr-ii in the presence of type i receptors after stimulation by op-1/bmp-7.

SIGNOR-30512

O43561

P62993

1

binding

up-regulates

0.804

Phosphorylated tyrosines 171, 191, and 226 [in LAT] bind to the SH2 domains of the Grb2 family of adaptor proteins and must be present for optimal signalling

SIGNOR-251520

P43403

Q13094

1

phosphorylation

up-regulates

0.804

Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient.

SIGNOR-46859

P53350

P30307

1

phosphorylation

up-regulates

0.804

The nuclear accumulation of active m-phase promoting factor (mpf) during prophase is thought to be essential for coordinating m-phase events in vertebrate cells. The protein phosphatase cdc25c, an activator of mpf, enters the nucleus to keep mpf active in the nucleus during prophase. these results suggest that plk1 phosphorylates cdc25c on ser198 and regulates nuclear translocation of cdc25c during prophase.

SIGNOR-115993

P52797

P29320

1

binding

up-regulates

0.804

The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. transmembrane ligands for eph receptors also exhibit properties of signal transducing molecules, suggesting that bidirectional signaling occurs when receptor-expressing cells contact ligand-expressing cells.

SIGNOR-52312

P12931

P56945

1

phosphorylation

up-regulates activity

0.803

Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of CasBased on these data, 11 tyrosine residues (132, 169, 183, 196, 238, 253, 271, 291, 301, 391, and 414) were phosphorylated by Src|the biological activity of Cas depends on its phosphorylation by Src (16–18). After phosphorylation, Cas associates with a number of proteins, including Crk, Src, phosphatidylinositol 3-kinase, Nck, and phospholipase Cgamma, via SH2 binding motifs

SIGNOR-246393

Q14258

O95786

1

ubiquitination

up-regulates activity

0.803

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

SIGNOR-278730

Q9Y4P1

Q9GZQ8

1

cleavage

up-regulates

0.803

Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.

SIGNOR-125449

O95271

P54274

1

ADP-ribosylation

down-regulates activity

0.803

Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA.

SIGNOR-263377

P35568

P62993

1

binding

up-regulates activity

0.803

Association ofinsulinreceptor substrate 1 (irs-1) y895 with grb-2 mediates theinsulinsignaling involved in irs-1-deficient brown adipocyte mitogenesis.

SIGNOR-236614

Q9Y2H0

P78352

1

binding

up-regulates activity

0.803

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-264212

Q2MKA7

Q9ULT6

1

relocalization

down-regulates quantity

0.803

Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3.

SIGNOR-260113

Q96EB6

P04637

1

deacetylation

down-regulates

0.803

Sirt1 has been shown to regulate cell fate in part by deacetylating the p53 protein at lysine 382 and inhibiting p53-mediated transcriptional activation and apoptosis.

SIGNOR-182515

Q8N2C7

Q9P2D8

1

binding

up-regulates activity

0.803

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

SIGNOR-265183

Q15465

Q9Y6C5

1

binding

down-regulates activity

0.803

Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.

SIGNOR-217776

P09429

Q15109

1

binding

up-regulates activity

0.803

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

SIGNOR-252059

Q9UQB8

Q9Y6W5

1

binding

up-regulates activity

0.802

Here we demonstrate that IRSp53, a substrate for insulin receptor with unknown function, is the 'missing link' between Rac and WAVE. Activated Rac binds to the amino terminus of IRSp53, and carboxy-terminal Src-homology-3 domain of IRSp53 binds to WAVE to form a trimolecular complex. From studies of ectopic expression, we found that IRSp53 is essential for Rac to induce membrane ruffling, probably because it recruits WAVE, which stimulates actin polymerization mediated by the Arp2/3 complex.

SIGNOR-265556

P36896

Q15796

1

phosphorylation

up-regulates activity

0.802

ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T²RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-²-like signaling pathway

SIGNOR-235157

P09429

O00206

1

binding

up-regulates activity

0.802

Here we show that Toll-like receptor 4 (TLR4), a pivotal receptor for activation of innate immunity and cytokine release, is required for HMGB1-dependent activation of macrophage TNF release.

SIGNOR-252057