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
Q13315	Q01094	1	phosphorylation	up-regulates quantity by stabilization	0.679	Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes.	SIGNOR-109416
Q9NR96	Q99836	1	binding	up-regulates activity	0.678	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266742
O60353	O14640	1	binding	up-regulates activity	0.678	When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.	SIGNOR-198828
O00755	O75084	1	binding	up-regulates activity	0.678	Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions	SIGNOR-255646
P55286	P35222	1	binding	up-regulates activity	0.678	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265870
P21675	P52655	1	phosphorylation	up-regulates activity	0.678	Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity.	SIGNOR-105688
P07948	P40259	1	phosphorylation	up-regulates activity	0.678	Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b	SIGNOR-251398
Q9UP38	O14641	1	binding	up-regulates activity	0.678	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.	SIGNOR-258952
Q4VCS5	Q9GZV5	1	relocalization	down-regulates	0.678	Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms.	SIGNOR-201132
O14544	P10721	1	ubiquitination	down-regulates	0.678	Suppressor of cytokine signaling 6 (socs6) is a member of the socs family of e3 ubiquitin ligases that can interact with c-kit and suppress c-kit-dependent pathways. / we demonstrate that socs6 has ubiquitin ligase activity toward c-kit and regulates c-kit protein turnover in cells	SIGNOR-169145
Q92838	Q9HAV5	1	binding	up-regulates	0.678	Identification of the major product of the eda gene (ectodysplasin a), a protein belonging to a group of tnf ligands, and molecular cloning of the cdna, encoding its receptor (edar), a member of the tnf receptor family, are presented. The role of an alternative eda receptor, localised on the x chromosome (xedar) in the developmental control of the differentiation of skin appendages, is discussed.	SIGNOR-90040
Q9Y4X5	O60573	1	ubiquitination	down-regulates quantity by destabilization	0.678	Human homologue of Drosophila ariadne (HHARI) is a RING-IBR-RING domain protein identified through its ability to bind the human ubiquitin-conjugating enzyme, UbcH7. Thus, by promoting the ubiquitin-mediated degradation of 4EHP, HHARI may have a role in both protein degradation and protein translation.	SIGNOR-268848
Q13387	O14733	1	binding	up-regulates	0.678	Thus, both jip1 and jip2 selectively bind the mapkk isoform mkk7.	SIGNOR-59944
P07949	Q8WU20	1	binding	up-regulates	0.678	Tyrosine 1062 in ret provides a site for the interaction of multiple signaling molecules and that the balance of shc and snt/frs2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated ret	SIGNOR-108244
P24941	P38398	1	phosphorylation	up-regulates	0.677	However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.	SIGNOR-187607
Q96HP0	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.677	Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton.	SIGNOR-275671
P42224	O14543	1	transcriptional regulation	up-regulates quantity by expression	0.677	Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways.	SIGNOR-249565
P43403	P29353	1	phosphorylation	up-regulates	0.677	The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2).	SIGNOR-59659
Q05655	P04637	1	phosphorylation	up-regulates	0.677	Here, we show that the pro-apoptotic kinase, protein kinase c delta (pkcdelta), is involved in phosphorylation of p53 on ser(46). pkcdelta potentiates p53-dependent apoptosis by ser(46) phosphorylation in response to genotoxic stress.	SIGNOR-143382
P12931	P31749	1	phosphorylation	up-regulates activity	0.677	Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity.	SIGNOR-252623
Q13490	Q9Y572	1	polyubiquitination	up-regulates activity	0.677	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272711
P10415	Q16611	1	binding	down-regulates	0.677	Bcl-2 bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim)	SIGNOR-55546
P19474	Q92985	1	ubiquitination	down-regulates quantity by destabilization	0.677	Furthermore, this Ro52 mediated degradation of IRF7 was inhibited in the presence of MG132, a proteasome inhibitor, indicating that IRF7 is targeted to the proteasome for degradation (XREF_FIG).\|Ro52 ubiquitinates IRF7 in a dose dependent manner.	SIGNOR-278619
O75460	Q12933	1	binding	up-regulates activity	0.677	Activated IRE1 has been demonstrated to recruit TRAF2 and ASK1 on the ER membrane and thus to activate ASK1\|ASK1 was found to associate with IRE1 only in the presence of TRAF2 and SOD1mut (Fig. 4B), suggesting that SOD1mut induces formation of an IRE1–TRAF2–ASK1 complex on the ER membrane and thus activates ASK1 by triggering ER stress-induced IRE1 activation.	SIGNOR-262790
Q15848	Q96A54	1	binding	up-regulates	0.677	Two adiponectin receptors, adipor1 and adipor2, have recently been identified.	SIGNOR-146170
Q99558	Q00653	1	phosphorylation	up-regulates activity	0.677	NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870	SIGNOR-105553
O14965	P38398	1	phosphorylation	up-regulates	0.677	Previous studies have shown that the brca1 breast cancer tumor suppressor also localizes to the centrosome and that brca1 inactivation results in loss of the g(2)-m checkpoint. We demonstrate here that aurora-a physically binds to and phosphorylates brca1. We propose that brca1 phosphorylation by aurora-a plays a role in g(2) to m transition of cell cycle	SIGNOR-123065
Q9NQC7	Q12933	1	deubiquitination	down-regulates activity	0.677	Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract)	SIGNOR-117860
Q9NR31	Q15437	1	binding	up-regulates quantity	0.677	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.	SIGNOR-265298
P18031	P42229	1	dephosphorylation	down-regulates activity	0.676	A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b	SIGNOR-248428
P12931	P51636	1	phosphorylation	down-regulates	0.676	Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1.	SIGNOR-129961
P18031	P51692	1	dephosphorylation	down-regulates activity	0.676	A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b	SIGNOR-248429
P48740	P0C0L5	1	cleavage	up-regulates activity	0.676	The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.\|Activation of C4 by Ct sand MASP-2 on western blots.	SIGNOR-263426
Q03135	O75581	1	binding	up-regulates	0.676	Overall, our data suggest that wnt-3a triggers the interaction of lrp6 with caveolin and promotes recruitment of axin to lrp6 phosphorylated by glycogen synthase kinase-3beta and that caveolin thereby inhibits the binding of beta-catenin to axin.	SIGNOR-148665
P40189	P23458	1	null	up-regulates	0.676	Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects.	SIGNOR-202036
P29460	P42701	1	binding	up-regulates	0.676	Characterization of the p40 proteins for binding and bioactivity showed that both the p40 monomer and dimer inhibited 125i-labeled il-12 binding to il-12r, but the 80-kda species, having a 50% inhibitory concentration (ic50) of 20 to 70 ng/ml, was at least 20-fold more effective than the monomer. The results suggest that the il-12 p40 subunit contains the essential epitopes for receptor binding.	SIGNOR-27690
Q8IUQ4	Q9Y6H5	1	ubiquitination	down-regulates	0.676	Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system	SIGNOR-140612
P23276	P14138	1	cleavage	up-regulates activity	0.676	These data demonstrate that the Kell blood group protein is a proteolytic enzyme that processes big ET-3, generating ET-3, a potent bioactive peptide with multiple biological roles.	SIGNOR-256354
O60674	Q14765	1	phosphorylation	up-regulates	0.676	Janus family tyrosine kinases jak2 and tyk2, which in turn phosphorylate stat4 on tyrosine 693. The p38 mitogen-activated protein kinase (mapk) signaling pathway is also activated in response to il-12, followed by phosphorylation of stat4 on serine 721, which is required for stat4 full transcriptional activity	SIGNOR-142736
P45983	P49023	1	phosphorylation	up-regulates activity	0.676	JNK1 phosphorylates serine 178 on paxillin, a focal adhesion adaptor, both in vitro and in intact cells. NBT-II cells expressing the Ser 178 --> Ala mutant of paxillin (Pax(S178A)) formed focal adhesions and exhibited the limited movement associated with such contacts in both single-cell-migration and wound-healing assays. In contrast, cells expressing wild-type paxillin moved rapidly and retained close contacts as the predominant adhesion.	SIGNOR-250129
P05412	Q13485	1	binding	up-regulates activity	0.676	Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter.	SIGNOR-236139
Q92831	P84022	1	binding	up-regulates	0.676	P/caf was found to interact directly with smad3 in vitro. Moreover, smad2 and smad3 interacted with p/caf upon tgf-beta type i receptor activation in cultured mammalian cells. these results demonstrate the co-activator function of p/caf for smad2 and smad3.	SIGNOR-83607
P35968	P19174	1	binding	up-regulates	0.675	(vegfr) phosphorylated y1175 creates a binding site for phospholipase cgamma1 (plc-gamma1)	SIGNOR-147870
P01574	P48551	1	binding	up-regulates	0.675	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-105934
P42574	Q13813	1	cleavage	down-regulates	0.675	Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis.	SIGNOR-57891
Q05209	P29353	1	dephosphorylation	down-regulates	0.675	The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions.	SIGNOR-44361
Q99717	Q13485	1	phosphorylation	up-regulates	0.675	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-168737
Q8N5V2	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.675	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-260562
P31751	Q96B36	1	phosphorylation	down-regulates	0.674	Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity.	SIGNOR-153931
P56706	O75197	1	binding	up-regulates	0.674	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131981
Q05397	P29353	1	phosphorylation	up-regulates activity	0.674	In vitro, FAK directly phosphorylated Shc Tyr-317 to promote Grb2 binding. FAK can associate and directly phosphorylate Shc at Tyr-317 to promote Grb2 binding and low-level signaling to ERK2.	SIGNOR-259854
P08581	Q13480	1	phosphorylation	up-regulates activity	0.674	Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF.	SIGNOR-250290
Q9UHD2	P42226	1	phosphorylation	up-regulates	0.674	We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing.	SIGNOR-176775
Q9UNS1	Q16526	1	binding	up-regulates activity	0.674	We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization.	SIGNOR-268053
P01213	P35372	1	chemical activation	up-regulates activity	0.674	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258414
O15524	P15260	1	binding	down-regulates	0.674	Suppressor of cytokine signaling (socs)-1, the key negative regulator of interferon (ifn)-gamma-dependent signaling, is induced in response to ifngamma. Socs-1 binds to and inhibits the ifngamma receptor-associated kinase janus-activated kinase (jak) 2 and inhibits its function in vitrothe binding of socs-1 to tyr441 also blocks the access of stat1 to tyr419 and that this effect may be the principal mechanism of inhibition of downstream signaling	SIGNOR-180140
P06493	Q08379	1	phosphorylation	down-regulates	0.674	Cdc2 kinase directly phosphorylates the cis-golgi matrix protein gm130 and is required for golgi fragmentation in mitosis. Mitotic fragmentation of the golgi apparatus can be largely explained by disruption of the interaction between gm130 and the vesicle-docking protein p115. Here we identify a single serine (ser-25) in gm130 as the key phosphorylated target and cdc2 as the responsible kinase	SIGNOR-60281
O95633	O14793	1	binding	down-regulates	0.674	Fstl3 inhibits myostatin via its n-terminal domain.	SIGNOR-199063
O43462	Q12772	1	cleavage	up-regulates activity	0.673	In order to activate transcription, the NH2-terminal domain of the SREBP must be released from the membrane so that it can enter the nucleus. This release has been studied most extensively for one of the SREBPs, namely, SREBP-2. However, the mechanism appears to be similar for the other SREBPs (SREBP-1a and -1c) (1). Release of the NH2-terminal domain is accomplished by a two-step proteolytic event that is regulated by sterols (3). In sterol-depleted mammalian cells, this proteolysis is initiated by the Site-1 protease (S1P), which cleaves human SREBP-2 between the Leu522-Ser523 bond in the sequence RSVL S (4). This cleavage requires formation of a complex between SREBP and SCAP, a polytopic membrane protein of the ER, and it is prevented when this complex is disrupted	SIGNOR-267498
Q13535	Q9BXW9	1	phosphorylation	up-regulates	0.673	In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents	SIGNOR-149305
Q06124	P01111	1	dephosphorylation	up-regulates activity	0.673	Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.	SIGNOR-255754
Q9UMX1	O00422	1	binding	up-regulates	0.673	Here we report that the mouse homolog of su(fu) [msu(fu)] specifically interacts with sap18, a component of the msin3 and histone deacetylase complex. In addition, we demonstrate that msu(fu) functionally cooperates with sap18 to repress transcription by recruiting the sap18-msin3 complex to promoters containing the gli-binding element.	SIGNOR-117311
Q9NUX5	O14746	1	binding	up-regulates	0.673	We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme.	SIGNOR-152327
P49759	Q07955	1	phosphorylation	up-regulates activity	0.673	In a previous study, we showed that CLK1 phosphorylates SRSF1 to a greater extent than SRPK1, inducing a hyper-phosphorylated state that can be readily detected by a gel shift on SDS-PAGE. xref In xref , the phosphorylation of SRSF1 in single turnover experiments using SRPK1 and CLK1 is shown.\|Unlike SRPK1, CLK1 induces a unique structural form of SRSF1 observed by SDS-PAGE that is exclusively the result of Ser-Pro rather than Arg-Ser phosphorylation.	SIGNOR-279608
P08254	P07585	1	cleavage	down-regulates quantity by destabilization	0.673	Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.	SIGNOR-256353
P09544	O75581	1	binding	up-regulates	0.673	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131730
Q6PHR2	P08151	1	phosphorylation	up-regulates activity	0.673	We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro. \| Our data suggest that serine/threonine kinase ULK3 is involved in the SHH pathway as a positive regulator of GLI proteins.	SIGNOR-260797
P39905	O00451	1	binding	up-regulates	0.673	Gdnf mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (gpi)-linked protein (designated gdnfr-alpha).	SIGNOR-49184
P43405	P12318	1	phosphorylation	up-regulates activity	0.673	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-247590
Q9UER7	Q00987	1	binding	up-regulates	0.673	The optimal function of mdm2 requires daxx, which stabilizes mdm2 through the deubiquitinase hausp/usp7 and also directly promotes mdm2's ubiquitin ligase activity towards p53.	SIGNOR-200892
O60603	Q99836	1	binding	up-regulates activity	0.673	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266740
P45984	P17275	1	binding	down-regulates	0.673	Jnk targets junb ubiquitination	SIGNOR-53827
Q2M1Z3	P60953	1	gtpase-activating protein	down-regulates activity	0.673	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-260490
P08620	P22455	1	binding	up-regulates	0.672	Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.	SIGNOR-18567
O96014	O60353	1	binding	up-regulates activity	0.672	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141431
P06241	P40259	1	phosphorylation	up-regulates activity	0.672	CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b	SIGNOR-251154
Q16539	Q9BUB5	1	phosphorylation	up-regulates	0.672	Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38.	SIGNOR-48346
Q12899	Q14653	1	polyubiquitination	down-regulates quantity by destabilization	0.672	TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.	SIGNOR-272440
P53041	Q16543	1	dephosphorylation	down-regulates activity	0.672	Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13\|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37.	SIGNOR-248539
P11142	P13569	1	binding	down-regulates quantity	0.672	JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex	SIGNOR-271492
Q06187	Q9UN19	1	phosphorylation	up-regulates activity	0.672	We present a number of lines of evidence that in vivo, Src-type tyrosine kinases are responsible for the phosphorylation of tyrosine 139 in DAPP-1. \| Although Btk appears to phosphorylate DAPP-1 relatively efficiently both in Sf9 cells and in vitro, we find no evidence that in either B cells or PAE cells Btk family kinases phosphorylate DAPP-1.	SIGNOR-250602
P27361	P14921	1	phosphorylation	up-regulates	0.672	We found that hgf/sf activates the erk1 map kinase, leading to the phosphorylation of the threonine 38 residue of ets1	SIGNOR-116494
Q9H2C0	Q13618	1	binding	up-regulates activity	0.672	Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B.	SIGNOR-268944
P51452	P28482	1	dephosphorylation	down-regulates activity	0.672	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.\|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2	SIGNOR-248536
O75636	P48740	1	binding	up-regulates activity	0.672	H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway\|Proteolytic activation of complement components by H-ficolin-MASP.	SIGNOR-263410
P45983	P38936	1	phosphorylation	up-regulates quantity by stabilization	0.672	The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.\|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro.	SIGNOR-89440
P45984	P35222	1	phosphorylation	up-regulates	0.671	Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt.	SIGNOR-178258
O75582	Q13541	1	phosphorylation	down-regulates activity	0.671	In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E	SIGNOR-262992
Q9Y297	P10071	1	ubiquitination	down-regulates quantity by destabilization	0.671	Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage.	SIGNOR-145116
P28482	P03372	1	phosphorylation	up-regulates	0.671	In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.	SIGNOR-156856
Q86XK2	P04637	1	neddylation	down-regulates	0.671	Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321	SIGNOR-150669
Q99952	P04626	1	dephosphorylation	down-regulates quantity by destabilization	0.671	PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. \|Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop.	SIGNOR-262596
P20393	O00327	1	transcriptional regulation	down-regulates quantity by repression	0.671	In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267983
P12931	Q13905	1	phosphorylation	up-regulates	0.671	C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases.	SIGNOR-128273
P22607	P42224	1	phosphorylation	up-regulates activity	0.671	Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.	SIGNOR-251138
Q96EQ8	O95786	1	polyubiquitination	down-regulates quantity by destabilization	0.671	Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.	SIGNOR-271647
Q96BN8	P0CG47	1	cleavage	up-regulates quantity	0.671	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-270819
O95988	P31749	1	binding	up-regulates	0.671	In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation.	SIGNOR-81713
Q9NTX7	Q9Y2T1	1	ubiquitination	down-regulates quantity by destabilization	0.671	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.	SIGNOR-263336
Q15797	Q13485	1	phosphorylation	up-regulates	0.671	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common(co-Smad; Smad4 in mammals) and shuttle into the nucleus.	SIGNOR-168734

Q13315

Q01094

1

phosphorylation

up-regulates quantity by stabilization

0.679

Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes.

SIGNOR-109416

Q9NR96

Q99836

1

binding

up-regulates activity

0.678

To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group

SIGNOR-266742

O60353

O14640

1

binding

up-regulates activity

0.678

When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.

SIGNOR-198828

O00755

O75084

1

binding

up-regulates activity

0.678

Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions

SIGNOR-255646

P55286

P35222

1

binding

up-regulates activity

0.678

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

SIGNOR-265870

P21675

P52655

1

phosphorylation

up-regulates activity

0.678

Taf(ii) 250 phosphorylates human transcription factor iia on serine residues important for tbp binding and transcription activity.

SIGNOR-105688

P07948

P40259

1

phosphorylation

up-regulates activity

0.678

Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b

SIGNOR-251398

Q9UP38

O14641

1

binding

up-regulates activity

0.678

Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.

SIGNOR-258952

Q4VCS5

Q9GZV5

1

relocalization

down-regulates

0.678

Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms.

SIGNOR-201132

O14544

P10721

1

ubiquitination

down-regulates

0.678

Suppressor of cytokine signaling 6 (socs6) is a member of the socs family of e3 ubiquitin ligases that can interact with c-kit and suppress c-kit-dependent pathways. / we demonstrate that socs6 has ubiquitin ligase activity toward c-kit and regulates c-kit protein turnover in cells

SIGNOR-169145

Q92838

Q9HAV5

1

binding

up-regulates

0.678

Identification of the major product of the eda gene (ectodysplasin a), a protein belonging to a group of tnf ligands, and molecular cloning of the cdna, encoding its receptor (edar), a member of the tnf receptor family, are presented. The role of an alternative eda receptor, localised on the x chromosome (xedar) in the developmental control of the differentiation of skin appendages, is discussed.

SIGNOR-90040

Q9Y4X5

O60573

1

ubiquitination

down-regulates quantity by destabilization

0.678

Human homologue of Drosophila ariadne (HHARI) is a RING-IBR-RING domain protein identified through its ability to bind the human ubiquitin-conjugating enzyme, UbcH7. Thus, by promoting the ubiquitin-mediated degradation of 4EHP, HHARI may have a role in both protein degradation and protein translation.

SIGNOR-268848

Q13387

O14733

1

binding

up-regulates

0.678

Thus, both jip1 and jip2 selectively bind the mapkk isoform mkk7.

SIGNOR-59944

P07949

Q8WU20

1

binding

up-regulates

0.678

Tyrosine 1062 in ret provides a site for the interaction of multiple signaling molecules and that the balance of shc and snt/frs2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated ret

SIGNOR-108244

P24941

P38398

1

phosphorylation

up-regulates

0.677

However, shrna-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated s phase cell-cycle arrest and the phosphorylation of a subset of atr/atm targets after dna damage. Loss of dna damage-induced checkpoint control was caused by a reduction in formation of brca1-containing foci. Mutation of brca1 at s1497 and s1189/s1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of brca1-containing foci.

SIGNOR-187607

Q96HP0

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.677

Dock6 is a guanine nucleotide exchange factor (GEF) that activates the Rho family guanosine triphosphatases Rac1 and Cdc42 to regulate the actin cytoskeleton.

SIGNOR-275671

P42224

O14543

1

transcriptional regulation

up-regulates quantity by expression

0.677

Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways.

SIGNOR-249565

P43403

P29353

1

phosphorylation

up-regulates

0.677

The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on shc1 (iso2).

SIGNOR-59659

Q05655

P04637

1

phosphorylation

up-regulates

0.677

Here, we show that the pro-apoptotic kinase, protein kinase c delta (pkcdelta), is involved in phosphorylation of p53 on ser(46). pkcdelta potentiates p53-dependent apoptosis by ser(46) phosphorylation in response to genotoxic stress.

SIGNOR-143382

P12931

P31749

1

phosphorylation

up-regulates activity

0.677

Regulation of Akt/PKB Activation by Tyrosine PhosphorylationAs shown in Fig. 2 d, while mutation of Tyr340 has little effect on either tyrosine phosphorylation or kinase activity of Akt induced by Src527F, substitution of Tyr315 or Tyr326 with a phenylalanine, respectively, dramatically reduces both the tyrosine phosphorylation and kinase activity of Akt. The combination of these two mutations abolishes Src-induced tyrosine phosphorylation of Akt as well as its kinase activity.

SIGNOR-252623

Q13490

Q9Y572

1

polyubiquitination

up-regulates activity

0.677

CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.

SIGNOR-272711

P10415

Q16611

1

binding

down-regulates

0.677

Bcl-2 bind to bax or five other pro-apoptotic relatives (bak, bad, bik, bid or bim)

SIGNOR-55546

P19474

Q92985

1

ubiquitination

down-regulates quantity by destabilization

0.677

Furthermore, this Ro52 mediated degradation of IRF7 was inhibited in the presence of MG132, a proteasome inhibitor, indicating that IRF7 is targeted to the proteasome for degradation (XREF_FIG).|Ro52 ubiquitinates IRF7 in a dose dependent manner.

SIGNOR-278619

O75460

Q12933

1

binding

up-regulates activity

0.677

Activated IRE1 has been demonstrated to recruit TRAF2 and ASK1 on the ER membrane and thus to activate ASK1|ASK1 was found to associate with IRE1 only in the presence of TRAF2 and SOD1mut (Fig. 4B), suggesting that SOD1mut induces formation of an IRE1–TRAF2–ASK1 complex on the ER membrane and thus activates ASK1 by triggering ER stress-induced IRE1 activation.

SIGNOR-262790

Q15848

Q96A54

1

binding

up-regulates

0.677

Two adiponectin receptors, adipor1 and adipor2, have recently been identified.

SIGNOR-146170

Q99558

Q00653

1

phosphorylation

up-regulates activity

0.677

NIK-induced p100 processing requires phosphorylation of p100 at serines 866 and 870

SIGNOR-105553

O14965

P38398

1

phosphorylation

up-regulates

0.677

Previous studies have shown that the brca1 breast cancer tumor suppressor also localizes to the centrosome and that brca1 inactivation results in loss of the g(2)-m checkpoint. We demonstrate here that aurora-a physically binds to and phosphorylates brca1. We propose that brca1 phosphorylation by aurora-a plays a role in g(2) to m transition of cell cycle

SIGNOR-123065

Q9NQC7

Q12933

1

deubiquitination

down-regulates activity

0.677

Cyld also interacts directly with tumour-necrosis factor receptor (tnfr)-associated factor 2 (traf2), an adaptor molecule involved in by members of the family of tnf/nerve growth factor receptors. (articolo-abstract)

SIGNOR-117860

Q9NR31

Q15437

1

binding

up-regulates quantity

0.677

Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.

SIGNOR-265298

P18031

P42229

1

dephosphorylation

down-regulates activity

0.676

A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b

SIGNOR-248428

P12931

P51636

1

phosphorylation

down-regulates

0.676

Here, we show that cav-2 is phosphorylated at both tyrosines 19 and 27. We reconstituted this phosphorylation event by recombinantly coexpressing c-src and cav-2.Further functional analysis revealed that tyrosine phosphorylation of cav-2 has no effect on its targeting to lipid rafts, but clearly disrupts the hetero-oligomerization of cav-2 with cav-1.

SIGNOR-129961

P18031

P51692

1

dephosphorylation

down-regulates activity

0.676

A Cytosolic Protein-tyrosine Phosphatase PTP1B Specifically Dephosphorylates and Deactivates Prolactin-activated STAT5a and STAT5b

SIGNOR-248429

P48740

P0C0L5

1

cleavage

up-regulates activity

0.676

The classical complement activation pathway, like the MELinitiated pathway, involves the generation of a C3-converting complex, C4b2b, through enzymatic activation of C4 and C2. In the C1 complex (C1qr2s2), this specific protease activity is exhibited by C1s after activation of this enzyme by C1r. When C4 is activated, its reactive thiol ester is exposed and C4b binds covalently to nearby amino or hydroxyl groups. The C4-activating abilities of MASP-1 and MASP-2 were compared.|Activation of C4 by Ct sand MASP-2 on western blots.

SIGNOR-263426

Q03135

O75581

1

binding

up-regulates

0.676

Overall, our data suggest that wnt-3a triggers the interaction of lrp6 with caveolin and promotes recruitment of axin to lrp6 phosphorylated by glycogen synthase kinase-3beta and that caveolin thereby inhibits the binding of beta-catenin to axin.

SIGNOR-148665

P40189

P23458

1

null

up-regulates

0.676

Il-6 family members typically signal through the common gp130 receptor, with the janus kinase/signal transducer and activator of transcription (jak/stat) pathway being the major intracellular mediator of their effects.

SIGNOR-202036

P29460

P42701

1

binding

up-regulates

0.676

Characterization of the p40 proteins for binding and bioactivity showed that both the p40 monomer and dimer inhibited 125i-labeled il-12 binding to il-12r, but the 80-kda species, having a 50% inhibitory concentration (ic50) of 20 to 70 ng/ml, was at least 20-fold more effective than the monomer. The results suggest that the il-12 p40 subunit contains the essential epitopes for receptor binding.

SIGNOR-27690

Q8IUQ4

Q9Y6H5

1

ubiquitination

down-regulates

0.676

Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system

SIGNOR-140612

P23276

P14138

1

cleavage

up-regulates activity

0.676

These data demonstrate that the Kell blood group protein is a proteolytic enzyme that processes big ET-3, generating ET-3, a potent bioactive peptide with multiple biological roles.

SIGNOR-256354

O60674

Q14765

1

phosphorylation

up-regulates

0.676

Janus family tyrosine kinases jak2 and tyk2, which in turn phosphorylate stat4 on tyrosine 693. The p38 mitogen-activated protein kinase (mapk) signaling pathway is also activated in response to il-12, followed by phosphorylation of stat4 on serine 721, which is required for stat4 full transcriptional activity

SIGNOR-142736

P45983

P49023

1

phosphorylation

up-regulates activity

0.676

JNK1 phosphorylates serine 178 on paxillin, a focal adhesion adaptor, both in vitro and in intact cells. NBT-II cells expressing the Ser 178 --> Ala mutant of paxillin (Pax(S178A)) formed focal adhesions and exhibited the limited movement associated with such contacts in both single-cell-migration and wound-healing assays. In contrast, cells expressing wild-type paxillin moved rapidly and retained close contacts as the predominant adhesion.

SIGNOR-250129

P05412

Q13485

1

binding

up-regulates activity

0.676

Our analysis of the regulation of dpc4 transcriptional activity by c-jun was consistent with the possibility that c-jun and dpc4 could interact and produce trans-activation of the 3tp-lux reporter.

SIGNOR-236139

Q92831

P84022

1

binding

up-regulates

0.676

P/caf was found to interact directly with smad3 in vitro. Moreover, smad2 and smad3 interacted with p/caf upon tgf-beta type i receptor activation in cultured mammalian cells. these results demonstrate the co-activator function of p/caf for smad2 and smad3.

SIGNOR-83607

P35968

P19174

1

binding

up-regulates

0.675

(vegfr) phosphorylated y1175 creates a binding site for phospholipase cgamma1 (plc-gamma1)

SIGNOR-147870

P01574

P48551

1

binding

up-regulates

0.675

Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.

SIGNOR-105934

P42574

Q13813

1

cleavage

down-regulates

0.675

Caspase-3 is required for alpha-fodrin cleavage but dispensable for cleavage of other death substrates in apoptosis.

SIGNOR-57891

Q05209

P29353

1

dephosphorylation

down-regulates

0.675

The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions.

SIGNOR-44361

Q99717

Q13485

1

phosphorylation

up-regulates

0.675

Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.

SIGNOR-168737

Q8N5V2

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.675

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-260562

P31751

Q96B36

1

phosphorylation

down-regulates

0.674

Insulin-stimulated phosphorylation of pras40 by akt/pkb suppresses its mtorc1 inhibitory activity.

SIGNOR-153931

P56706

O75197

1

binding

up-regulates

0.674

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131981

Q05397

P29353

1

phosphorylation

up-regulates activity

0.674

In vitro, FAK directly phosphorylated Shc Tyr-317 to promote Grb2 binding. FAK can associate and directly phosphorylate Shc at Tyr-317 to promote Grb2 binding and low-level signaling to ERK2.

SIGNOR-259854

P08581

Q13480

1

phosphorylation

up-regulates activity

0.674

Gab-1 is phosphorylated on the same residues by HGF and EGF receptors. Among 16 peptides only nine were phosphorylated by the EGF and HGF receptors, namely peptides containing the tyrosine residues 285, 307, 373, 407, 448, 473, 590, 628 and 660. we show that in the response to HGF or EGF, Gab1 is phosphorylated in vivo on the same residues. However, a sustained activation of signaling pathways downstream to Gab1 (as a result of its sustained phosphorylation) is achieved only in response to HGF.

SIGNOR-250290

Q9UHD2

P42226

1

phosphorylation

up-regulates

0.674

We now show that stat6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger sting (also named mita/eris) to recruit stat6 to the endoplasmic reticulum, leading to stat6 phosphorylation on ser(407) by tbk1 and tyr(641), independent of jaks. Phosphorylated stat6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing.

SIGNOR-176775

Q9UNS1

Q16526

1

binding

up-regulates activity

0.674

We performed a detailed molecular characterization of TIM interactions with the core clock protein CRY1 and the DNA damage signal transducer CHK1, and found that the N-terminus of TIM is required for association with both proteins, as well as for homodimerization.

SIGNOR-268053

P01213

P35372

1

chemical activation

up-regulates activity

0.674

Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.

SIGNOR-258414

O15524

P15260

1

binding

down-regulates

0.674

Suppressor of cytokine signaling (socs)-1, the key negative regulator of interferon (ifn)-gamma-dependent signaling, is induced in response to ifngamma. Socs-1 binds to and inhibits the ifngamma receptor-associated kinase janus-activated kinase (jak) 2 and inhibits its function in vitrothe binding of socs-1 to tyr441 also blocks the access of stat1 to tyr419 and that this effect may be the principal mechanism of inhibition of downstream signaling

SIGNOR-180140

P06493

Q08379

1

phosphorylation

down-regulates

0.674

Cdc2 kinase directly phosphorylates the cis-golgi matrix protein gm130 and is required for golgi fragmentation in mitosis. Mitotic fragmentation of the golgi apparatus can be largely explained by disruption of the interaction between gm130 and the vesicle-docking protein p115. Here we identify a single serine (ser-25) in gm130 as the key phosphorylated target and cdc2 as the responsible kinase

SIGNOR-60281

O95633

O14793

1

binding

down-regulates

0.674

Fstl3 inhibits myostatin via its n-terminal domain.

SIGNOR-199063

O43462

Q12772

1

cleavage

up-regulates activity

0.673

In order to activate transcription, the NH2-terminal domain of the SREBP must be released from the membrane so that it can enter the nucleus. This release has been studied most extensively for one of the SREBPs, namely, SREBP-2. However, the mechanism appears to be similar for the other SREBPs (SREBP-1a and -1c) (1). Release of the NH2-terminal domain is accomplished by a two-step proteolytic event that is regulated by sterols (3). In sterol-depleted mammalian cells, this proteolysis is initiated by the Site-1 protease (S1P), which cleaves human SREBP-2 between the Leu522-Ser523 bond in the sequence RSVL S (4). This cleavage requires formation of a complex between SREBP and SCAP, a polytopic membrane protein of the ER, and it is prevented when this complex is disrupted

SIGNOR-267498

Q13535

Q9BXW9

1

phosphorylation

up-regulates

0.673

In the present study, we identify two novel dna damage-inducible phosphorylation sites on fancd2, threonine 691 and serine 717. Atr phosphorylates fancd2 on these two sites, thereby promoting fancd2 monoubiquitination and enhancing cellular resistance to dna cross-linking agents

SIGNOR-149305

Q06124

P01111

1

dephosphorylation

up-regulates activity

0.673

Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.

SIGNOR-255754

Q9UMX1

O00422

1

binding

up-regulates

0.673

Here we report that the mouse homolog of su(fu) [msu(fu)] specifically interacts with sap18, a component of the msin3 and histone deacetylase complex. In addition, we demonstrate that msu(fu) functionally cooperates with sap18 to repress transcription by recruiting the sap18-msin3 complex to promoters containing the gli-binding element.

SIGNOR-117311

Q9NUX5

O14746

1

binding

up-regulates

0.673

We find that tpp1 and pot1 form a complex with telomeric dna that increases the activity and processivity of the human telomerase core enzyme.

SIGNOR-152327

P49759

Q07955

1

phosphorylation

up-regulates activity

0.673

In a previous study, we showed that CLK1 phosphorylates SRSF1 to a greater extent than SRPK1, inducing a hyper-phosphorylated state that can be readily detected by a gel shift on SDS-PAGE. xref In xref , the phosphorylation of SRSF1 in single turnover experiments using SRPK1 and CLK1 is shown.|Unlike SRPK1, CLK1 induces a unique structural form of SRSF1 observed by SDS-PAGE that is exclusively the result of Ser-Pro rather than Arg-Ser phosphorylation.

SIGNOR-279608

P08254

P07585

1

cleavage

down-regulates quantity by destabilization

0.673

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

SIGNOR-256353

P09544

O75581

1

binding

up-regulates

0.673

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131730

Q6PHR2

P08151

1

phosphorylation

up-regulates activity

0.673

We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro. | Our data suggest that serine/threonine kinase ULK3 is involved in the SHH pathway as a positive regulator of GLI proteins.

SIGNOR-260797

P39905

O00451

1

binding

up-regulates

0.673

Gdnf mediates its actions through a multicomponent receptor system composed of a ligand-binding glycosyl-phosphatidylinositol (gpi)-linked protein (designated gdnfr-alpha).

SIGNOR-49184

P43405

P12318

1

phosphorylation

up-regulates activity

0.673

To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and pointFyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.

SIGNOR-247590

Q9UER7

Q00987

1

binding

up-regulates

0.673

The optimal function of mdm2 requires daxx, which stabilizes mdm2 through the deubiquitinase hausp/usp7 and also directly promotes mdm2's ubiquitin ligase activity towards p53.

SIGNOR-200892

O60603

Q99836

1

binding

up-regulates activity

0.673

To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group

SIGNOR-266740

P45984

P17275

1

binding

down-regulates

0.673

Jnk targets junb ubiquitination

SIGNOR-53827

Q2M1Z3

P60953

1

gtpase-activating protein

down-regulates activity

0.673

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-260490

P08620

P22455

1

binding

up-regulates

0.672

Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.

SIGNOR-18567

O96014

O60353

1

binding

up-regulates activity

0.672

Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.

SIGNOR-141431

P06241

P40259

1

phosphorylation

up-regulates activity

0.672

CD79b cytoplasmic tail-containing GST fusion proteins were phosphorylated in vitro by baculovirus-produced Fyn, >80% of phosphorylation occurred on the N-terminal ITAM tyrosine. CD79a and CD79b function as transducers of B cell antigen receptor signals via a cytoplasmic sequence, termed the immunoreceptor tyrosine-based activation motif (ITAM). pY195 and pY206 in CD79b

SIGNOR-251154

Q16539

Q9BUB5

1

phosphorylation

up-regulates

0.672

Mnk1, but not mnk2, also binds strongly to the stress-activated kinase, p38.

SIGNOR-48346

Q12899

Q14653

1

polyubiquitination

down-regulates quantity by destabilization

0.672

TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.

SIGNOR-272440

P53041

Q16543

1

dephosphorylation

down-regulates activity

0.672

Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37.

SIGNOR-248539

P11142

P13569

1

binding

down-regulates quantity

0.672

JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex

SIGNOR-271492

Q06187

Q9UN19

1

phosphorylation

up-regulates activity

0.672

We present a number of lines of evidence that in vivo, Src-type tyrosine kinases are responsible for the phosphorylation of tyrosine 139 in DAPP-1. | Although Btk appears to phosphorylate DAPP-1 relatively efficiently both in Sf9 cells and in vitro, we find no evidence that in either B cells or PAE cells Btk family kinases phosphorylate DAPP-1.

SIGNOR-250602

P27361

P14921

1

phosphorylation

up-regulates

0.672

We found that hgf/sf activates the erk1 map kinase, leading to the phosphorylation of the threonine 38 residue of ets1

SIGNOR-116494

Q9H2C0

Q13618

1

binding

up-regulates activity

0.672

Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B.

SIGNOR-268944

P51452

P28482

1

dephosphorylation

down-regulates activity

0.672

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.|Catalysis by VHR requires the native structure of ERK and is specific for tyrosine 185 of ERK2

SIGNOR-248536

O75636

P48740

1

binding

up-regulates activity

0.672

H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP.

SIGNOR-263410

P45983

P38936

1

phosphorylation

up-regulates quantity by stabilization

0.672

The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro.

SIGNOR-89440

P45984

P35222

1

phosphorylation

up-regulates

0.671

Beta-catenin, upon entering the nucleus, in turn activates transcription of downstream target genes. Jnk2 phosphorylates Beta-catenin on critical residues (ser191 and ser605). Jnk activity is required for Beta-catenin nuclear localization in response to wnt.

SIGNOR-178258

O75582

Q13541

1

phosphorylation

down-regulates activity

0.671

In response to UV-B irradiation, the translation factor 4E-BP1 (eukaryotic initiation factor 4E [eIF4E]-binding protein 1) was phosphorylated at Thr36, Thr45, Ser64 and Thr69. Using either p38 MAPK inhibitors or the MSK inhibitor H89, UV-B-irradiation-induced phosphorylation was blocked [43]. 4E-BP1 binds to eIF4E in resting cells to prevent formation of a functional eIF4F complex, which is essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 leads to dissociation from eIF4E

SIGNOR-262992

Q9Y297

P10071

1

ubiquitination

down-regulates quantity by destabilization

0.671

Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage.

SIGNOR-145116

P28482

P03372

1

phosphorylation

up-regulates

0.671

In several estrogen response element-containing genes, the s118a mutation strongly reduced induction by e(2), and u0126 did not further reduce expression. Here, we show that serines 104 (s104) and 106 (s106) are also phosphorylated by mapk in vitro and upon stimulation of mapk activity in vivo.

SIGNOR-156856

Q86XK2

P04637

1

neddylation

down-regulates

0.671

Fbxo11 promotes the neddylation of p53 and inhibits its transcriptional activity / we found that fbxo11 also neddylates p53 on two lysines, lys-320 and lys-321

SIGNOR-150669

Q99952

P04626

1

dephosphorylation

down-regulates quantity by destabilization

0.671

PTPN18 knockdown selectively enhances the EGF-induced tyrosine phosphorylation of the HER2 Y1112, Y1196 and Y1248 sites. |Whereas the catalytic domain of PTPN18 blocks lysosomal routing and delays the degradation of HER2 by dephosphorylation of HER2 on pY(1112), the PEST domain of PTPN18 promotes K48-linked HER2 ubiquitination and its rapid destruction via the proteasome pathway and an HER2 negative feedback loop.

SIGNOR-262596

P20393

O00327

1

transcriptional regulation

down-regulates quantity by repression

0.671

In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.

SIGNOR-267983

P12931

Q13905

1

phosphorylation

up-regulates

0.671

C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases.

SIGNOR-128273

P22607

P42224

1

phosphorylation

up-regulates activity

0.671

Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.

SIGNOR-251138

Q96EQ8

O95786

1

polyubiquitination

down-regulates quantity by destabilization

0.671

Here, we found that RIG-I undergoes proteasomal degradation after conjugation to ubiquitin by RNF125. Further, RNF125 conjugates ubiquitin to MDA5, a family protein of RIG-I as well as IPS-1, which is also a downstream protein of RIG-I signaling that results in suppressing the functions of these proteins. Because RNF125 is enhanced by IFN, these functions constitute a negative regulatory loop circuit for IFN production.

SIGNOR-271647

Q96BN8

P0CG47

1

cleavage

up-regulates quantity

0.671

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-270819

O95988

P31749

1

binding

up-regulates

0.671

In vivo, tcl1 forms trimers, which associate with akt. Tcl1 facilitates the oligomerization and activation of akt. Our data show that tcl1 is a novel akt kinase coactivator, which promotes akt-induced cell survival and proliferation.

SIGNOR-81713

Q9NTX7

Q9Y2T1

1

ubiquitination

down-regulates quantity by destabilization

0.671

Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.

SIGNOR-263336

Q15797

Q13485

1

phosphorylation

up-regulates

0.671

Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common(co-Smad; Smad4 in mammals) and shuttle into the nucleus.

SIGNOR-168734