GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P12931	O14746	1	phosphorylation	down-regulates	0.418	Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via src kinase family-dependent phosphorylation of tyrosine 707	SIGNOR-102097
P18846	P35680	2	binding	up-regulates activity	0.307	The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays.	SIGNOR-241320
P40763	P08581	0	phosphorylation	up-regulates activity	0.706	It has been reported that c-Met can activate STAT3 at the endosome and phosphorylated STAT3 induced by c-Met is colocalized with EEA1, an early endosome marker.	SIGNOR-280041
P78368	O15534	1	phosphorylation	down-regulates	0.394	Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1.	SIGNOR-137751
Q96BI3	P49810	2	binding	up-regulates	0.923	Gamma secretase subunit. Leads to ps1/ps2 eterodimer complex stabilisation. By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.	SIGNOR-93265
P01116	Q92565	0	guanine nucleotide exchange factor	up-regulates	0.436	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183735
Q96CW9	Q9HBW1	2	binding	up-regulates activity	0.73	The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.	SIGNOR-264048
P01185	P30518	2	binding	up-regulates	0.738	We report here the cloning of a complementary dna encoding the hepatic v1a arginine vasopressin receptor. The liver cdna encodes a protein with seven putative transmembrane domains, which binds arginine vasopressin.	SIGNOR-20185
P0C0L4	P48740	0	cleavage	up-regulates activity	0.606	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-263438
P20248	Q6P3R8	2	binding	up-regulates activity	0.2	NEK5 promotes breast cancer cell proliferation through up-regulation of Cyclin A2	SIGNOR-273874
Q02962	P19544	2	transcriptional regulation	up-regulates quantity by expression	0.598	Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter.	SIGNOR-252290
P46100	O96006	2	binding	up-regulates activity	0.413	XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression.	SIGNOR-239729
O96017	Q9H4B4	0	phosphorylation	up-regulates activity	0.66	Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.	SIGNOR-276051
P35813	P84022	1	dephosphorylation	down-regulates activity	0.622	Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.	SIGNOR-232110
P78317	P41229	1	sumoylation	up-regulates activity	0.2	Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015).	SIGNOR-271576
Q92974	Q7KZI7	0	phosphorylation	down-regulates	0.503	We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation	SIGNOR-177100
O60610	P61586	0	null	up-regulates activity	0.785	We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.\|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.	SIGNOR-253108
O43612	O43614	2	binding	up-regulates	0.776	Identification and initial biological characterization of two orexins as well as their two receptors	SIGNOR-55848
O14757	Q92934	1	phosphorylation	down-regulates activity	0.2	Chkl binds and phosphorylates BAD protein.\|Taken together, our results suggest that Chk1 may inactivate BAD by associating with and phosphorylating residues critical for BAD function in response to DNA damage.	SIGNOR-279159
Q9UHD2	P06239	0	phosphorylation	down-regulates activity	0.2	The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.	SIGNOR-276724
P36507	P27361	1	phosphorylation	up-regulates	0.742	The primary structure of mek, a protein kinase that phosphorylates the erk gene product	SIGNOR-19244
P16220	Q9Y2T3	1	transcriptional regulation	up-regulates quantity by expression	0.2	In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches.	SIGNOR-268968
P10398	Q15796	1	phosphorylation	down-regulates quantity by destabilization	0.37	Araf promotes Smad2 linker phosphorylation through S253.\|In this study, we demonstrate that Araf can directly bind to and phosphorylate the linker of Smad2, leading to degradation of activated Smad2.	SIGNOR-279391
P01019-PRO_0000032458	P30556	2	binding	up-regulates activity	0.2	Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways	SIGNOR-260238
P19338	P10242	2	binding	down-regulates activity	0.401	We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity.	SIGNOR-221236
P20701	O60674	0	phosphorylation	up-regulates activity	0.268	PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.	SIGNOR-254739
Q16539	P47712	1	phosphorylation	up-regulates activity	0.668	These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets	SIGNOR-44673
Q13200	Q9P1W9	0	phosphorylation	up-regulates activity	0.2	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).	SIGNOR-273896
P54727	P35244	2	binding	up-regulates activity	0.522	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275700
P15927	O60934	2	binding	up-regulates	0.548	The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex. We observe a direct interaction between rpa with both nbs1 and mre11. By utilizing rpa bound to ssdna, we demonstrate that substituting rpa with phosphorylated rpa or a phosphomimetic weakens the interaction with the mrn complex.	SIGNOR-186651
Q13164	P29590	1	phosphorylation	down-regulates activity	0.474	Big MAP kinase 1 (BMK1) also phosphorylates PML at two sites : S403 and T409.\|Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation.	SIGNOR-279074
Q8IVL1	Q9ULU4	0	transcriptional regulation	up-regulates quantity by expression	0.2	We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.	SIGNOR-266209
P35222	Q6P1J9	2	binding	up-regulates	0.695	Parafibromin/hyrax activates wnt/wg target gene transcription by direct association with beta-catenin/armadillo	SIGNOR-146282
P29350	Q14247	1	dephosphorylation	down-regulates activity	0.2	Shp1 interacts with cortactin and reduces cortactin phosphorylation at tyrosine 421; 3.\|induction of Shp1-cortactin complex formation impairs cortactin scaffolding-activity and negatively affects invadopodia behaviour; 4.	SIGNOR-277003
Q13546	Q8WZ73	0	ubiquitination	down-regulates quantity by destabilization	0.468	We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappaB activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation.	SIGNOR-271482
P06213	Q07666	1	phosphorylation	up-regulates activity	0.363	Thus, Tyr phosphorylation of Sam68 by IR could modulate its association with the splicing machinery in a similar way to that described for p59 fyn, and this way, it could influence splice site selection.	SIGNOR-278946
Q14596	Q13501	2	binding	up-regulates	0.472	Nbr1 and p62 interact and form oligomers.	SIGNOR-184273
P46734	Q5S007	0	phosphorylation	up-regulates activity	0.393	LRRK2 phosphorylates MKK3 and MKK7 in vitro but has a relatively minor effect on MKK6 phosphorylation.	SIGNOR-279057
Q16539	Q16690	0	dephosphorylation	down-regulates	0.537	The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues.	SIGNOR-166574
Q96LB1	P09471	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257260
Q86Y07	O75531	1	phosphorylation	down-regulates	0.502	We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell	SIGNOR-143368
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
Q9H161	Q9UJU2	2	binding	up-regulates quantity by expression	0.445	Alx4 Stably Interacts with LEF-1. LEF-1 enhances Alx4 binding to DNA, suggesting that both interaction with LEF-1 and DNA binding are required to mediate its effects on the N-CAM promoter.	SIGNOR-254547
O14920	Q9UHD2	2	binding	up-regulates	0.403	A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway.	SIGNOR-121576
Q9NQU5	P35222	1	phosphorylation	down-regulates quantity	0.2	Moreover, we find that \u03b2-catenin is also localized with PAK6 in cell-cell junctions and is a novel PAK6 substrate.\|PAK6 binds to and phosphorylates beta-catenin.	SIGNOR-279546
O14965	P68431	1	phosphorylation	up-regulates activity	0.2	Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.	SIGNOR-98289
P33076	Q92769	0	deacetylation	down-regulates quantity by repression	0.413	We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays.	SIGNOR-254231
P36897	O75604	0	deubiquitination	up-regulates activity	0.2	Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1.	SIGNOR-273605
O60341	Q96BD5	2	binding	down-regulates activity	0.716	BHC80 Inhibits LSD1 Demethylase Activity In Vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity.	SIGNOR-264505
P15172	P17252	0	phosphorylation	down-regulates activity	0.363	FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains.	SIGNOR-248845
Q14493	P0C0S5	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265408
Q6UB99	Q9BR76	1	transcriptional regulation	up-regulates quantity by expression	0.2	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.	SIGNOR-266737
P06493	O15151	1	phosphorylation	down-regulates	0.407	Cdc2p34 phosphorylates mdmx on ser 96 in vitro. Mutation within this site (mdmx(s96a)) impairs, whereas phosphomimic substitution (mdmx(s96d)) increases the cytoplasmic localization of mdmx, suggesting that cdk2/cdc2p34 phosphorylation is required for export of mdmx from the nucleus	SIGNOR-134388
Q9NR19	Q13131	0	phosphorylation	up-regulates activity	0.275	This translocation is mediated by AMP-activated protein kinase (AMPK)-dependent ACSS2 Ser659 phosphorylation and subsequent exposure of the nuclear localization signal of ACSS2 to KPNA1/importin α5 for binding. In the nucleus, ACSS2 forms a complex with TFEB (transcription factor EB) and utilizes the acetate generated from histone deacetylation to locally produce acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes.	SIGNOR-271822
O75581	P12830	2	binding	up-regulates	0.363	P12Beta-catenin_ also associates to the_ wnt_ co-receptor lrp5/6, an interaction mediated by e-cadherin.	SIGNOR-168464
P49910	Q969W9	1	transcriptional regulation	down-regulates quantity by repression	0.271	ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1.	SIGNOR-266094
P28356	O00470	2	binding	up-regulates activity	0.508	We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9	SIGNOR-220721
Q9UN19	P06239	0	phosphorylation	up-regulates activity	0.646	Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines\|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins.	SIGNOR-249373
Q9Y4L5	P01106	1	ubiquitination	down-regulates quantity by destabilization	0.448	These results suggest that Rabring7 antagonizes function of c-Myc possibly through degradation of c-Myc.\|Unexpectedly, we found that Rabring7 more strongly binds to c-Myc than to MM-1 (XREF_FIG) and that Rabring7 stimulates poly-ubiquitination of c-Myc in a T58 dependent manner (XREF_FIG).	SIGNOR-278662
Q07817	Q14457	2	binding	down-regulates	0.915	The anti-apoptotic proteins bcl-2 and bcl-x(l) bind and inhibit beclin-1, an essential mediator of autophagy.	SIGNOR-154480
P67775	Q8TD08	1	dephosphorylation	down-regulates	0.289	Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20%	SIGNOR-142977
Q9NQ66	P63092	2	binding	up-regulates activity	0.324	The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits.	SIGNOR-265066
Q96GD4	Q92974	1	phosphorylation	down-regulates activity	0.25	The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity.	SIGNOR-276062
P12644	Q04206	0	transcriptional regulation	down-regulates quantity by repression	0.2	Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells	SIGNOR-266087
P84022	P59595	2	binding	up-regulates activity	0.2	In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis.	SIGNOR-260434
P08603	P01024	2	binding	down-regulates activity	0.918	As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)	SIGNOR-252141
P12830	Q05655	0	phosphorylation	down-regulates activity	0.2	Phosphorylation of E-cadherin at threonine 790 by protein kinase Cδ reduces β-catenin binding and suppresses the function of E-cadherin.	SIGNOR-260893
P12931	O14744	1	phosphorylation	down-regulates activity	0.261	Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity.	SIGNOR-277523
P23246	Q9UM73	0	phosphorylation	down-regulates	0.2	Furthermore, psf was shown to be a direct substrate of purified alk kinase domain in vitro, and psf tyr293 was identified as the site of phosphorylation. Psf phosphorylation also increased its binding to rna and decreased the psf-mediated suppression of gage6 expression.	SIGNOR-155298
Q99836	Q9Y4K3	2	binding	up-regulates activity	0.922	In innate immunity, nearly all Toll-like receptors (TLRs), as well as the receptors of the interleukin 1 (IL-1) family of cytokines, initiate signaling by recruiting the adaptor protein MyD88. This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8, 9). IRAK1 and IRAK2 can then interact with TRAF6 (10, 11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity	SIGNOR-260160
P37173	P36897	1	phosphorylation	up-regulates activity	0.722	Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta	SIGNOR-246728
Q92985	Q9UHD2	0	phosphorylation	up-regulates activity	0.768	In most cell types, IRF7 is phosphorylated and activated by IKK\u03b5 and TBK1 after viral infection.\|We found that phosphorylation of IRF7 on Ser477 and Ser479 by IKK\u03b5 or TBK1 is inhibited by ORF45.	SIGNOR-278216
O00141	P14672	1	phosphorylation	up-regulates activity	0.312	We evaluated the putative role of sgk1 in the modulation of glut4. Coexpression of the kinase along with glut4 in xenopus oocytes stimulated glucose transport. The enhanced glut4 activity was paralleled by increased transporter abundance in the plasma membrane. Disruption of the sgk1 phosphorylation site on glut4 ((s274a)glut4) abrogated the stimulating effect of sgk1. In summary, sgk1 promotes glucose transporter membrane abundance via glut4 phosphorylation at ser274.	SIGNOR-236653
Q99523	P02649	2	binding	up-regulates quantity	0.427	Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms.	SIGNOR-273721
Q13191	P10721	1	ubiquitination	down-regulates activity	0.328	KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT.	SIGNOR-260105
Q9Y243	O15111	1	phosphorylation	up-regulates	0.414	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-187062
Q01718	P42127	2	binding	down-regulates activity	0.498	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and α, β, and γ melanocyte–stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268695
P00519	Q8N488	2	binding	down-regulates	0.333	We identified a novel protein, aap1 (abl-associated protein 1), that associates with these c-abl domains and fails to bind to the sh3 domain in the activated oncoprotein bcrabl. we conclude that aap1 inhibits c-abl tyrosine kinase activity	SIGNOR-45325
Q8WZ42	O15273	2	binding	up-regulates activity	0.908	TCAP, a core sarcomeric component capping the titin proteins, was identified as a positive hit (Figure 1A). TCAP is a small (19 kDa), highly abundant cytoplasmic protein expressed exclusively in skeletal muscle and the heart (Valle et al., 1997). TCAP interacts with titin through its N-terminal beta sheet to anchor titin to the Z-disc	SIGNOR-264854
O43889	P68400	0	phosphorylation	down-regulates quantity by destabilization	0.2	Here, we found that human CREB3 is phosphorylated within its transcription activation domain on serine 46 by protein kinase CK2. However, phosphorylation at serine 46 reduced the stability of CREB3.	SIGNOR-277501
O75155	Q15386	0	ubiquitination	down-regulates quantity by destabilization	0.39	We show that KIAA10 indeed associates with 26 S proteasomes in mammalian cells but that this interaction is likely to depend on contacts with a subunit(s) besides S2/Rpn1. Most importantly, we provide strong evidence that TIP120B (TBP-interacting protein 120B (22)) is a specific substrate that is targeted for degradation in skeletal muscle through KIAA10-catalyzed polyubiquitination.	SIGNOR-271454
Q13237	Q12778	1	phosphorylation	up-regulates activity	0.356	Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2.	SIGNOR-279564
P0DP25	Q96RR4	2	binding	up-regulates	0.588	The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk.	SIGNOR-266345
P25103	O95837	2	binding	up-regulates activity	0.433	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257423
Q9H981	Q13315	0	phosphorylation	down-regulates activity	0.2	These findings indicate that ATM dependent phosphorylation on ARP8-S412 reduces ARP8 INO80 interaction.\|These findings raised the possibility that ATM negatively regulates the interaction of ARP8 with INO80 after etoposide treatment.	SIGNOR-279437
O15151	P31749	0	phosphorylation	up-regulates quantity by stabilization	0.509	We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2.	SIGNOR-252517
P11388	P05129	0	phosphorylation	up-regulates activity	0.359	Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. \| Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides.	SIGNOR-249196
Q04206	O14920	0	phosphorylation	up-regulates activity	0.886	Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k). We now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. Ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536.	SIGNOR-138903
P12830	P48730	0	phosphorylation	down-regulates activity	0.27	Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts\|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846	SIGNOR-274046
O94826	P07900	2	binding	up-regulates activity	0.2	The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting.	SIGNOR-261379
P68363	Q14980	2	binding	up-regulates	0.263	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116472
P36894	Q13253	2	binding	down-regulates activity	0.611	Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955).Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors.	SIGNOR-219221
Q9UPY8	Q96GD4	0	phosphorylation	up-regulates	0.472	Phosphorylation of eb3 at s176 by aurora b ensures successful cytokinesis completion by promoting midbody mt stability and midbody stabilization.	SIGNOR-202130
P68400	Q9ULV4	1	phosphorylation	up-regulates	0.2	We demonstrate that crn2 is a binding partner and substrate of protein kinase ck2, which phosphorylates crn2 at s463 in its c-terminal coiled coil domain	SIGNOR-196193
P35222	P33151	2	binding	up-regulates activity	0.76	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265867
P50052	P01019-PRO_0000032458	2	binding	up-regulates activity	0.2	Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways	SIGNOR-260237
Q03431	P50148	2	binding	up-regulates activity	0.275	This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11.	SIGNOR-270550
Q9P0J1	P24752	0	acetylation	down-regulates activity	0.34	We previously reported that the mitochondrial fraction of FLT3 activates acetyl-CoA acetyltransferase ACAT1 in mitochondria via Y407 phosphorylation to acetylate and inhibit mitochondrial pyruvate dehydrogenase A (PDHA) and PDH phosphatase 1 (PDP1)	SIGNOR-267635
P01375	P19438	2	binding	up-regulates activity	0.925	For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling.	SIGNOR-199091
P01106	Q9ULJ6	0	transcriptional regulation	up-regulates quantity by expression	0.362	The N-terminal domain (NTD) of Zmiz1 is important for driving Myc transcription and proliferation […] Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites.	SIGNOR-263939

P12931

O14746

1

phosphorylation

down-regulates

0.418

Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via src kinase family-dependent phosphorylation of tyrosine 707

SIGNOR-102097

P18846

P35680

2

binding

up-regulates activity

0.307

The mammalian two-hybrid system showed that the region aa 393 to 476 of LFB3 is involved in the interaction with CREB or ATF1. The importance of this region for mediating cAMP induction was confirmed in transient transfection assays.

SIGNOR-241320

P40763

P08581

0

phosphorylation

up-regulates activity

0.706

It has been reported that c-Met can activate STAT3 at the endosome and phosphorylated STAT3 induced by c-Met is colocalized with EEA1, an early endosome marker.

SIGNOR-280041

P78368

O15534

1

phosphorylation

down-regulates

0.394

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

SIGNOR-137751

Q96BI3

P49810

2

binding

up-regulates

0.923

Gamma secretase subunit. Leads to ps1/ps2 eterodimer complex stabilisation. By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.

SIGNOR-93265

P01116

Q92565

0

guanine nucleotide exchange factor

up-regulates

0.436

Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.

SIGNOR-183735

Q96CW9

Q9HBW1

2

binding

up-regulates activity

0.73

The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.

SIGNOR-264048

P01185

P30518

2

binding

up-regulates

0.738

We report here the cloning of a complementary dna encoding the hepatic v1a arginine vasopressin receptor. The liver cdna encodes a protein with seven putative transmembrane domains, which binds arginine vasopressin.

SIGNOR-20185

P0C0L4

P48740

0

cleavage

up-regulates activity

0.606

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-263438

P20248

Q6P3R8

2

binding

up-regulates activity

0.2

NEK5 promotes breast cancer cell proliferation through up-regulation of Cyclin A2

SIGNOR-273874

Q02962

P19544

2

transcriptional regulation

up-regulates quantity by expression

0.598

Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter.

SIGNOR-252290

P46100

O96006

2

binding

up-regulates activity

0.413

XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression.

SIGNOR-239729

O96017

Q9H4B4

0

phosphorylation

up-regulates activity

0.66

Plk3 phosphorylates Chk2 at two residues, serine 62 (S62) and serine 73 (S73) in vitro, and this phosphorylation facilitates subsequent phosphorylation of Chk2 on T68 by ATM in response to DNA damage. When the Chk2 mutant construct GFP-Chk2 S73A (serine 73 mutated to alanine) is transfected into cells, it no longer associates with a large complex in vivo, and manifests a significant reduction in kinase activity.

SIGNOR-276051

P35813

P84022

1

dephosphorylation

down-regulates activity

0.622

Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.

SIGNOR-232110

P78317

P41229

1

sumoylation

up-regulates activity

0.2

Hendriks and coworkers showed that, in response to alkylation damage by methyl methanesulfonate (MMS), SUMOylated JARID1B (KDM5B) is ubiquitylated by the SUMOtargeted ubiquitin ligase RNF4 and degraded by the proteasome, whereas JARID1C (KDM5C) is SUMOylated and recruited to the chromatin to demethylate histone H3K4 (Hendriks et al., 2015).

SIGNOR-271576

Q92974

Q7KZI7

0

phosphorylation

down-regulates

0.503

We also show that par1b-induced serine 885/serine 959 phosphorylation inhibits rhoa-specific gef activity of gef-h1. As a consequence, gef-h1 phosphorylated on both of the serine residues loses the ability to stimulate rhoa and thereby fails to induce rhoa-dependent stress fiber formation

SIGNOR-177100

O60610

P61586

0

null

up-regulates activity

0.785

We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.

SIGNOR-253108

O43612

O43614

2

binding

up-regulates

0.776

Identification and initial biological characterization of two orexins as well as their two receptors

SIGNOR-55848

O14757

Q92934

1

phosphorylation

down-regulates activity

0.2

Chkl binds and phosphorylates BAD protein.|Taken together, our results suggest that Chk1 may inactivate BAD by associating with and phosphorylating residues critical for BAD function in response to DNA damage.

SIGNOR-279159

Q9UHD2

P06239

0

phosphorylation

down-regulates activity

0.2

The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.

SIGNOR-276724

P36507

P27361

1

phosphorylation

up-regulates

0.742

The primary structure of mek, a protein kinase that phosphorylates the erk gene product

SIGNOR-19244

P16220

Q9Y2T3

1

transcriptional regulation

up-regulates quantity by expression

0.2

In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches.

SIGNOR-268968

P10398

Q15796

1

phosphorylation

down-regulates quantity by destabilization

0.37

Araf promotes Smad2 linker phosphorylation through S253.|In this study, we demonstrate that Araf can directly bind to and phosphorylate the linker of Smad2, leading to degradation of activated Smad2.

SIGNOR-279391

P01019-PRO_0000032458

P30556

2

binding

up-regulates activity

0.2

Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways

SIGNOR-260238

P19338

P10242

2

binding

down-regulates activity

0.401

We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity.

SIGNOR-221236

P20701

O60674

0

phosphorylation

up-regulates activity

0.268

PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.

SIGNOR-254739

Q16539

P47712

1

phosphorylation

up-regulates activity

0.668

These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets

SIGNOR-44673

Q13200

Q9P1W9

0

phosphorylation

up-regulates activity

0.2

Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).

SIGNOR-273896

P54727

P35244

2

binding

up-regulates activity

0.522

GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo

SIGNOR-275700

P15927

O60934

2

binding

up-regulates

0.548

The response to replication stress requires the recruitment of rpa and the mre11-rad50-nbs1 (mrn) complex. We observe a direct interaction between rpa with both nbs1 and mre11. By utilizing rpa bound to ssdna, we demonstrate that substituting rpa with phosphorylated rpa or a phosphomimetic weakens the interaction with the mrn complex.

SIGNOR-186651

Q13164

P29590

1

phosphorylation

down-regulates activity

0.474

Big MAP kinase 1 (BMK1) also phosphorylates PML at two sites : S403 and T409.|Mutational analysis demonstrated that BMK1 drives suppression of PML directly through its phosphorylation.

SIGNOR-279074

Q8IVL1

Q9ULU4

0

transcriptional regulation

up-regulates quantity by expression

0.2

We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.

SIGNOR-266209

P35222

Q6P1J9

2

binding

up-regulates

0.695

Parafibromin/hyrax activates wnt/wg target gene transcription by direct association with beta-catenin/armadillo

SIGNOR-146282

P29350

Q14247

1

dephosphorylation

down-regulates activity

0.2

Shp1 interacts with cortactin and reduces cortactin phosphorylation at tyrosine 421; 3.|induction of Shp1-cortactin complex formation impairs cortactin scaffolding-activity and negatively affects invadopodia behaviour; 4.

SIGNOR-277003

Q13546

Q8WZ73

0

ubiquitination

down-regulates quantity by destabilization

0.468

We report that CARP-2, a RING domain-containing ubiquitin protein ligase (E3), is a negative regulator of TNF-induced NF-kappaB activation. By virtue of its phospholipid-binding FYVE domain, CARP-2 localized to endocytic vesicles, where it interacted with internalized TNF-receptor complex, resulting in RIP ubiquitination and degradation.

SIGNOR-271482

P06213

Q07666

1

phosphorylation

up-regulates activity

0.363

Thus, Tyr phosphorylation of Sam68 by IR could modulate its association with the splicing machinery in a similar way to that described for p59 fyn, and this way, it could influence splice site selection.

SIGNOR-278946

Q14596

Q13501

2

binding

up-regulates

0.472

Nbr1 and p62 interact and form oligomers.

SIGNOR-184273

P46734

Q5S007

0

phosphorylation

up-regulates activity

0.393

LRRK2 phosphorylates MKK3 and MKK7 in vitro but has a relatively minor effect on MKK6 phosphorylation.

SIGNOR-279057

Q16539

Q16690

0

dephosphorylation

down-regulates

0.537

The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues.

SIGNOR-166574

Q96LB1

P09471

2

binding

up-regulates activity

0.2

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

SIGNOR-257260

Q86Y07

O75531

1

phosphorylation

down-regulates

0.502

We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell

SIGNOR-143368

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

Q9H161

Q9UJU2

2

binding

up-regulates quantity by expression

0.445

Alx4 Stably Interacts with LEF-1. LEF-1 enhances Alx4 binding to DNA, suggesting that both interaction with LEF-1 and DNA binding are required to mediate its effects on the N-CAM promoter.

SIGNOR-254547

O14920

Q9UHD2

2

binding

up-regulates

0.403

A physical and functional map of the human tnf-alpha/nf-kappa b signal transduction pathway.

SIGNOR-121576

Q9NQU5

P35222

1

phosphorylation

down-regulates quantity

0.2

Moreover, we find that \u03b2-catenin is also localized with PAK6 in cell-cell junctions and is a novel PAK6 substrate.|PAK6 binds to and phosphorylates beta-catenin.

SIGNOR-279546

O14965

P68431

1

phosphorylation

up-regulates activity

0.2

Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. Phosphorylation at ser-11 (h3s10ph) by aurkb is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis.

SIGNOR-98289

P33076

Q92769

0

deacetylation

down-regulates quantity by repression

0.413

We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays.

SIGNOR-254231

P36897

O75604

0

deubiquitination

up-regulates activity

0.2

Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1.

SIGNOR-273605

O60341

Q96BD5

2

binding

down-regulates activity

0.716

BHC80 Inhibits LSD1 Demethylase Activity In Vitro. in contrast to CoREST, which is a positive regulator of LSD1 activity, the in vitro evidence presented above suggests that BHC80 may function to inhibit LSD1 activity.

SIGNOR-264505

P15172

P17252

0

phosphorylation

down-regulates activity

0.363

FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains.

SIGNOR-248845

Q14493

P0C0S5

1

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265408

Q6UB99

Q9BR76

1

transcriptional regulation

up-regulates quantity by expression

0.2

Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.

SIGNOR-266737

P06493

O15151

1

phosphorylation

down-regulates

0.407

Cdc2p34 phosphorylates mdmx on ser 96 in vitro. Mutation within this site (mdmx(s96a)) impairs, whereas phosphomimic substitution (mdmx(s96d)) increases the cytoplasmic localization of mdmx, suggesting that cdk2/cdc2p34 phosphorylation is required for export of mdmx from the nucleus

SIGNOR-134388

Q9NR19

Q13131

0

phosphorylation

up-regulates activity

0.275

This translocation is mediated by AMP-activated protein kinase (AMPK)-dependent ACSS2 Ser659 phosphorylation and subsequent exposure of the nuclear localization signal of ACSS2 to KPNA1/importin α5 for binding. In the nucleus, ACSS2 forms a complex with TFEB (transcription factor EB) and utilizes the acetate generated from histone deacetylation to locally produce acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes.

SIGNOR-271822

O75581

P12830

2

binding

up-regulates

0.363

P12Beta-catenin_ also associates to the_ wnt_ co-receptor lrp5/6, an interaction mediated by e-cadherin.

SIGNOR-168464

P49910

Q969W9

1

transcriptional regulation

down-regulates quantity by repression

0.271

ZNF165 drives the unrestrained activation of transforming growth factor β (TGFβ) signalling by directly inactivating the expression of negative feedback pathway regulators, SMURF2, SMAD7 and PMEPA1.

SIGNOR-266094

P28356

O00470

2

binding

up-regulates activity

0.508

We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9

SIGNOR-220721

Q9UN19

P06239

0

phosphorylation

up-regulates activity

0.646

Src family kinases mediate receptor-stimulated, phosphoinositide 3-kinase-dependent, tyrosine phosphorylation of dual adaptor for phosphotyrosine and 3-phosphoinositides-1 in endothelial and B cell lines|yrosine phosphorylation of DAPP-1 appears important for appropriate intracellular targeting and creates a potential binding site for Src homology 2 domain-containing proteins.

SIGNOR-249373

Q9Y4L5

P01106

1

ubiquitination

down-regulates quantity by destabilization

0.448

These results suggest that Rabring7 antagonizes function of c-Myc possibly through degradation of c-Myc.|Unexpectedly, we found that Rabring7 more strongly binds to c-Myc than to MM-1 (XREF_FIG) and that Rabring7 stimulates poly-ubiquitination of c-Myc in a T58 dependent manner (XREF_FIG).

SIGNOR-278662

Q07817

Q14457

2

binding

down-regulates

0.915

The anti-apoptotic proteins bcl-2 and bcl-x(l) bind and inhibit beclin-1, an essential mediator of autophagy.

SIGNOR-154480

P67775

Q8TD08

1

dephosphorylation

down-regulates

0.289

Erk8 (extracellular-signal-regulated protein kinase 8) expressed in escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the thr-glu-tyr motif. Dephosphorylation of the threonine residue by pp2a (protein serine/threonine phosphatase 2a) decreased erk8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by ptp1b (protein tyrosine phosphatase 1b) decreased activity by only 15-20%

SIGNOR-142977

Q9NQ66

P63092

2

binding

up-regulates activity

0.324

The beta- but not the gamma- and delta-type isozymes of inositol phospholipid-specific phospholipase c (plc) are activated by g protein alpha q and beta gamma subunits.

SIGNOR-265066

Q96GD4

Q92974

1

phosphorylation

down-regulates activity

0.25

The mitotic kinases Aurora A/B and Cdk1/Cyclin B phosphorylate GEF-H1, thereby inhibiting GEF-H1 catalytic activity.

SIGNOR-276062

P12644

Q04206

0

transcriptional regulation

down-regulates quantity by repression

0.2

Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells

SIGNOR-266087

P84022

P59595

2

binding

up-regulates activity

0.2

In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis.

SIGNOR-260434

P08603

P01024

2

binding

down-regulates activity

0.918

As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)

SIGNOR-252141

P12830

Q05655

0

phosphorylation

down-regulates activity

0.2

Phosphorylation of E-cadherin at threonine 790 by protein kinase Cδ reduces β-catenin binding and suppresses the function of E-cadherin.

SIGNOR-260893

P12931

O14744

1

phosphorylation

down-regulates activity

0.261

Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity.

SIGNOR-277523

P23246

Q9UM73

0

phosphorylation

down-regulates

0.2

Furthermore, psf was shown to be a direct substrate of purified alk kinase domain in vitro, and psf tyr293 was identified as the site of phosphorylation. Psf phosphorylation also increased its binding to rna and decreased the psf-mediated suppression of gage6 expression.

SIGNOR-155298

Q99836

Q9Y4K3

2

binding

up-regulates activity

0.922

In innate immunity, nearly all Toll-like receptors (TLRs), as well as the receptors of the interleukin 1 (IL-1) family of cytokines, initiate signaling by recruiting the adaptor protein MyD88. This is followed by the interaction of IL-1-receptor (IL-R)-associated kinase 4 (IRAK4) with MyD88 and then the interaction of other IRAK family members with IRAK4, to form an oligomeric complex, termed the Myddosome (8, 9). IRAK1 and IRAK2 can then interact with TRAF6 (10, 11) and induce TRAF6 dimerization (12), which triggers the activation of its E3 ligase activity

SIGNOR-260160

P37173

P36897

1

phosphorylation

up-regulates activity

0.722

Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta

SIGNOR-246728

Q92985

Q9UHD2

0

phosphorylation

up-regulates activity

0.768

In most cell types, IRF7 is phosphorylated and activated by IKK\u03b5 and TBK1 after viral infection.|We found that phosphorylation of IRF7 on Ser477 and Ser479 by IKK\u03b5 or TBK1 is inhibited by ORF45.

SIGNOR-278216

O00141

P14672

1

phosphorylation

up-regulates activity

0.312

We evaluated the putative role of sgk1 in the modulation of glut4. Coexpression of the kinase along with glut4 in xenopus oocytes stimulated glucose transport. The enhanced glut4 activity was paralleled by increased transporter abundance in the plasma membrane. Disruption of the sgk1 phosphorylation site on glut4 ((s274a)glut4) abrogated the stimulating effect of sgk1. In summary, sgk1 promotes glucose transporter membrane abundance via glut4 phosphorylation at ser274.

SIGNOR-236653

Q99523

P02649

2

binding

up-regulates quantity

0.427

Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms.

SIGNOR-273721

Q13191

P10721

1

ubiquitination

down-regulates activity

0.328

KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT.

SIGNOR-260105

Q9Y243

O15111

1

phosphorylation

up-regulates

0.414

Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta

SIGNOR-187062

Q01718

P42127

2

binding

down-regulates activity

0.498

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

SIGNOR-268695

P00519

Q8N488

2

binding

down-regulates

0.333

We identified a novel protein, aap1 (abl-associated protein 1), that associates with these c-abl domains and fails to bind to the sh3 domain in the activated oncoprotein bcrabl. we conclude that aap1 inhibits c-abl tyrosine kinase activity

SIGNOR-45325

Q8WZ42

O15273

2

binding

up-regulates activity

0.908

TCAP, a core sarcomeric component capping the titin proteins, was identified as a positive hit (Figure 1A). TCAP is a small (19 kDa), highly abundant cytoplasmic protein expressed exclusively in skeletal muscle and the heart (Valle et al., 1997). TCAP interacts with titin through its N-terminal beta sheet to anchor titin to the Z-disc

SIGNOR-264854

O43889

P68400

0

phosphorylation

down-regulates quantity by destabilization

0.2

Here, we found that human CREB3 is phosphorylated within its transcription activation domain on serine 46 by protein kinase CK2. However, phosphorylation at serine 46 reduced the stability of CREB3.

SIGNOR-277501

O75155

Q15386

0

ubiquitination

down-regulates quantity by destabilization

0.39

We show that KIAA10 indeed associates with 26 S proteasomes in mammalian cells but that this interaction is likely to depend on contacts with a subunit(s) besides S2/Rpn1. Most importantly, we provide strong evidence that TIP120B (TBP-interacting protein 120B (22)) is a specific substrate that is targeted for degradation in skeletal muscle through KIAA10-catalyzed polyubiquitination.

SIGNOR-271454

Q13237

Q12778

1

phosphorylation

up-regulates activity

0.356

Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2.

SIGNOR-279564

P0DP25

Q96RR4

2

binding

up-regulates

0.588

The ca2+-calmodulin-dependent protein kinase (cam kinase) cascade includes three kinases: cam-kinase kinase (camkk);and the cam kinases camki and camkiv, which are phosphorylated and activated by camkk.

SIGNOR-266345

P25103

O95837

2

binding

up-regulates activity

0.433

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

SIGNOR-257423

Q9H981

Q13315

0

phosphorylation

down-regulates activity

0.2

These findings indicate that ATM dependent phosphorylation on ARP8-S412 reduces ARP8 INO80 interaction.|These findings raised the possibility that ATM negatively regulates the interaction of ARP8 with INO80 after etoposide treatment.

SIGNOR-279437

O15151

P31749

0

phosphorylation

up-regulates quantity by stabilization

0.509

We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2.

SIGNOR-252517

P11388

P05129

0

phosphorylation

up-regulates activity

0.359

Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides.

SIGNOR-249196

Q04206

O14920

0

phosphorylation

up-regulates activity

0.886

Rela is phosphorylated at ser536 by ikkbeta, ikkalfa, ikkepsilon, nf-kb activating kinase (nak, also known as tank-binding kinase-1 tbk1) and rsk1 (also known as p90 ribosomal protein s6 kinase (p90s6k). We now present evidence that suggests that the upstream kinase ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536. Ikkbeta plays an important role in tax-induced p53 inhibition through phosphorylation of p65/rela at ser-536.

SIGNOR-138903

P12830

P48730

0

phosphorylation

down-regulates activity

0.27

Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts|CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846

SIGNOR-274046

O94826

P07900

2

binding

up-regulates activity

0.2

The Tom70 receptor is a membrane-localized cochaperone that integrates the Hsp70/Hsp90 chaperones with mitochondrial preprotein targeting and translocation. In mammals, preprotein in the cytosol is associated with both Hsp90 and Hsp70 in a multichaperone complex, and docking of Hsp90 and/or Hsp70 onto Tom70 is essential for preprotein targeting.

SIGNOR-261379

P68363

Q14980

2

binding

up-regulates

0.263

Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.

SIGNOR-116472

P36894

Q13253

2

binding

down-regulates activity

0.611

Noggin binds the domain that is re-quired for bmp-7 to interact with bmp type i and type ii receptors (PMID 22298955).Noggin Inhibits bmp by blocking the molecular interfaces of the binding epitopes for both type i and type ii receptors.

SIGNOR-219221

Q9UPY8

Q96GD4

0

phosphorylation

up-regulates

0.472

Phosphorylation of eb3 at s176 by aurora b ensures successful cytokinesis completion by promoting midbody mt stability and midbody stabilization.

SIGNOR-202130

P68400

Q9ULV4

1

phosphorylation

up-regulates

0.2

We demonstrate that crn2 is a binding partner and substrate of protein kinase ck2, which phosphorylates crn2 at s463 in its c-terminal coiled coil domain

SIGNOR-196193

P35222

P33151

2

binding

up-regulates activity

0.76

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

SIGNOR-265867

P50052

P01019-PRO_0000032458

2

binding

up-regulates activity

0.2

Ang II initiates most of the RAS-attributed physiologic effects through selective interactions with G-proteincoupled Ang II type 1 (AT1) or type 2 (AT2) receptors and subsequent activation of distinct intra cellular signaling pathways

SIGNOR-260237

Q03431

P50148

2

binding

up-regulates activity

0.275

This calciotropic hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple heterotrimeric G proteins, including Gs and Gq/11.

SIGNOR-270550

Q9P0J1

P24752

0

acetylation

down-regulates activity

0.34

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

SIGNOR-267635

P01375

P19438

2

binding

up-regulates activity

0.925

For TNFR1, the cytokine TNFα binds to the receptor and triggers its trimerization, which leads to the assembly of the receptor complex and initiation of signaling.

SIGNOR-199091

P01106

Q9ULJ6

0

transcriptional regulation

up-regulates quantity by expression

0.362

The N-terminal domain (NTD) of Zmiz1 is important for driving Myc transcription and proliferation […] Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites.

SIGNOR-263939