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
P48058	Q5JU85	0	relocalization	up-regulates quantity	0.2	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264915
P15692	P35968	2	binding	up-regulates	0.82	Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability.	SIGNOR-157100
P27361	Q13322	1	phosphorylation	up-regulates	0.298	Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation	SIGNOR-138171
P48736	P01116	2	binding	up-regulates	0.778	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner.	SIGNOR-59819
Q96N67	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.739	As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover.	SIGNOR-261886
Q00535	Q99490	1	phosphorylation	up-regulates	0.262	Here, we demonstrate that cyclin dependent kinase 5 (cdk5), a protein known to function mainly in postmitotic neurons, directly phosphorylates pike-a at ser-279 in its gtpase domain in glioblastoma cells. This phosphorylation event stimulates pike-a gtpase activity and the activity of its downstream effector akt.	SIGNOR-178660
P13725	P40189	2	binding	up-regulates	0.751	Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2.	SIGNOR-48114
O43603	P30679	2	binding	up-regulates activity	0.288	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-257226
Q99558	Q96Q05	2	binding	up-regulates activity	0.478	We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates.	SIGNOR-269672
Q70Z35	P67775	0	dephosphorylation	up-regulates activity	0.2	PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ.	SIGNOR-277184
P05231	Q04206	0	transcriptional regulation	up-regulates quantity by expression	0.692	Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation	SIGNOR-251737
P01584	Q16665	0	transcriptional regulation	up-regulates quantity by expression	0.336	We finally confirmed that in the absence of HIF-1α there was a significant reduction at the protein level in pro-caspase-1, activated caspase-1, pro-IL-1β, and ultimately active IL-1β (Fig. 4g and h). These data show that adenosine induced up-regulation of IL-1β is dependent on a CREB/HIF-1α pathway which is distinct from the NF-kB pathway used for initial production of IL-1β in response to LPS.	SIGNOR-251718
Q13043	Q9H8S9	1	phosphorylation	up-regulates	0.9	Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity	SIGNOR-201306
Q9UL17	Q96NM4	0	transcriptional regulation	up-regulates quantity by expression	0.294	We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET).	SIGNOR-266097
P35869	P53350	0	phosphorylation	down-regulates activity	0.251	In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events.	SIGNOR-277885
P06493	Q9ULW0	1	phosphorylation	down-regulates activity	0.637	In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. \|Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle	SIGNOR-265096
P35968	P48730	0	phosphorylation	down-regulates activity	0.328	CKIdelta phosphorylates VEGFR2 at both DSG and DDTD phosphodegrons to promote its interaction with beta-TRCP1.\|In a reciprocal set of experiments, we found that overexpression of CKIdelta markedly decreased the half-life of VEGFR2 (XREF_FIG).	SIGNOR-280235
P17252	Q8NFA2	1	phosphorylation	up-regulates	0.2	Phosphorylation of thr341 allows noxo1 to sufficiently interact with noxa1, an interaction that participates in nox1 activation.	SIGNOR-202482
Q00535	O14939	1	phosphorylation	up-regulates activity	0.368	In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion.\|We determined that Cdk5 phosphorylates PLD2 at Ser 134 of PLD2 and that this phosphorylation was suggested to be important for EGF-dependent insulin secretion.	SIGNOR-278395
Q9Y243	P78563	1	phosphorylation	down-regulates activity	0.2	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276195
P28827	O60716	1	dephosphorylation	down-regulates quantity	0.541	Specifically, RPTP\u03bc dephosphorylated p120 catenin, subsequently leading to a lower level of cytoplasmic protein compared with that observed with the vector control and RPTP\u03bc-CS.	SIGNOR-277042
Q07021	P04264	2	binding	up-regulates activity	0.373	Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored.	SIGNOR-251881
Q12931	Q9BXM7	0	phosphorylation	up-regulates activity	0.612	This would mean that PINK1 knockdown should reduce TRAP1 activity, thereby potentiating BAY induced cell death.\|PINK1 can phosphorylate TRAP1 to prevent apoptosis induced by oxidative stress.	SIGNOR-278186
P21333	P48454	0	dephosphorylation	down-regulates quantity by destabilization	0.2	Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin \|Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.	SIGNOR-248507
Q96B36	O43781	0	phosphorylation	down-regulates	0.34	When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40	SIGNOR-201002
P51617	Q8N2H9	2	phosphorylation	up-regulates	0.729	Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity.	SIGNOR-103983
Q13627	Q07820	1	phosphorylation	up-regulates quantity	0.2	Furthermore, DYRK1A likely directly bound and phosphorylated Mcl-1, thereby enhancing Mcl-1 protein stability and contributing to the development of acquired resistance to Bcl-2 inhibitors.\|DYRK1A upregulates Mcl-1 expression in NSCLC cells.\|We demonstrated that DYRK1A suppression by siRNA or harmine decreased the phosphorylation of Mcl-1 at Ser159/Thr163.	SIGNOR-279704
P49841	P12036	1	phosphorylation	down-regulates	0.302	Gsk3beta was shown to phosphorylate at ser-493 in vitro by phosphopeptide mapping and site-directed mutagenesis, and in vivo in hek293 cells. The role of ser-493 phosphorylation is also a question to be addressed in the future. Because the e-segment appears to be involved in filament formation (27, 42), phosphorylation in that region may also play a regulatory role in filament formation. Secondary structure prediction suggests that phosphorylation of ser-493 in combination with following the pro residue interrupts _-helix of the e-segment	SIGNOR-90668
P0DTC9	Q13283	2	binding	down-regulates activity	null	N targets stress granule protein G3BP1, an essential antiviral protein which is known to induce innate immune response through multiple mechanisms	SIGNOR-260749
P43405	Q02548	1	phosphorylation	down-regulates activity	0.422	PAX5 tyrosine phosphorylation by SYK co-operatively functions with its serine phosphorylation to cancel the PAX5-dependent repression of BLIMP1: A mechanism for antigen-triggered plasma cell differentiation.	SIGNOR-269084
P16220	P17612	0	phosphorylation	up-regulates activity	0.581	Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression.	SIGNOR-131307
Q8TAB3	P48169	2	binding	up-regulates quantity by stabilization	0.2	Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.	SIGNOR-267220
P63096	O95622	2	binding	down-regulates activity	0.607	Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3	SIGNOR-278074
P31947	P46937	1	relocalization	down-regulates activity	0.461	Verteporfin increases the level of 14-3-3σ, which promotes the translocation of YAP from nucleus to cytoplasm.	SIGNOR-278130
P07900	P53041	2	binding	up-regulates	0.771	Hsp90 causes substantial activation of ppp5 by competing for tpr_phosphatase domain contacts and allowing access to the catalytic site.	SIGNOR-131564
P19525	P04637	1	phosphorylation	up-regulates	0.571	The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.	SIGNOR-68033
P35626	P35372	1	phosphorylation	down-regulates activity	0.2	These results demonstrate that the T180A mutation probably blocks GRK3- and arr3-mediated desensitization of MOR by preventing a critical agonist-dependent receptor phosphorylation and suggest a novel GRK3 site of regulation not yet described for other G-protein-coupled receptors	SIGNOR-247915
P16066	P19652	1	phosphorylation	up-regulates activity	0.2	On TORC1 inhibition by rapamycin treatment or nutrient limitation, Npr1 phosphorylates and activates Orm1 and Orm2, which in turn promotes synthesis of complex sphingolipids downstream of SPT.\|Thus Npr1 directly phosphorylates Orm1 and Orm2 downstream of TORC1.	SIGNOR-279747
P08754	O43603	2	binding	up-regulates activity	0.45	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-256884
Q15067	O15350	2	binding	down-regulates quantity by destabilization	0.2	Downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. ACOX1 reduced p73 expression by destabilizing p73 protein. We also found that ACOX1 interacted with p73 protein	SIGNOR-261056
Q13217	P19525	2	binding	down-regulates activity	0.635	The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK	SIGNOR-246207
Q9UPX8	O14490	0	relocalization	up-regulates activity	0.827	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264587
P04070	P38435	0	carboxylation	up-regulates activity	0.572	Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z	SIGNOR-265925
Q92913	Q99250	2	binding	down-regulates activity	0.269	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253427
Q92753	P04001	1	transcriptional regulation	up-regulates quantity by expression	0.2	These observations indicate that RORβ is required for the induction of S opsin and support the conclusion that RORβ regulates Opn1sw transcription in a direct manner through ROREs within its proximal promoter region. In addition, they explain the greatly diminished expression of Opn1sw observed in the retina of RORβ-/- mice.	SIGNOR-266851
Q86SG6	Q86SG6	2	phosphorylation	up-regulates activity	0.2	Multimerization and autophosphorylation of Nek8 are important for its activation.Our data suggests that one site for Nek8 autophosphorylation may be Thr-210 within the activation loop.	SIGNOR-250298
P0CG48	P45974	0	cleavage	up-regulates quantity	0.847	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-270822
Q9Y653	Q9Y653	2	cleavage	up-regulates activity	0.2	Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); \| We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation.	SIGNOR-253980
Q969H0	P46531	1	ubiquitination	down-regulates quantity by destabilization	0.613	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-130706
P59594	O15393	0	cleavage	up-regulates activity	0.2	Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.	SIGNOR-260217
Q99578	Q01851	2	binding	up-regulates activity	0.525	we describe the evidence for a functional interaction between Brn-3a and Rin and demonstrate the role of Rin in modulating the activation of the Brn-3a regulated egr-1 promoter by the N-terminal domain of Brn-3a.	SIGNOR-224546
Q92914	Q15858	2	binding	down-regulates activity	0.2	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253426
P30556	O95837	2	binding	up-regulates activity	0.49	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-257133
Q9Y4P1	Q9BXW4	1	cleavage	up-regulates activity	0.757	Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.	SIGNOR-125489
Q9UM73	P50750	1	phosphorylation	up-regulates activity	0.296	We report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes.	SIGNOR-277607
O75487	P56704	2	binding	up-regulates	0.35	Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways	SIGNOR-195749
Q96LB2	P63092	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256786
O14757	Q86UE8	1	phosphorylation	down-regulates activity	0.269	Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b).	SIGNOR-262740
P49841	P57059	1	phosphorylation	up-regulates activity	0.2	Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates Ser/Thr residues located at the fourth position ahead of the pre-phosphorylated Ser/Thr residues, and inhibitors of GSK-3beta reduce the phosphorylation at Thr182. The results of an in vitro reconstitution assay also indicate that GSK-3beta could be the SIK1 kinase. However, overexpression and knockdown of GSK-3beta in LKB1-defective HeLa cells suggests that GSK-3beta alone may not be able to phosphorylate or activate SIK1, indicating that LKB1 may play a crucial role by phosphorylating SIK1 at Thr182, possibly as an initiator of the autophosphorylation cascade, and GSK-3beta may phosphorylate SIK1 at Thr182 by recognizing the priming-autophosphorylation at Ser186 in cultured cells.	SIGNOR-279742
P27930	P01584	2	binding	down-regulates	0.878	Interleukin-1 (il-1) interacts with cells through two types of binding molecules, il-1 type i receptor (il-1r i) and il-1r ii. Il-1r ii inhibits il-1 activity by acting as a decoy target for il-1	SIGNOR-38302
Q9UQ88	O95257	2	binding	down-regulates activity	0.2	Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 \|We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58.	SIGNOR-273025
P03186	Q9Y6K9	1	deubiquitination	down-regulates activity	0.2	In the current study, we have found that BPLF1 interferes with innate immune activation by targeting multiple intermediates along the TLR signal transduction pathway, including TRAF6, NEMO, and IκBα. BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes.	SIGNOR-266743
P31947	O95863	1	relocalization	down-regulates	0.2	Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding	SIGNOR-168540
P05412	P01112	0	phosphorylation	up-regulates activity	0.5	c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells	SIGNOR-235522
Q12888	O75925	0	sumoylation	up-regulates	0.494	Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation.	SIGNOR-162156
O15530	P04049	1	phosphorylation	up-regulates activity	0.311	PDK1, but not PKCs, phosphorylate and activate Raf1 in MAPK pathway when platelets are stimulated with 2MeSADP.	SIGNOR-280063
Q13485	P05412	2	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
Q3KP22	O94901	2	binding	up-regulates activity	0.2	In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. \| It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex.	SIGNOR-263300
P46734	Q9Y463	1	phosphorylation	up-regulates	0.348	Mkk3 enhanced mirk kinase activity. Mkk3 possibly activates mirk by phosphorylating it.	SIGNOR-86731
P19525	P16333	1	phosphorylation	down-regulates activity	0.2	In these assays, we observed that GST\u2013Nck-1 was clearly phosphorylated by GST\u2013PKR while GST was not ( Fig. 4 , upper panels).	SIGNOR-279039
P62714	P11233	1	dephosphorylation	down-regulates	0.289	Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function	SIGNOR-155349
P78352	Q05086	0	ubiquitination	down-regulates quantity by destabilization	0.349	E6-induced degradation of DLG4 depends on E6AP in vivo. Our findings as a whole indicate that E6AP is involved in E6-mediated ubiquitination and degradation of DLG4 both in vivo and in vitro.	SIGNOR-271397
Q9H0M0	O15105	1	relocalization	up-regulates activity	0.731	We found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor.	SIGNOR-126578
P84022	Q13705	0	phosphorylation	up-regulates activity	0.69	It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains	SIGNOR-254985
Q9Y2T7	P31751	0	phosphorylation	up-regulates quantity by stabilization	0.2	In this context, YBX2 is a dual substrate for both AMPK and Akt2. The phosphorylation at Thr115 by AMPK or at Ser137 by Akt2 facilitates YBX2 accumulation in brown adipocytes by decreasing ubiquitination-mediated degradation.	SIGNOR-277869
P18825	P08754	2	binding	up-regulates activity	0.488	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-256842
P20338	Q96T51	2	binding	up-regulates activity	0.68	Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.\|We also found that enlargement of early endosomes mediated by RUFY1 requires its interaction with Rab4	SIGNOR-261280
P04183	Q9UM11	2	binding	down-regulates quantity by destabilization	0.342	We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif.	SIGNOR-272945
P42345	Q8TB45	2	phosphorylation	down-regulates	0.755	Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome.	SIGNOR-176849
Q9GZV5	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.2	GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3 phosphorylation, whereas the Ser-66 is not (Fig. 4D).	SIGNOR-277646
P12830	P40424	0	transcriptional regulation	up-regulates quantity by expression	0.267	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267241
P63279	O75030	1	ubiquitination	down-regulates	0.565	Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo.	SIGNOR-75117
Q13547	P68400	0	phosphorylation	up-regulates	0.62	Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1.	SIGNOR-111015
P17612	P14136	1	phosphorylation	down-regulates activity	0.283	GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments.	SIGNOR-249713
P00738	P02647	2	binding	up-regulates quantity by stabilization	0.726	Haptoglobin binding to apolipoprotein A-I prevents damage from hydroxyl radicals on its stimulatory activity of the enzyme lecithin-cholesterol acyl-transferase. haptoglobin, when circulating at enhanced levels with free Hb during the acute phase of inflammation, might protect ApoA-I structure and function against hydroxyl radicals.	SIGNOR-252106
Q13490	Q9NR28	2	ubiquitination	down-regulates quantity by destabilization	0.895	Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac.	SIGNOR-271392
O14829	O14737	1	dephosphorylation	down-regulates quantity by destabilization	0.349	Here, we report that the serine/threonine phosphatase PPEF-1 interacts with and dephosphorylates PDCD5 at Ser 119, which leads to PDCD5 destabilization.\|These results demonstrate that PPEF-1 reduces PDCD5 stability via PDCD5 dephosphorylation.	SIGNOR-277008
Q13315	P46527	1	phosphorylation	up-regulates quantity by stabilization	0.419	We also uncovered that ATM phosphorylates p27Kip1 on a previously uncharacterized residue (Ser-140), which leads to its stabilization after induction of DNA double-strand breaks.	SIGNOR-279392
P04637	O15527	1	transcriptional regulation	up-regulates quantity by expression	0.429	Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter. In addition we demonstrated that supplementing p53 in HCT116p53-/- cells enhanced the transcription of hOGG1.	SIGNOR-255440
O95886	Q9BYB0	1	relocalization	up-regulates activity	0.2	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264594
O43395	P68400	0	phosphorylation	up-regulates	0.2	Our findings provide new insights into the biology of hprp3p and suggest that the loss of hprp3p phosphorylation at thr494 is a key step for initiating thr494met aberrant interactions within u4/u6 snrnp complex and that these are likely linked to the rp18 phenotype.	SIGNOR-158319
Q9Y4C1	O60674	0	phosphorylation	up-regulates activity	0.2	KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2 phosphorylates KDM3A at tyrosine 1101 residue.	SIGNOR-277884
P62987	Q9BXM7	0	phosphorylation	up-regulates	0.385	Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential.	SIGNOR-270342
P31751	Q6ZWJ1	1	phosphorylation	down-regulates activity	0.42	Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4.	SIGNOR-262635
P25100	P50148	2	binding	up-regulates activity	0.585	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-257080
Q13547	P36952	1	transcriptional regulation	down-regulates quantity by repression	0.413	We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1.	SIGNOR-268494
Q86U44	Q92995	1	post transcriptional regulation	up-regulates quantity by stabilization	0.2	Furthermore, N6-methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the m6A reader IGF2BP2.	SIGNOR-275839
O15111	Q13546	1	phosphorylation	down-regulates activity	0.54	Indeed, IKKa and IKKb may directly repress RIPK1 kinase activity by addition of an inhibitory phosphate group on RIPK1.\|Mass spectrometry analysis of kinase assays performed with recombinant proteins allowed us to identify Ser166, Ser331, and Ser416 as highly conserved RIPK1 residues phosphorylated by IKKa and IKKb.	SIGNOR-278927
P45984	P14778	0	phosphorylation	up-regulates activity	0.281	Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab	SIGNOR-249514
Q99418	P05129	0	phosphorylation	down-regulates activity	0.332	ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'.	SIGNOR-249025

P48058

Q5JU85

0

relocalization

up-regulates quantity

0.2

BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.

SIGNOR-264915

P15692

P35968

2

binding

up-regulates

0.82

Binding of vegf to the receptor induces dimerisation and autophosphorylation of specific intracellular tyrosine residues. Activation of intracellular cascades results in proliferation, migration, survival and increased permeability.

SIGNOR-157100

P27361

Q13322

1

phosphorylation

up-regulates

0.298

Phosphorylation of grb10 by mitogen-activated protein kinase: identification of ser150 and ser476 of human grb10zeta as major phosphorylation sitesreplacing ser(150) and ser(476) with alanines reduced the inhibitory effect of human grb10zeta on insulin-stimulated irs1 tyrosine phosphorylation

SIGNOR-138171

P48736

P01116

2

binding

up-regulates

0.778

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

SIGNOR-59819

Q96N67

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.739

As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover.

SIGNOR-261886

Q00535

Q99490

1

phosphorylation

up-regulates

0.262

Here, we demonstrate that cyclin dependent kinase 5 (cdk5), a protein known to function mainly in postmitotic neurons, directly phosphorylates pike-a at ser-279 in its gtpase domain in glioblastoma cells. This phosphorylation event stimulates pike-a gtpase activity and the activity of its downstream effector akt.

SIGNOR-178660

P13725

P40189

2

binding

up-regulates

0.751

Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2.

SIGNOR-48114

O43603

P30679

2

binding

up-regulates activity

0.288

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-257226

Q99558

Q96Q05

2

binding

up-regulates activity

0.478

We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates.

SIGNOR-269672

Q70Z35

P67775

0

dephosphorylation

up-regulates activity

0.2

PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ.

SIGNOR-277184

P05231

Q04206

0

transcriptional regulation

up-regulates quantity by expression

0.692

Recent reports show that in mice the microbiome, comprising commensal microorganisms that colonize body surfaces, promotes a partial and low-grade M1-like phenotype in macrophages throughout the body, including those in lymphoid organs (119, 120). This M1-like priming of macrophages induces chromatin remodeling with increased H3K4me3 marks at Ifnb, Il6, and Tnf promoters, which is associated with increased binding of NF-κB p65, IRF3, and Pol II upon cell stimulation

SIGNOR-251737

P01584

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.336

We finally confirmed that in the absence of HIF-1α there was a significant reduction at the protein level in pro-caspase-1, activated caspase-1, pro-IL-1β, and ultimately active IL-1β (Fig. 4g and h). These data show that adenosine induced up-regulation of IL-1β is dependent on a CREB/HIF-1α pathway which is distinct from the NF-kB pathway used for initial production of IL-1β in response to LPS.

SIGNOR-251718

Q13043

Q9H8S9

1

phosphorylation

up-regulates

0.9

Mob1, when phosphorylated by MST1/2, binds to the autoinhibitory motif in Lats1/2, which in turn leads to the phosphorylation of the Lats activation loop (Lats1 S909 and Lats2 S872) and thereby an increase of their kinase activity

SIGNOR-201306

Q9UL17

Q96NM4

0

transcriptional regulation

up-regulates quantity by expression

0.294

We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET).

SIGNOR-266097

P35869

P53350

0

phosphorylation

down-regulates activity

0.251

In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events.

SIGNOR-277885

P06493

Q9ULW0

1

phosphorylation

down-regulates activity

0.637

In this study, we characterize the phosphorylation of threonine 72 (Thr(72)) in human TPX2, a residue highly conserved across species. We find that Cdk1/2 phosphorylate TPX2 in vitro and in vivo. |Endogenous TPX2 phosphorylated at Thr(72) does not associate with the mitotic spindle. Furthermore, ectopic GFP-TPX2 T72A preferentially concentrates on the spindle

SIGNOR-265096

P35968

P48730

0

phosphorylation

down-regulates activity

0.328

CKIdelta phosphorylates VEGFR2 at both DSG and DDTD phosphodegrons to promote its interaction with beta-TRCP1.|In a reciprocal set of experiments, we found that overexpression of CKIdelta markedly decreased the half-life of VEGFR2 (XREF_FIG).

SIGNOR-280235

P17252

Q8NFA2

1

phosphorylation

up-regulates

0.2

Phosphorylation of thr341 allows noxo1 to sufficiently interact with noxa1, an interaction that participates in nox1 activation.

SIGNOR-202482

Q00535

O14939

1

phosphorylation

up-regulates activity

0.368

In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion.|We determined that Cdk5 phosphorylates PLD2 at Ser 134 of PLD2 and that this phosphorylation was suggested to be important for EGF-dependent insulin secretion.

SIGNOR-278395

Q9Y243

P78563

1

phosphorylation

down-regulates activity

0.2

AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively

SIGNOR-276195

P28827

O60716

1

dephosphorylation

down-regulates quantity

0.541

Specifically, RPTP\u03bc dephosphorylated p120 catenin, subsequently leading to a lower level of cytoplasmic protein compared with that observed with the vector control and RPTP\u03bc-CS.

SIGNOR-277042

Q07021

P04264

2

binding

up-regulates activity

0.373

Cytokeratin 1 binds to both gC1qR and u-PAR. Our data suggest that formation of HK (and Factor XII) binding sites along endothelial cell membranes consists of bimolecular com-plexes of gC1qR-cytokeratin 1 and u-PAR-cytokeratin 1, with gC1qR binding being favored.

SIGNOR-251881

Q12931

Q9BXM7

0

phosphorylation

up-regulates activity

0.612

This would mean that PINK1 knockdown should reduce TRAP1 activity, thereby potentiating BAY induced cell death.|PINK1 can phosphorylate TRAP1 to prevent apoptosis induced by oxidative stress.

SIGNOR-278186

P21333

P48454

0

dephosphorylation

down-regulates quantity by destabilization

0.2

Filamin is a phosphoprotein that organizes actin filaments into networks. We report that a purified C-terminal recombinant region of filamin is a suitable substrate for calcineurin |Mutagenesis analysis showed that a dephosphorylation step occurred in Ser 2152, which was previously shown to provide resistance to calpain cleavage when endogenous PKA is activated. In contrast, phosphorylation of Ser 2152 was recently reported to be necessary for membrane dynamic changes. In this regard, we found that CsA protects filamin in platelets from calpain degradation.

SIGNOR-248507

Q96B36

O43781

0

phosphorylation

down-regulates

0.34

When dyrk3 is active, it allows stress granule dissolution, releasing mtorc1 for signaling and promoting its activity by directly phosphorylating the mtorc1 inhibitor pras40

SIGNOR-201002

P51617

Q8N2H9

2

phosphorylation

up-regulates

0.729

Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity.

SIGNOR-103983

Q13627

Q07820

1

phosphorylation

up-regulates quantity

0.2

Furthermore, DYRK1A likely directly bound and phosphorylated Mcl-1, thereby enhancing Mcl-1 protein stability and contributing to the development of acquired resistance to Bcl-2 inhibitors.|DYRK1A upregulates Mcl-1 expression in NSCLC cells.|We demonstrated that DYRK1A suppression by siRNA or harmine decreased the phosphorylation of Mcl-1 at Ser159/Thr163.

SIGNOR-279704

P49841

P12036

1

phosphorylation

down-regulates

0.302

Gsk3beta was shown to phosphorylate at ser-493 in vitro by phosphopeptide mapping and site-directed mutagenesis, and in vivo in hek293 cells. The role of ser-493 phosphorylation is also a question to be addressed in the future. Because the e-segment appears to be involved in filament formation (27, 42), phosphorylation in that region may also play a regulatory role in filament formation. Secondary structure prediction suggests that phosphorylation of ser-493 in combination with following the pro residue interrupts _-helix of the e-segment

SIGNOR-90668

P0DTC9

Q13283

2

binding

down-regulates activity

null

N targets stress granule protein G3BP1, an essential antiviral protein which is known to induce innate immune response through multiple mechanisms

SIGNOR-260749

P43405

Q02548

1

phosphorylation

down-regulates activity

0.422

PAX5 tyrosine phosphorylation by SYK co-operatively functions with its serine phosphorylation to cancel the PAX5-dependent repression of BLIMP1: A mechanism for antigen-triggered plasma cell differentiation.

SIGNOR-269084

P16220

P17612

0

phosphorylation

up-regulates activity

0.581

Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression.

SIGNOR-131307

Q8TAB3

P48169

2

binding

up-regulates quantity by stabilization

0.2

Here, we found that PCDH19 binds the alpha subunits of GABAAR and regulates its surface availability and currents in cultured hippocampal neurons. The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain. PCDH19 shRNA-mediated downregulation reduces GABAAR surface expression and affects the frequency and kinetics of miniature inhibitory postsynaptic currents (mIPSCs) in cultured hippocampal neurons.

SIGNOR-267220

P63096

O95622

2

binding

down-regulates activity

0.607

Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3

SIGNOR-278074

P31947

P46937

1

relocalization

down-regulates activity

0.461

Verteporfin increases the level of 14-3-3σ, which promotes the translocation of YAP from nucleus to cytoplasm.

SIGNOR-278130

P07900

P53041

2

binding

up-regulates

0.771

Hsp90 causes substantial activation of ppp5 by competing for tpr_phosphatase domain contacts and allowing access to the catalytic site.

SIGNOR-131564

P19525

P04637

1

phosphorylation

up-regulates

0.571

The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.

SIGNOR-68033

P35626

P35372

1

phosphorylation

down-regulates activity

0.2

These results demonstrate that the T180A mutation probably blocks GRK3- and arr3-mediated desensitization of MOR by preventing a critical agonist-dependent receptor phosphorylation and suggest a novel GRK3 site of regulation not yet described for other G-protein-coupled receptors

SIGNOR-247915

P16066

P19652

1

phosphorylation

up-regulates activity

0.2

On TORC1 inhibition by rapamycin treatment or nutrient limitation, Npr1 phosphorylates and activates Orm1 and Orm2, which in turn promotes synthesis of complex sphingolipids downstream of SPT.|Thus Npr1 directly phosphorylates Orm1 and Orm2 downstream of TORC1.

SIGNOR-279747

P08754

O43603

2

binding

up-regulates activity

0.45

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-256884

Q15067

O15350

2

binding

down-regulates quantity by destabilization

0.2

Downregulation of ACOX1 increased p73, but not p53, expression. p73 expression was critical for apoptosis induction induced by ACOX1 downregulation. ACOX1 reduced p73 expression by destabilizing p73 protein. We also found that ACOX1 interacted with p73 protein

SIGNOR-261056

Q13217

P19525

2

binding

down-regulates activity

0.635

The protein p58IPK {also known asDnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2 kinases PKR (dsRNA-dependent protein kinase/eIF2 kinase 2) and PERK

SIGNOR-246207

Q9UPX8

O14490

0

relocalization

up-regulates activity

0.827

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264587

P04070

P38435

0

carboxylation

up-regulates activity

0.572

Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z

SIGNOR-265925

Q92913

Q99250

2

binding

down-regulates activity

0.269

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253427

Q92753

P04001

1

transcriptional regulation

up-regulates quantity by expression

0.2

These observations indicate that RORβ is required for the induction of S opsin and support the conclusion that RORβ regulates Opn1sw transcription in a direct manner through ROREs within its proximal promoter region. In addition, they explain the greatly diminished expression of Opn1sw observed in the retina of RORβ-/- mice.

SIGNOR-266851

Q86SG6

2

phosphorylation

up-regulates activity

0.2

Multimerization and autophosphorylation of Nek8 are important for its activation.Our data suggests that one site for Nek8 autophosphorylation may be Thr-210 within the activation loop.

SIGNOR-250298

P0CG48

P45974

0

cleavage

up-regulates quantity

0.847

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-270822

Q9Y653

2

cleavage

up-regulates activity

0.2

Like many other adhesion GPCRs, GPR56 is cleaved via a GPCR autoproteolysis-inducing (GAIN) domain into N- and C-terminal fragments (GPR56N and GPR56C); | We demonstrate that ligand binding releases GPR56N from the membrane-bound GPR56C and triggers the association of GPR56C with lipid rafts and RhoA activation.

SIGNOR-253980

Q969H0

P46531

1

ubiquitination

down-regulates quantity by destabilization

0.613

Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.

SIGNOR-130706

P59594

O15393

0

cleavage

up-regulates activity

0.2

Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming.

SIGNOR-260217

Q99578

Q01851

2

binding

up-regulates activity

0.525

we describe the evidence for a functional interaction between Brn-3a and Rin and demonstrate the role of Rin in modulating the activation of the Brn-3a regulated egr-1 promoter by the N-terminal domain of Brn-3a.

SIGNOR-224546

Q92914

Q15858

2

binding

down-regulates activity

0.2

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253426

P30556

O95837

2

binding

up-regulates activity

0.49

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-257133

Q9Y4P1

Q9BXW4

1

cleavage

up-regulates activity

0.757

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

SIGNOR-125489

Q9UM73

P50750

1

phosphorylation

up-regulates activity

0.296

We report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes.

SIGNOR-277607

O75487

P56704

2

binding

up-regulates

0.35

Gpc4 bound to wnt3a and wnt5a which activate the beta-catenin-dependent and -independent pathways, respectively, and colocalized with wnts on the cell surface. Expression of gpc4 enhanced the wnt3a-dependent beta-catenin pathway and the wnt5a-dependent beta-catenin-independent pathway, and knockdown of gpc4 suppressed both pathways

SIGNOR-195749

Q96LB2

P63092

2

binding

up-regulates activity

0.2

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

SIGNOR-256786

O14757

Q86UE8

1

phosphorylation

down-regulates activity

0.269

Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b).

SIGNOR-262740

P49841

P57059

1

phosphorylation

up-regulates activity

0.2

Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates Ser/Thr residues located at the fourth position ahead of the pre-phosphorylated Ser/Thr residues, and inhibitors of GSK-3beta reduce the phosphorylation at Thr182. The results of an in vitro reconstitution assay also indicate that GSK-3beta could be the SIK1 kinase. However, overexpression and knockdown of GSK-3beta in LKB1-defective HeLa cells suggests that GSK-3beta alone may not be able to phosphorylate or activate SIK1, indicating that LKB1 may play a crucial role by phosphorylating SIK1 at Thr182, possibly as an initiator of the autophosphorylation cascade, and GSK-3beta may phosphorylate SIK1 at Thr182 by recognizing the priming-autophosphorylation at Ser186 in cultured cells.

SIGNOR-279742

P27930

P01584

2

binding

down-regulates

0.878

Interleukin-1 (il-1) interacts with cells through two types of binding molecules, il-1 type i receptor (il-1r i) and il-1r ii. Il-1r ii inhibits il-1 activity by acting as a decoy target for il-1

SIGNOR-38302

Q9UQ88

O95257

2

binding

down-regulates activity

0.2

Western blot analysis for SPDEF revealed that overexpression of GADD45α, β and γ prevents SPDEF degradation mediated by CDK11p58 |We identified CDK11p58 as an interaction partner of GADD45α by co-immunoprecipitation analysis. We corroborated these data by co-immunoprecipitation in vitro translation assays, showing that all three members of the GADD45 family interact with CDK11p58.

SIGNOR-273025

P03186

Q9Y6K9

1

deubiquitination

down-regulates activity

0.2

In the current study, we have found that BPLF1 interferes with innate immune activation by targeting multiple intermediates along the TLR signal transduction pathway, including TRAF6, NEMO, and IκBα. BPLF1 can remove ubiquitin tags from proteins in the TLR signaling cascade. This inhibits TLR signaling and decreases the expression of immune response genes.

SIGNOR-266743

P31947

O95863

1

relocalization

down-regulates

0.2

Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding

SIGNOR-168540

P05412

P01112

0

phosphorylation

up-regulates activity

0.5

c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells

SIGNOR-235522

Q12888

O75925

0

sumoylation

up-regulates

0.494

Pias1 and pias4 are recruited to dna-damage sites and mediate 53bp1 recruitment and sumoylation.

SIGNOR-162156

O15530

P04049

1

phosphorylation

up-regulates activity

0.311

PDK1, but not PKCs, phosphorylate and activate Raf1 in MAPK pathway when platelets are stimulated with 2MeSADP.

SIGNOR-280063

Q13485

P05412

2

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

Q3KP22

O94901

2

binding

up-regulates activity

0.2

In this study, we found that SUN1 not only interacted with TERB1 but also interacted with MAJIN, and the interaction of SUN1 with MAJIN is stronger than TERB1. We also found that SUN1 interacted with SPDYA, an activator of CDK2. | It will be of great interest to test this hypothesis to fully understand the mechanisms of stable telomere–NE connection and telomere movement along the NE driven by the LINC complex.

SIGNOR-263300

P46734

Q9Y463

1

phosphorylation

up-regulates

0.348

Mkk3 enhanced mirk kinase activity. Mkk3 possibly activates mirk by phosphorylating it.

SIGNOR-86731

P19525

P16333

1

phosphorylation

down-regulates activity

0.2

In these assays, we observed that GST\u2013Nck-1 was clearly phosphorylated by GST\u2013PKR while GST was not ( Fig. 4 , upper panels).

SIGNOR-279039

P62714

P11233

1

dephosphorylation

down-regulates

0.289

Pp2a abeta-containing complexes dephosphorylate rala at ser183 and ser194, inactivating rala and abolishing its transforming function

SIGNOR-155349

P78352

Q05086

0

ubiquitination

down-regulates quantity by destabilization

0.349

E6-induced degradation of DLG4 depends on E6AP in vivo. Our findings as a whole indicate that E6AP is involved in E6-mediated ubiquitination and degradation of DLG4 both in vivo and in vitro.

SIGNOR-271397

Q9H0M0

O15105

1

relocalization

up-regulates activity

0.731

We found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor.

SIGNOR-126578

P84022

Q13705

0

phosphorylation

up-regulates activity

0.69

It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains

SIGNOR-254985

Q9Y2T7

P31751

0

phosphorylation

up-regulates quantity by stabilization

0.2

In this context, YBX2 is a dual substrate for both AMPK and Akt2. The phosphorylation at Thr115 by AMPK or at Ser137 by Akt2 facilitates YBX2 accumulation in brown adipocytes by decreasing ubiquitination-mediated degradation.

SIGNOR-277869

P18825

P08754

2

binding

up-regulates activity

0.488

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-256842

P20338

Q96T51

2

binding

up-regulates activity

0.68

Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.|We also found that enlargement of early endosomes mediated by RUFY1 requires its interaction with Rab4

SIGNOR-261280

P04183

Q9UM11

2

binding

down-regulates quantity by destabilization

0.342

We show that hTK1 is degraded via a ubiquitin-proteasome pathway in mammalian cells and that anaphase-promoting complex/cyclosome (APC/C) activator Cdh1 is not only a necessary but also a rate-limiting factor for mitotic degradation of hTK1. By in vitro ubiquitinylation assays, we demonstrated that hTK1 is targeted for degradation by the APC/C-Cdh1 ubiquitin ligase dependent on this KEN box motif.

SIGNOR-272945

P42345

Q8TB45

2

phosphorylation

down-regulates

0.755

Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome.

SIGNOR-176849

Q9GZV5

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

GSK3 destabilizes TAZ. TAZS58A/S62A but not the TAZ S66A mutant diminished phos- phorylation by GSK3 , suggesting that Ser-58 and Ser-62 are important for GSK3 phosphorylation, whereas the Ser-66 is not (Fig. 4D).

SIGNOR-277646

P12830

P40424

0

transcriptional regulation

up-regulates quantity by expression

0.267

We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.

SIGNOR-267241

P63279

O75030

1

ubiquitination

down-regulates

0.565

Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo.

SIGNOR-75117

Q13547

P68400

0

phosphorylation

up-regulates

0.62

Human hdac1 protein was analyzed by ion trap mass spectrometry, and two phosphorylated serine residues, ser(421) and ser(423), were unambiguously identified. Loss of phosphorylation at ser(421) and ser(423) due to mutation to alanine or disruption of the casein kinase 2 consensus sequence directing phosphorylation reduced the enzymatic activity and complex formation of hdac1.

SIGNOR-111015

P17612

P14136

1

phosphorylation

down-regulates activity

0.283

GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments.

SIGNOR-249713

P00738

P02647

2

binding

up-regulates quantity by stabilization

0.726

Haptoglobin binding to apolipoprotein A-I prevents damage from hydroxyl radicals on its stimulatory activity of the enzyme lecithin-cholesterol acyl-transferase. haptoglobin, when circulating at enhanced levels with free Hb during the acute phase of inflammation, might protect ApoA-I structure and function against hydroxyl radicals.

SIGNOR-252106

Q13490

Q9NR28

2

ubiquitination

down-regulates quantity by destabilization

0.895

Here we show that cIAP1 and cIAP2 are E3 ubiquitin-protein isopeptide ligases (ubiquitin ligases) for Smac. cIAPs stimulate Smac ubiquitination both in vivo and in vitro, leading to Smac degradation. cIAP1 and cIAP2 associate with overlapping but distinct subsets of E2 (ubiquitin carrier protein) ubiquitin-conjugating enzymes. The substrate-dependent E3 activity of cIAPs is mediated by their RING domains and is dependent on the specific interactions between cIAPs and Smac.

SIGNOR-271392

O14829

O14737

1

dephosphorylation

down-regulates quantity by destabilization

0.349

Here, we report that the serine/threonine phosphatase PPEF-1 interacts with and dephosphorylates PDCD5 at Ser 119, which leads to PDCD5 destabilization.|These results demonstrate that PPEF-1 reduces PDCD5 stability via PDCD5 dephosphorylation.

SIGNOR-277008

Q13315

P46527

1

phosphorylation

up-regulates quantity by stabilization

0.419

We also uncovered that ATM phosphorylates p27Kip1 on a previously uncharacterized residue (Ser-140), which leads to its stabilization after induction of DNA double-strand breaks.

SIGNOR-279392

P04637

O15527

1

transcriptional regulation

up-regulates quantity by expression

0.429

Using gel-shift assays, we showed that p53 binds to its putative cis-elements within the hOGG1 promoter. In addition we demonstrated that supplementing p53 in HCT116p53-/- cells enhanced the transcription of hOGG1.

SIGNOR-255440

O95886

Q9BYB0

1

relocalization

up-regulates activity

0.2

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264594

O43395

P68400

0

phosphorylation

up-regulates

0.2

Our findings provide new insights into the biology of hprp3p and suggest that the loss of hprp3p phosphorylation at thr494 is a key step for initiating thr494met aberrant interactions within u4/u6 snrnp complex and that these are likely linked to the rp18 phenotype.

SIGNOR-158319

Q9Y4C1

O60674

0

phosphorylation

up-regulates activity

0.2

KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2 phosphorylates KDM3A at tyrosine 1101 residue.

SIGNOR-277884

P62987

Q9BXM7

0

phosphorylation

up-regulates

0.385

Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential.

SIGNOR-270342

P31751

Q6ZWJ1

1

phosphorylation

down-regulates activity

0.42

Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. These data demonstrate that insulin activation of Akt2 specifically regulates the docking/fusion step of GLUT4-containing vesicles at the plasma membrane through the regulation of Synip phosphorylation and Synip-Syntaxin4 interaction.Thus, our data demonstrate that insulin-stimulated Akt2-dependent phosphorylation of Synip on serine residue 99 results in reduced binding interactions between Synip and Syntaxin4.

SIGNOR-262635

P25100

P50148

2

binding

up-regulates activity

0.585

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-257080

Q13547

P36952

1

transcriptional regulation

down-regulates quantity by repression

0.413

We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1.

SIGNOR-268494

Q86U44

Q92995

1

post transcriptional regulation

up-regulates quantity by stabilization

0.2

Furthermore, N6-methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the m6A reader IGF2BP2.

SIGNOR-275839

O15111

Q13546

1

phosphorylation

down-regulates activity

0.54

Indeed, IKKa and IKKb may directly repress RIPK1 kinase activity by addition of an inhibitory phosphate group on RIPK1.|Mass spectrometry analysis of kinase assays performed with recombinant proteins allowed us to identify Ser166, Ser331, and Ser416 as highly conserved RIPK1 residues phosphorylated by IKKa and IKKb.

SIGNOR-278927

P45984

P14778

0

phosphorylation

up-regulates activity

0.281

Il-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (map) kinases, c-jun nh2-terminal kinase (jnk) and p38 map kinase, as well as transcription factor nuclear factor kappab (nf-kappab

SIGNOR-249514

Q99418

P05129

0

phosphorylation

down-regulates activity

0.332

ARNO is phosphorylated in vivo by PKC on a single serine residue, S392, located within the carboxy-terminal polybasic domain. Mutation of S392 to alanine does not prevent ARNO-mediated actin rearrangements, suggesting that phosphorylation does not lead to ARNO activation [6]. Here, we report that phosphorylation negatively regulates ARNO exchange activity through a 'PH domain electrostatic switch'.

SIGNOR-249025