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
Q05397	Q00535	0	phosphorylation	up-regulates	0.305	Here, we show that fak phosphorylation by cdk5 at s732 is important for microtubule organization, nuclear movement, and neuronal migration. In cultured neurons, s732-phosphorylated fak is enriched along a centrosome-associated microtubule fork that abuts the nucleus. Overexpression of the nonphosphorylatable mutant fak s732a results in disorganization of the microtubule fork and impairment of nuclear movement in vitro, and neuronal positioning defects in vivo.	SIGNOR-86223
P0C6X7-PRO_0000037312	O75348	1	cleavage	down-regulates activity	0.2	Cleavage of the V-ATPase G1 fusion protein by SARS-CoV 3CLpro was found in this study (Fig. 3), implying that 3CLpro potentially cleaves the cellular V-ATPase G1, and affects the function of vacuolar H(+)-ATPase. Meanwhile, a significant intracellular acidification has been demonstrated in the 3CLpro-expressing cells (Fig. 4D). The result correlated well with previous reports in that V-ATPase-specific inhibitors cause acidic pHi [28], [29], and influences cell apoptosis	SIGNOR-260264
O60566	Q96SN8	0	transcriptional regulation	up-regulates quantity by expression	0.27	These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter	SIGNOR-260312
Q92569	P42336	2	binding	up-regulates	0.846	The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha	SIGNOR-53597
Q96BR1	O15530	0	phosphorylation	up-regulates	0.461	Full-length sgk3 contains a complete phox homology (px) domain that targets the protein to endosomes. Both a functional px domain and pi3k activation are necessary for phosphorylation of sgk3 at two regulatory sites (thr-320 and ser-486) and subsequent induction of kinase activity. Pdk1 phosphorylates endosome-associated sgk3 at thr-320	SIGNOR-147213
P47901	P38405	2	binding	up-regulates activity	0.25	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-256934
P26367	P84022	2	binding	down-regulates activity	0.399	The paired domain of Pax6 interacts with the MH1 domain of Smad3. Smad3 prevents Pax6 paired domain from binding DNA	SIGNOR-251875
Q00987	Q13263	2	binding	up-regulates activity	0.598	we present evidence that MDM2 interacts with the nuclear corepressor KAP1. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation.	SIGNOR-240405
P36956	P23443	0	phosphorylation	up-regulates activity	0.424	Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation.\|Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element-binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation ( xref ).	SIGNOR-280120
O15350	Q05655	0	phosphorylation	up-regulates	0.307	The results show that pkcdeltacf phosphorylates the p73beta transactivation and dna-binding domains. pkcdeltacf-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation.	SIGNOR-90279
P25963	P06239	0	phosphorylation	down-regulates quantity by destabilization	0.586	Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. \|Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors	SIGNOR-249374
P10767	P21802	2	binding	up-regulates	0.753	The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors.	SIGNOR-42380
P04637	P55957	1	transcriptional regulation	up-regulates quantity by expression	0.519	Bid is a p53 primary-response gene.	SIGNOR-140248
P98177	Q00987	0	ubiquitination	down-regulates activity	0.63	Mdm2 Induces Mono-Ubiquitination of FOXO4.\|higher amounts of Mdm2 transfected resulted in reduced FOXO4 transcriptional activity.	SIGNOR-278656
Q9Y4K3	P36406	0	ubiquitination	up-regulates activity	0.313	We show here that the upregulation of NF-kappaB by UL144 is dependent upon cellular tripartite motif 23 (TRIM23) protein. We propose a mechanism by which UL144 activates NF-kappaB through a direct interaction with the cellular protein TRIM23 in a complex containing TRAF6. we propose that TRIM23 mediates TRAF6 autoubiquitination in the presence of UL144, resulting in the virally controlled activation of NF-κB stimulation at early times of HCMV infection.	SIGNOR-266655
Q14393	Q12866	2	binding	up-regulates	0.762	We also found that gas6 stimulated tyrosine phosphorylation of axl, sky, and mer receptors ectopically expressed in chinese hamster ovary cells. Taken together, these findings suggest that gas6 is a common ligand for axl, sky, and mer, all known members of an axl/sky receptor subfamily.	SIGNOR-44953
Q92698	P24941	0	phosphorylation	down-regulates activity	0.347	Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM.	SIGNOR-273599
P30291	P06493	2	phosphorylation	down-regulates	0.858	The wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (cdk1), thereby delaying entry into mitosis until appropriate conditions have been met	SIGNOR-139491
P35354	P59595	0	transcriptional regulation	up-regulates activity	0.2	SARS-CoV N protein activates COX-2 promoter and induces COX-2 protein expression	SIGNOR-262314
Q9UPY6	P00519	0	phosphorylation	up-regulates activity	0.582	WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3.	SIGNOR-259077
Q13464	P48436	1	phosphorylation	up-regulates	0.305	Rho kinase-dependent activation of sox9 in chondrocytes. In vitro, rock directly phosphorylated sox9 at ser(181), and the overexpression of rock or the activation of the rhoa pathway in sw1353 chondrosarcoma cells increased sox9(ser181) phosphorylation	SIGNOR-162643
P01920	Q86YJ5	0	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271539
Q8TD94	Q9NYA1	1	transcriptional regulation	up-regulates quantity by expression	0.2	KLF14 Is a Transcriptional Activator of SK1 Gene Expression in Endothelial Cells	SIGNOR-266047
Q9H4H8	P48729	2	binding	up-regulates quantity	0.384	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273749
Q5JTC6	P19544	2	binding	up-regulates	0.437	Wtx binds wt1, a zinc-finger transcription factor that is inactivated in wilms tumor. / the ability of wtx to enhance wt1-mediated transactivation suggests a physiologically significant interaction between these 2 tumor suppressors.	SIGNOR-185644
Q7Z434	P0DTC5	2	binding	down-regulates activity	0.1	Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions.	SIGNOR-262515
Q9BXH1	P04626	0	phosphorylation	down-regulates quantity by destabilization	0.281	HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life.	SIGNOR-276474
Q12770	P36956	2	binding	up-regulates activity	0.692	Insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis.	SIGNOR-256210
Q00987	Q02878	1	ubiquitination	down-regulates quantity by destabilization	0.432	Furthermore, we also demonstrated that RPL6 is a substrate for HDM2-mediated ubiquitination and proteasomal degradation.\|The interaction of RPL6 and HDM2 drives HDM2 mediated RPL6 polyubiquitination and proteasomal degradation.	SIGNOR-278630
Q969V1	O95837	2	binding	up-regulates activity	0.435	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-257334
Q16665	Q13315	0	phosphorylation	up-regulates	0.432	Here we show that hypoxia results in ataxia telangiectasia mutated (atm)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (hif-1_) on serine(696) and mediates downregulation of mtorc1 signaling. phosphorylation of hif-1_ by atm is required for its stability	SIGNOR-169999
Q9ULZ2	P42229	2	binding	up-regulates activity	0.421	STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.	SIGNOR-261821
P40189	P13725	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
Q13618	Q9H3F6	2	binding	up-regulates activity	0.494	BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.	SIGNOR-264234
Q9H0B6	Q9BQS8	2	binding	up-regulates activity	0.344	Interestingly, bead capture assays indicated that the middle part of FYCO1 (residues 585–1233) interacts directly with the KLC2 light chain of kinesin 1 (Fig. 3a and Extended Data Fig. 7a, b). Residues 735–773 of FYCO1 were found to be necessary for its kinesin-1 binding (Fig. 3c and Extended Data Fig. 7b, c), and FYCO1(Δ735–773)-positive LEs failed to translocate to the cell periphery (Extended Data Fig. 7e).	SIGNOR-260599
P48454	P0DP24	2	binding	up-regulates	0.521	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266324
P35790	P00533	2	binding	up-regulates activity	0.401	We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. CHKA is required for maximum EGF-dependent cell growth in mammary epithelium-derived cell lines	SIGNOR-266352
Q03112	Q00526	0	phosphorylation	up-regulates activity	0.2	The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.	SIGNOR-273431
P16581	Q14242	2	binding	up-regulates	0.771	PSGL-1 was shown to mediate rolling of human neutrophils on p- and e-selectin in vitro.	SIGNOR-46330
Q9ULB1	Q9NR48	0	transcriptional regulation	down-regulates quantity by repression	0.259	Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning.	SIGNOR-269056
P08754	P24530	2	binding	up-regulates activity	0.437	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-257166
Q5SGD2	Q9Y5P4	1	dephosphorylation	up-regulates activity	0.2	The expression of PP2Cepsilon also enhanced the association between CERT and VAPA.\|These results suggest that CERT is a physiological substrate of PP2Cepsilon and that dephosphorylation of CERT by PP2Cepsilon may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus.	SIGNOR-277113
Q96J02	P41240	0	phosphorylation	down-regulates activity	0.2	CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro.	SIGNOR-245327
P62136	Q8TCU6	1	dephosphorylation	up-regulates activity	0.2	MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.\|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation.	SIGNOR-277024
P19419	P28482	0	phosphorylation	up-regulates activity	0.563	We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-235455
Q9UP38	O14641	2	binding	up-regulates activity	0.678	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.	SIGNOR-258952
P05000	P17181	2	binding	up-regulates	0.728	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-105979
P55287	P35222	2	binding	up-regulates activity	0.654	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265851
Q13131	P05771	0	phosphorylation	down-regulates activity	0.2	Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle.	SIGNOR-276460
P26842	P32970	2	binding	up-regulates	0.772	The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner.	SIGNOR-36357
P10619	Q9NR19	0	transcriptional regulation	up-regulates quantity by expression	0.2	Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy\|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1\|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants	SIGNOR-276550
P14923	Q9UI47	0	relocalization	up-regulates quantity	0.484	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265494
P06493	Q99661	1	phosphorylation	down-regulates	0.686	We show here that cyclin-dependent kinase 1 (cdk1) phosphorylates t537 in the core domain of mcak and attenuates its microtubule-destabilizing activity in vitro and in vivo. Phosphorylation of mcak by cdk1 promotes the release of mcak from centrosomes and is required for proper spindle formation.	SIGNOR-164761
P50148	P49683	2	binding	up-regulates activity	0.275	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-257089
Q99683	P54652	2	binding	down-regulates	0.2	Coimmunoprecipitation analysis revealed a physical interaction between endogenous hsp72 and ask1 in nih 3t3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ask1 and ask1-dependent apoptosis.	SIGNOR-94565
P78314	P43405	0	phosphorylation	up-regulates activity	0.552	By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk.	SIGNOR-246596
O75365	P12931	0	phosphorylation	down-regulates activity	0.358	Our results show that Src kinase activity leads to the tyrosine phosphorylation of PRL-3, primarily on Y53.\|Collectively these results support a model in which Src causes phosphorylation of PRL-3 on Y53 to promote its pro-invasion functions, and suggest for the first time that the metastasis-associated tyrosine phosphatase PRL-3 may itself be regulated by post-translational modification.	SIGNOR-278262
Q14790	P27361	0	phosphorylation	down-regulates	0.717	We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity	SIGNOR-203480
Q8NEB9	Q99570	2	binding	up-regulates	0.939	Recombinant p150 associated with ptdins 3-kinase in vitro in a stable manner, resulting in a 2-fold increase in lipid kinase activity.	SIGNOR-45664
P53350	Q99741	1	phosphorylation	up-regulates	0.566	Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression.	SIGNOR-169184
Q13131	Q15831	0	phosphorylation	up-regulates activity	0.599	The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase.	SIGNOR-139297
P10275	Q9ULJ6	2	binding	up-regulates activity	0.709	Our results demonstrate that hZimp10 is a novel AR interacting protein that augments AR-mediated transcription. Moreover, hZimp10 co-localized with AR and SUMO-1 at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo.	SIGNOR-263935
P0DOX3	Q99856	0	transcriptional regulation	up-regulates quantity by expression	0.2	In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.\| Figure 3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene.	SIGNOR-268531
P31751	P04792	1	phosphorylation	down-regulates	0.289	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-186776
P34972	Q8NB16	0	phosphorylation	down-regulates quantity by destabilization	0.2	Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R.	SIGNOR-274121
Q13627	P24385	1	phosphorylation	down-regulates	0.395	Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells.	SIGNOR-202838
Q9BYG3	P49840	0	phosphorylation	up-regulates activity	0.2	The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1.	SIGNOR-262697
P84077	Q9Y6D6	0	guanine nucleotide exchange factor	up-regulates activity	0.6	Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) is an approximately 200-kDa brefeldin A-inhibited guanine nucleotide-exchange protein that preferentially activates ADP-ribosylation factor 1 (ARF1) and ARF3.	SIGNOR-272147
P63000	P52565	0	guanine nucleotide exchange factor	down-regulates activity	0.811	Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma.	SIGNOR-268436
Q16539	Q13202	0	dephosphorylation	down-regulates	0.591	M3/6 (dusp8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of jnk and, to a lesser extent, p38 mapk	SIGNOR-199695
P24928	P27361	0	phosphorylation	down-regulates	0.316	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120176
P61586	Q12802	0	guanine nucleotide exchange factor	up-regulates activity	0.744	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260527
Q16143	P34947	0	phosphorylation	down-regulates activity	0.321	GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser118 practically abolishes Œ≤-synuclein phosphorylation by both GRK2 and GRK5	SIGNOR-251203
P06493	P48200	1	phosphorylation	down-regulates	0.353	Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity	SIGNOR-179171
Q14534	Q12772	0	transcriptional regulation	up-regulates quantity by expression	0.595	The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription	SIGNOR-265162
Q04721	Q8NES3	2	binding	up-regulates	0.697	These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch. It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2.	SIGNOR-107702
Q01151	Q8TEB7	0	polyubiquitination	down-regulates quantity by destabilization	0.352	In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83.	SIGNOR-271850
P28566	P19086	2	binding	up-regulates activity	0.253	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-257100
P21730	P05771	0	phosphorylation	down-regulates	0.2	Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization	SIGNOR-151011
Q15466	O75469	2	binding	down-regulates	0.56	Our results suggest that shp is a negative regulator of pxr transcriptional activity. This conclusion derives from_ in vitro, cell culture, and_ in vivo_ experiments.	SIGNOR-101924
P10827	P23769	2	binding	down-regulates activity	0.2	We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2.	SIGNOR-267257
Q9NQ88	P04637	0	transcriptional regulation	up-regulates quantity by expression	0.2	TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR is the only known phosphatase glycolytic modulator regulated by TP53. The current study delineates the role of TIGAR in OXPHOS and glycolytic metabolic reprogramming in breast cancer.	SIGNOR-267365
Q8IXI1	Q9BXM7	0	phosphorylation	down-regulates quantity by destabilization	0.719	PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C).	SIGNOR-272727
P17252	O60341	1	phosphorylation	up-regulates activity	0.352	Together, these data indicate that LPS-induced LSD1 phosphorylation by PKC\u03b1 is required for its interaction with p65 in the nucleus.\|We have previously reported that LSD1 is phosphorylated by PKCalpha on serine 112 site, and knockin mice bearing phosphorylation defective Lsd1 SA/SA alleles show altered circadian rhythms and impaired phase resetting (Nam et al., 2014).	SIGNOR-279425
P18031	Q9NZJ5	1	dephosphorylation	down-regulates activity	0.267	Finally, we demonstrated that wild-type PTP1B directly dephosphorylated myc-tagged PERK that had been isolated from tunicamycin-treated HEK293T cells by immunoprecipitation ( xref ).\|The ability of PTP1B to dephosphorylate Tyr619 and inactivate PERK is fine tuned by the production of H 2 S by CSE in response to ER stress.	SIGNOR-277051
Q99731	Q9NPB9	2	binding	up-regulates activity	0.664	In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.	SIGNOR-268416
O75582	P16220	1	phosphorylation	up-regulates	0.731	Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb.	SIGNOR-59458
P49674	Q01974	1	phosphorylation	up-regulates	0.268	We also show that ror2 is phosphorylated by ckiepsilon on serine/threonine residues.	SIGNOR-129117
P07196	P62258	2	binding	down-regulates activity	0.276	These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.	SIGNOR-252398
P24941	Q02535	1	phosphorylation	down-regulates	0.342	We now show that an analogous cell-cycle-regulated phosphorylation of id3 alters the specificity of id3 for abrogating both e-box-dependent bhlh homo- or heterodimer complex formation in vitro and e-box-dependent reporter gene function in vivo._	SIGNOR-53306
P24941	P09874	1	phosphorylation	up-regulates activity	0.358	CDK2 dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells.\|Hormone dependent phosphorylation of PARP-1 by CDK2, within the catalytic domain, enhances its enzymatic capabilities.	SIGNOR-279146
Q13285	P28482	0	phosphorylation	up-regulates activity	0.463	Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein. Moreover, phosphorylation-dependent SF-1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway.	SIGNOR-249431
Q9UQ13	O14807	2	binding	up-regulates	0.69	Sur-8 interacts with ras and raf and is able to form a ternary complex with the two proteins. Thus, sur-8 may function as a scaffold that enhances ras-map kinase signal transduction by facilitating the interaction between ras and raf.	SIGNOR-77082
P09874	Q05655	0	phosphorylation	down-regulates activity	0.2	Interestingly, comparable experiments with the Ca 2+ -independent PKC\u03b4 isoform revealed that PKC\u03b4 phosphorylates ARTD1 at the N-terminus (amino acids 1\u2013214) and phosphorylation of ARTD1 by PKC\u03b4 inhibited DNA-induced PAR formation by ARTD1 in vitro (Supplementary Figure S6A and S6B), suggesting that the observed stimulatory effect of the PKCi on PAR formation might be due to inhibition of ARTD1 by PKC\u03b4.	SIGNOR-280085
Q9NYY3	P30533	1	phosphorylation	up-regulates activity	0.3	Inhibition of Ras and activation of Rap by Plk2.\|Plk2 phosphorylation of Ras and Rap regulators controls surface AMPARs.	SIGNOR-279476
O14727	Q96GX9	2	binding	down-regulates	0.525	Taken together, these results suggest that apip functions to inhibit muscle ischemic damage by binding to apaf-1 in the apaf-1/caspase-9 apoptosis pathway.	SIGNOR-126797
P31749	P36776	1	phosphorylation	up-regulates activity	0.253	In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity.	SIGNOR-265724
Q8IVT5	O43318	0	phosphorylation	down-regulates	0.2	C-tak1 constitutively associates with mammalian ksr1 and phosphorylates serine 392 to confer 14-3-3 binding and cytoplasmic sequestration of ksr1 in unstimulated cells. In response to signal activation, the phosphorylation state of s392 is reduced, allowing the ksr1 complex to colocalize with activated ras and raf-1 at the plasma membrane	SIGNOR-112779
P62166	Q9NP60	2	binding	up-regulates activity	0.321	IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.	SIGNOR-264476
Q15139	P35236	1	phosphorylation	up-regulates activity	0.2	HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. (Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient.	SIGNOR-276046

Q05397

Q00535

0

phosphorylation

up-regulates

0.305

Here, we show that fak phosphorylation by cdk5 at s732 is important for microtubule organization, nuclear movement, and neuronal migration. In cultured neurons, s732-phosphorylated fak is enriched along a centrosome-associated microtubule fork that abuts the nucleus. Overexpression of the nonphosphorylatable mutant fak s732a results in disorganization of the microtubule fork and impairment of nuclear movement in vitro, and neuronal positioning defects in vivo.

SIGNOR-86223

P0C6X7-PRO_0000037312

O75348

1

cleavage

down-regulates activity

0.2

Cleavage of the V-ATPase G1 fusion protein by SARS-CoV 3CLpro was found in this study (Fig. 3), implying that 3CLpro potentially cleaves the cellular V-ATPase G1, and affects the function of vacuolar H(+)-ATPase. Meanwhile, a significant intracellular acidification has been demonstrated in the 3CLpro-expressing cells (Fig. 4D). The result correlated well with previous reports in that V-ATPase-specific inhibitors cause acidic pHi [28], [29], and influences cell apoptosis

SIGNOR-260264

O60566

Q96SN8

0

transcriptional regulation

up-regulates quantity by expression

0.27

These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter

SIGNOR-260312

Q92569

P42336

2

binding

up-regulates

0.846

The region between the src homology 2 (sh2) domains of p55pik bound to the nh2 terminus region of p110alpha

SIGNOR-53597

Q96BR1

O15530

0

phosphorylation

up-regulates

0.461

Full-length sgk3 contains a complete phox homology (px) domain that targets the protein to endosomes. Both a functional px domain and pi3k activation are necessary for phosphorylation of sgk3 at two regulatory sites (thr-320 and ser-486) and subsequent induction of kinase activity. Pdk1 phosphorylates endosome-associated sgk3 at thr-320

SIGNOR-147213

P47901

P38405

2

binding

up-regulates activity

0.25

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-256934

P26367

P84022

2

binding

down-regulates activity

0.399

The paired domain of Pax6 interacts with the MH1 domain of Smad3. Smad3 prevents Pax6 paired domain from binding DNA

SIGNOR-251875

Q00987

Q13263

2

binding

up-regulates activity

0.598

we present evidence that MDM2 interacts with the nuclear corepressor KAP1. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation.

SIGNOR-240405

P36956

P23443

0

phosphorylation

up-regulates activity

0.424

Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation.|Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element-binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation ( xref ).

SIGNOR-280120

O15350

Q05655

0

phosphorylation

up-regulates

0.307

The results show that pkcdeltacf phosphorylates the p73beta transactivation and dna-binding domains. pkcdeltacf-mediated phosphorylation of p73beta is associated with accumulation of p73beta and induction of p73beta-mediated transactivation.

SIGNOR-90279

P25963

P06239

0

phosphorylation

down-regulates quantity by destabilization

0.586

Loss of tyrosine kinase p56lck in Jurkat cells abolished NFkappaB activation and partially suppressed and delayed phosphorylation of Tyr-42 of IkappaB upon pervanadate treatment. |Transfection of these cells with wild type Lck but not with mutant Lck F394 followed by H/R induces the tyrosine phosphorylation of inhibitor of nuclear factor kappaB (IkappaBalpha) and transcriptional activation of NFkappaB, and these are inhibited by Lck inhibitors

SIGNOR-249374

P10767

P21802

2

binding

up-regulates

0.753

The nine known fgf ligands and the four signaling fgf receptors (and their alternatively spliced variants) are expressed in specific spatial and temporal patterns. The activity of this signaling pathway is regulated by ligand binding specificity, heparan sulfate proteoglycans, and the differential signaling capacity of individual fgf receptors.

SIGNOR-42380

P04637

P55957

1

transcriptional regulation

up-regulates quantity by expression

0.519

Bid is a p53 primary-response gene.

SIGNOR-140248

P98177

Q00987

0

ubiquitination

down-regulates activity

0.63

Mdm2 Induces Mono-Ubiquitination of FOXO4.|higher amounts of Mdm2 transfected resulted in reduced FOXO4 transcriptional activity.

SIGNOR-278656

Q9Y4K3

P36406

0

ubiquitination

up-regulates activity

0.313

We show here that the upregulation of NF-kappaB by UL144 is dependent upon cellular tripartite motif 23 (TRIM23) protein. We propose a mechanism by which UL144 activates NF-kappaB through a direct interaction with the cellular protein TRIM23 in a complex containing TRAF6. we propose that TRIM23 mediates TRAF6 autoubiquitination in the presence of UL144, resulting in the virally controlled activation of NF-κB stimulation at early times of HCMV infection.

SIGNOR-266655

Q14393

Q12866

2

binding

up-regulates

0.762

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

SIGNOR-44953

Q92698

P24941

0

phosphorylation

down-regulates activity

0.347

Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM.

SIGNOR-273599

P30291

P06493

2

phosphorylation

down-regulates

0.858

The wee1 kinase phosphorylates and inhibits cyclin-dependent kinase 1 (cdk1), thereby delaying entry into mitosis until appropriate conditions have been met

SIGNOR-139491

P35354

P59595

0

transcriptional regulation

up-regulates activity

0.2

SARS-CoV N protein activates COX-2 promoter and induces COX-2 protein expression

SIGNOR-262314

Q9UPY6

P00519

0

phosphorylation

up-regulates activity

0.582

WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3.

SIGNOR-259077

Q13464

P48436

1

phosphorylation

up-regulates

0.305

Rho kinase-dependent activation of sox9 in chondrocytes. In vitro, rock directly phosphorylated sox9 at ser(181), and the overexpression of rock or the activation of the rhoa pathway in sw1353 chondrosarcoma cells increased sox9(ser181) phosphorylation

SIGNOR-162643

P01920

Q86YJ5

0

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.

SIGNOR-271539

Q8TD94

Q9NYA1

1

transcriptional regulation

up-regulates quantity by expression

0.2

KLF14 Is a Transcriptional Activator of SK1 Gene Expression in Endothelial Cells

SIGNOR-266047

Q9H4H8

P48729

2

binding

up-regulates quantity

0.384

We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.

SIGNOR-273749

Q5JTC6

P19544

2

binding

up-regulates

0.437

Wtx binds wt1, a zinc-finger transcription factor that is inactivated in wilms tumor. / the ability of wtx to enhance wt1-mediated transactivation suggests a physiologically significant interaction between these 2 tumor suppressors.

SIGNOR-185644

Q7Z434

P0DTC5

2

binding

down-regulates activity

0.1

Here, we identified SARS-CoV-2 membrane glycoprotein M as a negative regulator of the innate immune response. We found that the M protein interacted with the central adaptor protein MAVS in the innate immune response pathways. This interaction impaired MAVS aggregation and its recruitment of downstream TRAF3, TBK1, and IRF3, leading to attenuation of the innate antiviral response. Our findings reveal a mechanism by which SARS-CoV-2 evades the innate immune response and suggest that the M protein of SARS-CoV-2 is a potential target for the development of SARS-CoV-2 interventions.

SIGNOR-262515

Q9BXH1

P04626

0

phosphorylation

down-regulates quantity by destabilization

0.281

HER2 phosphorylates and destabilizes pro-apoptotic PUMA. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life.

SIGNOR-276474

Q12770

P36956

2

binding

up-regulates activity

0.692

Insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi. By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis.

SIGNOR-256210

Q00987

Q02878

1

ubiquitination

down-regulates quantity by destabilization

0.432

Furthermore, we also demonstrated that RPL6 is a substrate for HDM2-mediated ubiquitination and proteasomal degradation.|The interaction of RPL6 and HDM2 drives HDM2 mediated RPL6 polyubiquitination and proteasomal degradation.

SIGNOR-278630

Q969V1

O95837

2

binding

up-regulates activity

0.435

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-257334

Q16665

Q13315

0

phosphorylation

up-regulates

0.432

Here we show that hypoxia results in ataxia telangiectasia mutated (atm)-dependent phosphorylation of hypoxia-inducible factor 1-alpha (hif-1_) on serine(696) and mediates downregulation of mtorc1 signaling. phosphorylation of hif-1_ by atm is required for its stability

SIGNOR-169999

Q9ULZ2

P42229

2

binding

up-regulates activity

0.421

STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.

SIGNOR-261821

P40189

P13725

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

Q13618

Q9H3F6

2

binding

up-regulates activity

0.494

BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex.

SIGNOR-264234

Q9H0B6

Q9BQS8

2

binding

up-regulates activity

0.344

Interestingly, bead capture assays indicated that the middle part of FYCO1 (residues 585–1233) interacts directly with the KLC2 light chain of kinesin 1 (Fig. 3a and Extended Data Fig. 7a, b). Residues 735–773 of FYCO1 were found to be necessary for its kinesin-1 binding (Fig. 3c and Extended Data Fig. 7b, c), and FYCO1(Δ735–773)-positive LEs failed to translocate to the cell periphery (Extended Data Fig. 7e).

SIGNOR-260599

P48454

P0DP24

2

binding

up-regulates

0.521

Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.

SIGNOR-266324

P35790

P00533

2

binding

up-regulates activity

0.401

We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. CHKA is required for maximum EGF-dependent cell growth in mammary epithelium-derived cell lines

SIGNOR-266352

Q03112

Q00526

0

phosphorylation

up-regulates activity

0.2

The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.

SIGNOR-273431

P16581

Q14242

2

binding

up-regulates

0.771

PSGL-1 was shown to mediate rolling of human neutrophils on p- and e-selectin in vitro.

SIGNOR-46330

Q9ULB1

Q9NR48

0

transcriptional regulation

down-regulates quantity by repression

0.259

Our results reveal that a novel process of activity-dependent transcriptional repression exists in neurons and that Ash1L mediates the long-term repression of nrxn1α, thus implicating an important role for epigenetic modification in brain functioning.

SIGNOR-269056

P08754

P24530

2

binding

up-regulates activity

0.437

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-257166

Q5SGD2

Q9Y5P4

1

dephosphorylation

up-regulates activity

0.2

The expression of PP2Cepsilon also enhanced the association between CERT and VAPA.|These results suggest that CERT is a physiological substrate of PP2Cepsilon and that dephosphorylation of CERT by PP2Cepsilon may play an important role in the regulation of ceramide trafficking from the ER to the Golgi apparatus.

SIGNOR-277113

Q96J02

P41240

0

phosphorylation

down-regulates activity

0.2

CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro.

SIGNOR-245327

P62136

Q8TCU6

1

dephosphorylation

up-regulates activity

0.2

MS analysis of wild-type P-Rex1 and a PP1\u03b1-binding-deficient mutant revealed that endogenous PP1\u03b1 dephosphorylates P-Rex1 on at least three residues, Ser834, Ser1001 and Ser1165.|The phosphatase activity of PP1\u03b1 is required for P-Rex1 activation.

SIGNOR-277024

P19419

P28482

0

phosphorylation

up-regulates activity

0.563

We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency.

SIGNOR-235455

Q9UP38

O14641

2

binding

up-regulates activity

0.678

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

SIGNOR-258952

P05000

P17181

2

binding

up-regulates

0.728

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

SIGNOR-105979

P55287

P35222

2

binding

up-regulates activity

0.654

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

SIGNOR-265851

Q13131

P05771

0

phosphorylation

down-regulates activity

0.2

Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle.

SIGNOR-276460

P26842

P32970

2

binding

up-regulates

0.772

The molecule defining the cd70 ag is identical to the recently defined ligand for cd27. Bioassays demonstrated that the cd70 cdna clone expressed in african green monkey kidney cells would induce the proliferation of pha-costimulated t cells. Ramos cells were mixed with increasing numbers of transfected cells that expressed cd70 (cd27l) or cd154 (cd40l), both of which are expressed by activated t cells, in the presence of anti-igm ab. Cd27 ligation as well as cd40 ligation inhibited bcr-mediated apoptosis in a dose-dependent manner.

SIGNOR-36357

P10619

Q9NR19

0

transcriptional regulation

up-regulates quantity by expression

0.2

Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants

SIGNOR-276550

P14923

Q9UI47

0

relocalization

up-regulates quantity

0.484

Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14

SIGNOR-265494

P06493

Q99661

1

phosphorylation

down-regulates

0.686

We show here that cyclin-dependent kinase 1 (cdk1) phosphorylates t537 in the core domain of mcak and attenuates its microtubule-destabilizing activity in vitro and in vivo. Phosphorylation of mcak by cdk1 promotes the release of mcak from centrosomes and is required for proper spindle formation.

SIGNOR-164761

P50148

P49683

2

binding

up-regulates activity

0.275

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-257089

Q99683

P54652

2

binding

down-regulates

0.2

Coimmunoprecipitation analysis revealed a physical interaction between endogenous hsp72 and ask1 in nih 3t3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ask1 and ask1-dependent apoptosis.

SIGNOR-94565

P78314

P43405

0

phosphorylation

up-regulates activity

0.552

By using the transient expression system in COS-7 cells, we have demonstrated that 3BP2 was predominantly phosphorylated on Tyr174, Tyr183, and Tyr446 when it was coexpressed with Syk.

SIGNOR-246596

O75365

P12931

0

phosphorylation

down-regulates activity

0.358

Our results show that Src kinase activity leads to the tyrosine phosphorylation of PRL-3, primarily on Y53.|Collectively these results support a model in which Src causes phosphorylation of PRL-3 on Y53 to promote its pro-invasion functions, and suggest for the first time that the metastasis-associated tyrosine phosphatase PRL-3 may itself be regulated by post-translational modification.

SIGNOR-278262

Q14790

P27361

0

phosphorylation

down-regulates

0.717

We demonstrate that perk 1/2 can phosphorylate pro-caspase-8 at s387 by knocking-down the endogenous pro-caspase-8 using rnai and replacing it with its non-phosphorylatable counterpart (s387a), a significant increase in caspase-8 activity

SIGNOR-203480

Q8NEB9

Q99570

2

binding

up-regulates

0.939

Recombinant p150 associated with ptdins 3-kinase in vitro in a stable manner, resulting in a 2-fold increase in lipid kinase activity.

SIGNOR-45664

P53350

Q99741

1

phosphorylation

up-regulates

0.566

Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression.

SIGNOR-169184

Q13131

Q15831

0

phosphorylation

up-regulates activity

0.599

The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase.

SIGNOR-139297

P10275

Q9ULJ6

2

binding

up-regulates activity

0.709

Our results demonstrate that hZimp10 is a novel AR interacting protein that augments AR-mediated transcription. Moreover, hZimp10 co-localized with AR and SUMO-1 at replication foci throughout S phase, and it was capable of enhancing sumoylation of AR in vivo.

SIGNOR-263935

P0DOX3

Q99856

0

transcriptional regulation

up-regulates quantity by expression

0.2

In this work, we show that TFII-I directly interacts with human Bright through amino acids in Bright's protein interaction domain and that specific tyrosine residues of TFII-I are essential for Bright-induced activity of an immunoglobulin reporter gene. Moreover, inhibition of TFII-I function in a B-cell line resulted in decreased heavy-chain transcript levels.| Figure 3 shows that both anti-Bright and anti-TFII-I precipitated the bf150 Bright binding site from the B-cell line but not from a T-cell line that contains but does not express the V1 gene.

SIGNOR-268531

P31751

P04792

1

phosphorylation

down-regulates

0.289

First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.

SIGNOR-186776

P34972

Q8NB16

0

phosphorylation

down-regulates quantity by destabilization

0.2

Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2-dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R.

SIGNOR-274121

Q13627

P24385

1

phosphorylation

down-regulates

0.395

Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells.

SIGNOR-202838

Q9BYG3

P49840

0

phosphorylation

up-regulates activity

0.2

The forkhead-associated (FHA) domain of human Ki67 interacts with the human nucleolar protein hNIFK, recognizing a 44-residue fragment, hNIFK226-269, phosphorylated at Thr234. Here we show that high-affinity binding requires sequential phosphorylation by two kinases, CDK1 and GSK3, yielding pThr238, pThr234 and pSer230. phosphorylation of Thr234 by GSK3 proceeds only after Thr238 is already phosphorylated by CDK1.

SIGNOR-262697

P84077

Q9Y6D6

0

guanine nucleotide exchange factor

up-regulates activity

0.6

Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) is an approximately 200-kDa brefeldin A-inhibited guanine nucleotide-exchange protein that preferentially activates ADP-ribosylation factor 1 (ARF1) and ARF3.

SIGNOR-272147

P63000

P52565

0

guanine nucleotide exchange factor

down-regulates activity

0.811

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

SIGNOR-268436

Q16539

Q13202

0

dephosphorylation

down-regulates

0.591

M3/6 (dusp8) is a dual-specificity phosphatase implicated in the dephosphorylation and inactivation of jnk and, to a lesser extent, p38 mapk

SIGNOR-199695

P24928

P27361

0

phosphorylation

down-regulates

0.316

Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.

SIGNOR-120176

P61586

Q12802

0

guanine nucleotide exchange factor

up-regulates activity

0.744

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260527

Q16143

P34947

0

phosphorylation

down-regulates activity

0.321

GRK5 prefers alpha-synuclein as a substrate. GRK-mediated phosphorylation inhibits synuclein's interaction with both phospholipids and PLD2. Mutation of Ser118 practically abolishes Œ≤-synuclein phosphorylation by both GRK2 and GRK5

SIGNOR-251203

P06493

P48200

1

phosphorylation

down-regulates

0.353

Irp2 ser-157 is phosphorylated by cdk1/cyclin b1 during g(2)/m / ser-157 phosphorylation during g(2)/m reduces irp2 rna-binding activity

SIGNOR-179171

Q14534

Q12772

0

transcriptional regulation

up-regulates quantity by expression

0.595

The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription

SIGNOR-265162

Q04721

Q8NES3

2

binding

up-regulates

0.697

These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch. It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2.

SIGNOR-107702

Q01151

Q8TEB7

0

polyubiquitination

down-regulates quantity by destabilization

0.352

In this study, we show that GRAIL can down-modulate the expression of CD83 (previously described as a cell surface marker for mature dendritic cells) on CD4 T cells. GRAIL-mediated down-modulation of CD83 is dependent on an intact GRAIL extracellular protease-associated domain and an enzymatically active cytosolic RING domain, and proceeds via the ubiquitin-dependent 26S proteosome pathway. Ubiquitin modification of lysine residues K168 and K183, but not K192, in the cytoplasmic domain of CD83 was shown to be necessary for GRAIL-mediated degradation of CD83.

SIGNOR-271850

P28566

P19086

2

binding

up-regulates activity

0.253

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-257100

P21730

P05771

0

phosphorylation

down-regulates

0.2

Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization

SIGNOR-151011

Q15466

O75469

2

binding

down-regulates

0.56

Our results suggest that shp is a negative regulator of pxr transcriptional activity. This conclusion derives from_ in vitro, cell culture, and_ in vivo_ experiments.

SIGNOR-101924

P10827

P23769

2

binding

down-regulates activity

0.2

We found that the T3-bound TR inhibits this reporter construct driven by GATA2 alone, indicating that the target of T3-bound TR repression is GATA2.

SIGNOR-267257

Q9NQ88

P04637

0

transcriptional regulation

up-regulates quantity by expression

0.2

TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. TIGAR is the only known phosphatase glycolytic modulator regulated by TP53. The current study delineates the role of TIGAR in OXPHOS and glycolytic metabolic reprogramming in breast cancer.

SIGNOR-267365

Q8IXI1

Q9BXM7

0

phosphorylation

down-regulates quantity by destabilization

0.719

PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C).

SIGNOR-272727

P17252

O60341

1

phosphorylation

up-regulates activity

0.352

Together, these data indicate that LPS-induced LSD1 phosphorylation by PKC\u03b1 is required for its interaction with p65 in the nucleus.|We have previously reported that LSD1 is phosphorylated by PKCalpha on serine 112 site, and knockin mice bearing phosphorylation defective Lsd1 SA/SA alleles show altered circadian rhythms and impaired phase resetting (Nam et al., 2014).

SIGNOR-279425

P18031

Q9NZJ5

1

dephosphorylation

down-regulates activity

0.267

Finally, we demonstrated that wild-type PTP1B directly dephosphorylated myc-tagged PERK that had been isolated from tunicamycin-treated HEK293T cells by immunoprecipitation ( xref ).|The ability of PTP1B to dephosphorylate Tyr619 and inactivate PERK is fine tuned by the production of H 2 S by CSE in response to ER stress.

SIGNOR-277051

Q99731

Q9NPB9

2

binding

up-regulates activity

0.664

In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.

SIGNOR-268416

O75582

P16220

1

phosphorylation

up-regulates

0.731

Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb.

SIGNOR-59458

P49674

Q01974

1

phosphorylation

up-regulates

0.268

We also show that ror2 is phosphorylated by ckiepsilon on serine/threonine residues.

SIGNOR-129117

P07196

P62258

2

binding

down-regulates activity

0.276

These results suggest the important role of 14-3-3 in the dynamic regulation of NF-L assembly, and in the capacity to prevent the formation of NF-L aggregates. all seven isoforms specifically interacted with NF-L, but not NF-M or NF-H. specific interaction of 14-3-3 proteins with phosphorylated NF-L subunits also indicated the role of 14-3-3 and NF-L phosphorylation in the disassembly of neurofilaments. What is more, binding of 14-3-3 to phosphorylated NF-L subunits may prevent the dephosphorylation of these subunits by phosphatases, maintaining the hyperphosphorylation state of the subunits, which facilitates the disassembly of neurofilaments.

SIGNOR-252398

P24941

Q02535

1

phosphorylation

down-regulates

0.342

We now show that an analogous cell-cycle-regulated phosphorylation of id3 alters the specificity of id3 for abrogating both e-box-dependent bhlh homo- or heterodimer complex formation in vitro and e-box-dependent reporter gene function in vivo._

SIGNOR-53306

P24941

P09874

1

phosphorylation

up-regulates activity

0.358

CDK2 dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells.|Hormone dependent phosphorylation of PARP-1 by CDK2, within the catalytic domain, enhances its enzymatic capabilities.

SIGNOR-279146

Q13285

P28482

0

phosphorylation

up-regulates activity

0.463

Here we show that maximal SF-1-mediated transcription and interaction with general nuclear receptor cofactors depends on phosphorylation of a single serine residue (Ser-203) located in a major activation domain (AF-1) of the protein. Moreover, phosphorylation-dependent SF-1 activation is likely mediated by the mitogen-activated protein kinase (MAPK) signaling pathway.

SIGNOR-249431

Q9UQ13

O14807

2

binding

up-regulates

0.69

Sur-8 interacts with ras and raf and is able to form a ternary complex with the two proteins. Thus, sur-8 may function as a scaffold that enhances ras-map kinase signal transduction by facilitating the interaction between ras and raf.

SIGNOR-77082

P09874

Q05655

0

phosphorylation

down-regulates activity

0.2

Interestingly, comparable experiments with the Ca 2+ -independent PKC\u03b4 isoform revealed that PKC\u03b4 phosphorylates ARTD1 at the N-terminus (amino acids 1\u2013214) and phosphorylation of ARTD1 by PKC\u03b4 inhibited DNA-induced PAR formation by ARTD1 in vitro (Supplementary Figure S6A and S6B), suggesting that the observed stimulatory effect of the PKCi on PAR formation might be due to inhibition of ARTD1 by PKC\u03b4.

SIGNOR-280085

Q9NYY3

P30533

1

phosphorylation

up-regulates activity

0.3

Inhibition of Ras and activation of Rap by Plk2.|Plk2 phosphorylation of Ras and Rap regulators controls surface AMPARs.

SIGNOR-279476

O14727

Q96GX9

2

binding

down-regulates

0.525

Taken together, these results suggest that apip functions to inhibit muscle ischemic damage by binding to apaf-1 in the apaf-1/caspase-9 apoptosis pathway.

SIGNOR-126797

P31749

P36776

1

phosphorylation

up-regulates activity

0.253

In mitochondria, LonP1 is phosphorylated by Akt on Ser173 and Ser181, enhancing its protease activity.

SIGNOR-265724

Q8IVT5

O43318

0

phosphorylation

down-regulates

0.2

C-tak1 constitutively associates with mammalian ksr1 and phosphorylates serine 392 to confer 14-3-3 binding and cytoplasmic sequestration of ksr1 in unstimulated cells. In response to signal activation, the phosphorylation state of s392 is reduced, allowing the ksr1 complex to colocalize with activated ras and raf-1 at the plasma membrane

SIGNOR-112779

P62166

Q9NP60

2

binding

up-regulates activity

0.321

IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.

SIGNOR-264476

Q15139

P35236

1

phosphorylation

up-regulates activity

0.2

HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. (Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient.

SIGNOR-276046