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
Q8TBJ5	Q16650	0	transcriptional regulation	down-regulates quantity by repression	0.486	We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression of Fezf2 and CTIP2.\|(3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in the Fezf2 gene.	SIGNOR-268967
Q9HC35	Q8TDX7	0	phosphorylation	up-regulates activity	0.274	The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression.	SIGNOR-273884
P35222	P35712	2	binding	down-regulates activity	0.654	SOX6 interacts with β-catenin in adipocytes, suggesting an inhibition of WNT/β-catenin signaling, thereby promoting adipogenesis.	SIGNOR-256073
P23634-6	Q05397	0	phosphorylation	up-regulates activity	0.2	Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. equence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif.	SIGNOR-263194
Q9BXL7	P62714	0	dephosphorylation	down-regulates activity	0.2	NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane\|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.	SIGNOR-248607
P10645	P16220	0	transcriptional regulation	up-regulates quantity by expression	0.265	Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.	SIGNOR-254276
P49840	P20807	0	cleavage	up-regulates activity	0.2	Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase	SIGNOR-251606
P05112	P35354	0	null	up-regulates	0.444	Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression	SIGNOR-255967
O96013	O43426	1	phosphorylation	up-regulates activity	0.2	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.	SIGNOR-263024
P48729	P37840	1	phosphorylation	up-regulates	0.371	In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes.	SIGNOR-73799
P49841	P84022	1	phosphorylation	down-regulates quantity by destabilization	0.488	Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation.	SIGNOR-160318
O00512	P35222	2	binding	up-regulates	0.938	The transcriptional activity of beta-catenin depends on bcl-9. Bcl-9 functions in targeting beta-catenin to the nucleus and thus increases the transcriptional activity of beta-catenin	SIGNOR-126059
P16298	Q92934	1	dephosphorylation	up-regulates activity	0.364	Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD\|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.	SIGNOR-248384
Q7Z5K2	Q96FF9	2	binding	down-regulates activity	0.2	We show that DNA replication and cohesin acetylation promote binding of Sororin to cohesin, and that Sororin displaces Wapl from its binding partner Pds5.	SIGNOR-265266
P43405	Q13177	0	phosphorylation	up-regulates activity	0.271	This is supported by in vitro studies showing that Pak2 phosphorylates and activates Syk.	SIGNOR-279083
P00533	P63096	1	phosphorylation	up-regulates activity	0.464	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277227
P62745	P48729	0	phosphorylation	down-regulates	0.2	Mass spectrometry analysis demonstrates that rhob is monophosphorylated by ck1, in its c-terminal end, on serine 185. lastly we show that the inhibition of ck1 activates rhob and promotes rhob dependent actin fiber formation and egf-r level.	SIGNOR-179255
P12931	Q8NEB9	1	phosphorylation	up-regulates activity	0.42	Given that VPS34 is activated by Src mediated tyrosine phosphorylation, we next determined if VPS34 was tyrosine phosphorylated following insulin treatment.\|These data indicate that VPS34 is an effector of insulin-mediated signal transduction and that Src phosphorylation of VPS34 is required for this function.	SIGNOR-278456
P17612	Q96SB3	1	phosphorylation	down-regulates activity	0.31	Spinophilin is phosphorylated in vitro by protein kinase A (PKA). two major sites of phosphorylation, Ser-94 and Ser-177, that are located within the actin-binding domain of spinophilin. Phosphorylation of spinophilin by PKA modulated the association between spinophilin and the actin cytoskeleton. phosphorylation of spinophilin reduced the stoichiometry of the spinophilin-actin interaction. In contrast, the ability of spinophilin to bind to PP1 remained unchanged.	SIGNOR-250035
P27361	Q9H9Z2	1	phosphorylation	down-regulates activity	0.277	Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200.	SIGNOR-277337
P63096	P48039	2	binding	up-regulates activity	0.476	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-256706
P32121	Q99835	2	binding	up-regulates	0.661	Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2	SIGNOR-132759
Q9H0K1	P27986	1	phosphorylation	up-regulates activity	0.322	The Regulatory Subunit of PI3K Is a Direct Catalytic Target of SIK2. These data confirm that p85α is a direct catalytic substrate of SIK2 and that SIK2 S154 phosphorylation significantly increases the activity of the PI3K/AKT pathway in ovarian cancer cells.	SIGNOR-277269
P22607	P05230	2	binding	up-regulates	0.801	Reports also show that fgf/fgfr3 signals mediate some of the effects of tgf-beta on embryonic bone formation	SIGNOR-195585
P29350	P06241	0	phosphorylation	up-regulates activity	0.551	By contrast, receptor multivalent aggregation induced a Fyn-dependent SHP-1 S591 phosphorylation (Fig.\u00a0 xref ).\|Fyn simultaneously activates the PI3K-PKC\u03b1 pathway, leading to SHP-1 phosphorylation on serine 591.	SIGNOR-279716
Q04760	P35916	0	phosphorylation	up-regulates activity	0.2	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276180
P17676	P35318	1	transcriptional regulation	up-regulates quantity by expression	0.245	These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells.	SIGNOR-254047
Q5VWQ8	P98082	2	binding	up-regulates activity	0.521	In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation.	SIGNOR-254744
P12034	P21802	2	binding	up-regulates	0.702	Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2	SIGNOR-38995
P35222	P68400	0	phosphorylation	up-regulates activity	0.556	The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability.	SIGNOR-250849
Q03060	P27361	0	phosphorylation	down-regulates quantity by destabilization	0.41	The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.	SIGNOR-275978
Q96L34	Q5BJF6	1	phosphorylation	up-regulates activity	0.516	Collectively, our data indicate that MARK4 interacts with ODF2 in vivo and phosphorylates ODF2 in vitro.\|Collectively, our data support the model that MARK4 promotes ciliogenesis by acting upstream of ODF2.	SIGNOR-278961
P36897	P63000	1	null	up-regulates activity	0.28	Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity.	SIGNOR-227496
Q13424	P29475	1	relocalization	up-regulates	0.558	biochemical studies showed that the N-terminal PDZ domain of nNOS binds to a similar PDZ domain of syntrophin (Fig. 1), a dystrophin-associated protein	SIGNOR-236916
Q09472	P35222	2	binding	up-regulates	0.705	Ctnnb1 forms a ternary complex with lef1 and ep300 that is disrupted by ctnnbip1 binding	SIGNOR-76987
P24941	Q12834	1	phosphorylation	down-regulates activity	0.684	Here we show that cyclin A2-Cdk2 binds and phosphorylates Cdc20 in interphase and this inhibits APC/C-Cdc20 activity.\|Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry.	SIGNOR-279322
P60484	P35568	1	dephosphorylation	down-regulates activity	0.576	In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser 307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon HCV infection occurred in a PTEN dependent manner.\|In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser-307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon Hepatitis C virus infection occurred in a PTEN-dependent manner.	SIGNOR-277078
Q13829	P68400	0	phosphorylation	up-regulates	0.2	It was demonstrated that ck2 could phosphorylate tnfaip1 in vitro and in vivo, which facilitated the distribution of tnfaip1 in nucleus and enhanced its interaction with pcna. It is suggested that the phosphorylation of tnfaip1 may be required for its functions.	SIGNOR-188849
P30154	P67775	2	binding	up-regulates activity	0.943	Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity	SIGNOR-217872
Q86XK2	P41182	2	binding	down-regulates	0.49	Fbxo11 targets bcl6 for degradation	SIGNOR-177652
Q9BXS5	Q2M2I8	0	phosphorylation	up-regulates	0.2	Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis.	SIGNOR-115589
Q13009	P48729	0	phosphorylation	down-regulates quantity by destabilization	0.309	Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site.	SIGNOR-276673
P19544	P00441	1	transcriptional regulation	up-regulates quantity by expression	0.265	The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments.	SIGNOR-253898
P10997	P29120	0	cleavage	up-regulates activity	0.446	The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule	SIGNOR-261782
P48431	Q9NQU5	0	phosphorylation	up-regulates quantity	0.2	PAK5 promotes the cell stemness ability by phosphorylating SOX2 in lung squamous cell carcinomas.\|The absence of PAK5 abolishes self-renewal ability of LUSC cells by decreasing the expression and phosphorylation of SOX2 in vitro and in vivo.	SIGNOR-280060
Q15077	Q14344	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257398
Q96P31	P29350	2	binding	up-regulates activity	0.39	Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.	SIGNOR-274013
Q96HS1	P48163	1	dephosphorylation	up-regulates activity	0.2	PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation.	SIGNOR-275569
P15498	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.75	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-260580
P43378	P04626	1	dephosphorylation	down-regulates activity	0.304	Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.\|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells.	SIGNOR-277170
Q13233	P01116	2	binding	up-regulates	0.366	Mitogen-activated protein kinase kinase kinase (mekk1) is a serine-threonine kinase that regulates sequential protein kinase pathways involving stress-activated protein kinases and mitogen-activated protein kinases. Mekk1 is activated in response to growth factor stimulation of cells and by expression of activated ras. mekk1 directly binds ras.GTP. Thus, ras interacts with protein kinases of both the raf and mekk families.	SIGNOR-32620
P17706	O00401	1	dephosphorylation	down-regulates	0.29	Similarly, the t cell phosphatase has a 30-fold lower kcat/km toward autoinhibited p-n-wasp than toward the isolated p-gbd, and again this effect is largely reversed by that cdc42	SIGNOR-141652
Q6ZMZ0	P68036	2	binding	up-regulates activity	0.481	We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM. We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and	SIGNOR-271591
P43353	Q9NXK8	2	binding	down-regulates quantity by destabilization	0.32	We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members.	SIGNOR-272815
Q9NP62	Q9UKT8	2	binding	down-regulates quantity	0.538	FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system	SIGNOR-271524
Q03591	P08603	2	binding	down-regulates activity	0.504	Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.\|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. \|these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b	SIGNOR-263476
P63092	Q14831	2	binding	up-regulates activity	0.357	MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.	SIGNOR-264080
Q9UKT8	Q9NP62	2	binding	down-regulates quantity	0.538	FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system	SIGNOR-271524
Q16539	P10415	1	phosphorylation	down-regulates activity	0.334	Bcl-2 phosphorylation by p38 mapkin this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, ser(87) and thr(56) as the bcl-2 residues phosphorylated by p38 mapk and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of bcl-2 protein.	SIGNOR-146786
P35354	Q12968	0	transcriptional regulation	up-regulates quantity by expression	0.279	NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration	SIGNOR-264028
Q02297	P04626	2	binding	up-regulates	0.792	Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.	SIGNOR-26875
Q9BW19	Q13535	0	phosphorylation	up-regulates quantity by stabilization	0.257	ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro.	SIGNOR-277296
Q15722	Q03113	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-257196
P08754	O95136	2	binding	up-regulates activity	0.387	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-256871
P62256	P17542	0	transcriptional regulation	up-regulates quantity by expression	0.326	Tal1 expression activated UBE2H expression, whereas Tal1 knock-down reduced UBE2H expression and ubiquitin transfer activity.\|Binding of Tal1 to UBE2H was confirmed by chromatin immunoprecipitation.	SIGNOR-269000
Q8TDB6	P62805	1	monoubiquitination	down-regulates activity	0.2	Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. In response to DNA damage, BBAP expression increases and the E3 ligase selectively monoubiquitylates H4K91. Disruption of BBAP-mediated monoubiquitylation of H4K91 is associated with loss of chromatin-associated PR-Set7/Set8 and mono- and dimethyl H4K20, delayed kinetics of 53BP1 foci formation and increased sensitivity to DNA damage.	SIGNOR-271897
Q96R06	P53350	0	phosphorylation	up-regulates activity	0.394	Phosphorylation of the astrin N-terminal domain by Plk1 contributes to kinetochore\u2013microtubule attachment stability.\|Taken together with the localisation data in XREF_FIG B, these data suggest that the presence of the Plk1 phosphorylated astrin N-terminus promotes the accumulation of the astrin complex at attached kinetochores, without which attachments appear more prone to dissociate.	SIGNOR-279423
P05549	P54646	0	phosphorylation	up-regulates activity	0.307	Inhibition of AMPKalpha2 with either siRNA or compound C significantly suppressed the AngII- or nicotine enhanced AP-2alpha activity and the binding of AP-2alpha to DNA.\|We report that nicotine, a major component of cigarette smoke, activates AMPK in VSMCs and that AMPKalpha2 phosphorylates AP-2alpha at serine 219 resulting in aberrant expression of MMP2 and consequent AAA formation.	SIGNOR-279648
P60510	Q9GZM8	1	dephosphorylation	down-regulates activity	0.395	Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation\|PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome.\|We next examined the ability of PP4c to dephosphorylate a Cdk1 phosphorylation site, phospho-T219	SIGNOR-248550
P08069	O14654	1	phosphorylation	up-regulates	0.657	Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4.	SIGNOR-56604
P81274	Q96KB5	0	phosphorylation	up-regulates	0.27	We found that the 450th threonine (thr450) of lgn/gpsm2 was phosphorylated by the serine/threonine kinase pbk/topk during mitosis. Western blot analysis indicated the highest expression and the phosphorylated form of lgn/gpsm2 protein in g2/m phase.	SIGNOR-166461
Q9HCK8	Q9HD90	1	transcriptional regulation	down-regulates quantity	0.2	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268918
Q15303	P62993	2	binding	up-regulates	0.83	Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength.	SIGNOR-146876
Q13315	Q5XUX0	1	phosphorylation	up-regulates	0.406	We find that dna damage induced by gamma-irradiation results in increased fbxo31 levels, which requires phosphorylation of fbxo31 by the ddr-initiating kinase atm	SIGNOR-185635
Q7L7X3	Q13043	1	phosphorylation	up-regulates	0.368	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-201324
O14965	Q9ULW0	1	phosphorylation	up-regulates activity	0.965	Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.\|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.\| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells	SIGNOR-265089
Q7Z2W4	Q14258	0	ubiquitination	up-regulates activity	0.398	Our data demonstrates that TRIM25 triggers ubiquitination of ZAP and enhances its antiviral activity through inhibition of viral translation, highlighting the importance of cofactors in the mechanisms of broadly antiviral proteins.	SIGNOR-278565
Q9H2X6	Q9NY61	1	phosphorylation	down-regulates quantity	0.346	HIPK2 phosphorylates Che-1.\|Here we demonstrate that HIPK2, a proapoptotic kinase, is involved in Che-1 degradation.	SIGNOR-278942
P49662	Q63HK5	0	transcriptional regulation	down-regulates quantity by repression	0.27	Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD.	SIGNOR-264815
P01137	P35555	2	binding	up-regulates quantity	0.489	We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling.	SIGNOR-251888
P63000	Q8N1I0	0	guanine nucleotide exchange factor	up-regulates activity	0.586	DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia.	SIGNOR-266823
P46527	O60674	0	phosphorylation	down-regulates activity	0.696	JAK2 phosphorylates tyrosine residue 88 (Y88) of p27(Kip1).	SIGNOR-278260
Q15303	P27361	0	phosphorylation	down-regulates activity	0.534	We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala) significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation.	SIGNOR-277448
Q13555	P07101	1	phosphorylation	up-regulates activity	0.332	In both isoforms, Ser-40 was found to be phosphorylated by PKA, and Ser-19 and Ser-40 were found to be phosphorylated by CaM-PK II. The putative phosphorylation site generated by alternative splicing (Ser-31) was phosphorylated specifically by CaM-PK II in TH-2 only. \| Unlike TH-1, phosphorylation of TH-2 by CaM-PK II resulted in an increase of the Ki value for dopamine.	SIGNOR-250709
Q9Y253	P51587	2	binding	up-regulates	0.553	Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates	SIGNOR-204538
P62136	Q9UD71	2	binding	down-regulates activity	0.599	DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.â€šÂ	SIGNOR-264957
O43255	Q9Y6H5	1	ubiquitination	down-regulates	0.62	Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system	SIGNOR-140651
Q00722	P62873	2	binding	up-regulates	0.554	Activation of plc-beta 2 by beta gamma subunits may be an important mechanism by which pertussis toxin-sensitive g proteins stimulate plc.	SIGNOR-19447
P51812	P18846	1	phosphorylation	up-regulates activity	0.318	ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinase. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.\|ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinases.	SIGNOR-280117
P38405	P30559	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-256936
P57059	Q6UUV9	1	phosphorylation	down-regulates	0.494	These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities.	SIGNOR-147669
Q9Y5Z9	P01112	2	binding	down-regulates activity	0.2	This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells.	SIGNOR-256206
P25098	Q8IXH6	1	phosphorylation	down-regulates activity	0.2	In conclusion, experimental results demonstrate that GRK2 chronically downregulates DOR functional competence at the PM in peripheral sensory neurons, as well as peripheral DOR anti-nociception in vivo.\|These data demonstrate that BK does not affect GRK2 mediated phosphorylation of DOR at its primary desensitization site.	SIGNOR-279739
Q13557	P13688	1	phosphorylation	up-regulates	0.2	Camkiid specifically phosphorylates thr-457 on ceacam1-sf, which in turn regulates the process of lumen formation via apoptosis of the central acinar cells.	SIGNOR-203402
Q13489	Q13489	2	ubiquitination	down-regulates activity	0.2	Ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria.	SIGNOR-121880
Q00535	Q9Y490	1	phosphorylation	up-regulates	0.458	Cdk5 phosphorylated talin head at ser 425, inhibiting its binding to smurf1, thus preventing talin head ubiquitylation and degradation.	SIGNOR-185210
Q92968	O75381	2	binding	up-regulates activity	0.92	Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import	SIGNOR-253029
Q6P0Q8	P48764	1	phosphorylation	down-regulates activity	0.456	Coexpression of MAST205 inhibits the activity of Na +/H+ exchanger NHE3.\|Consistent with these results, we found that MAST205 phosphorylated NHE3 under in vitro conditions.	SIGNOR-279229
Q12974	P24941	1	dephosphorylation	up-regulates	0.2	Cells overexpressing prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity	SIGNOR-119478
P46527	O15111	0	phosphorylation	down-regulates activity	0.372	Reduced nuclear p27 was also found in MCF7 human breast cancer cells that were transiently transfected with an IKKalpha expression vector; increased IKKalpha expression resulted in a dose dependent decrease in nuclear p27 and increased cytoplasmic p27 (XREF_FIG).\|We found that IKKalpha phosphorylates p27 at S183 to cause its nuclear export.	SIGNOR-278438

Q8TBJ5

Q16650

0

transcriptional regulation

down-regulates quantity by repression

0.486

We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression of Fezf2 and CTIP2.|(3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in the Fezf2 gene.

SIGNOR-268967

Q9HC35

Q8TDX7

0

phosphorylation

up-regulates activity

0.274

The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression.

SIGNOR-273884

P35222

P35712

2

binding

down-regulates activity

0.654

SOX6 interacts with β-catenin in adipocytes, suggesting an inhibition of WNT/β-catenin signaling, thereby promoting adipogenesis.

SIGNOR-256073

P23634-6

Q05397

0

phosphorylation

up-regulates activity

0.2

Results of co-immunoprecipitation, treatment with tyrosine kinase inhibitors and integrin inhibition experiments suggest that FAK is responsible for PMCA4b tyrosine phosphorylation during platelet activation. equence analysis indicates that Y(1176) is a likely substrate for focal adhesion kinase (FAK), while Y(1122) is not located in a tyrosine phosphorylation motif.

SIGNOR-263194

Q9BXL7

P62714

0

dephosphorylation

down-regulates activity

0.2

NF-kappaB activation is triggered by PKCtheta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCtheta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCtheta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.

SIGNOR-248607

P10645

P16220

0

transcriptional regulation

up-regulates quantity by expression

0.265

Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.

SIGNOR-254276

P49840

P20807

0

cleavage

up-regulates activity

0.2

Thus, it has been shown that calpain cleaves the inhibitory domain of GSK3 generating two fragments of 40 and 30 kDa. This cleavage enhanced activity of the kinase

SIGNOR-251606

P05112

P35354

0

null

up-regulates

0.444

Cox2 Is a Direct Srf Target Gene and Controls Il4 Expression

SIGNOR-255967

O96013

O43426

1

phosphorylation

up-regulates activity

0.2

We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.

SIGNOR-263024

P48729

P37840

1

phosphorylation

up-regulates

0.371

In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes.

SIGNOR-73799

P49841

P84022

1

phosphorylation

down-regulates quantity by destabilization

0.488

Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation.

SIGNOR-160318

O00512

P35222

2

binding

up-regulates

0.938

The transcriptional activity of beta-catenin depends on bcl-9. Bcl-9 functions in targeting beta-catenin to the nucleus and thus increases the transcriptional activity of beta-catenin

SIGNOR-126059

P16298

Q92934

1

dephosphorylation

up-regulates activity

0.364

Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD|Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis.

SIGNOR-248384

Q7Z5K2

Q96FF9

2

binding

down-regulates activity

0.2

We show that DNA replication and cohesin acetylation promote binding of Sororin to cohesin, and that Sororin displaces Wapl from its binding partner Pds5.

SIGNOR-265266

P43405

Q13177

0

phosphorylation

up-regulates activity

0.271

This is supported by in vitro studies showing that Pak2 phosphorylates and activates Syk.

SIGNOR-279083

P00533

P63096

1

phosphorylation

up-regulates activity

0.464

RTKs directly phosphorylate Gαi on Y154, 155, and Y320.

SIGNOR-277227

P62745

P48729

0

phosphorylation

down-regulates

0.2

Mass spectrometry analysis demonstrates that rhob is monophosphorylated by ck1, in its c-terminal end, on serine 185. lastly we show that the inhibition of ck1 activates rhob and promotes rhob dependent actin fiber formation and egf-r level.

SIGNOR-179255

P12931

Q8NEB9

1

phosphorylation

up-regulates activity

0.42

Given that VPS34 is activated by Src mediated tyrosine phosphorylation, we next determined if VPS34 was tyrosine phosphorylated following insulin treatment.|These data indicate that VPS34 is an effector of insulin-mediated signal transduction and that Src phosphorylation of VPS34 is required for this function.

SIGNOR-278456

P17612

Q96SB3

1

phosphorylation

down-regulates activity

0.31

Spinophilin is phosphorylated in vitro by protein kinase A (PKA). two major sites of phosphorylation, Ser-94 and Ser-177, that are located within the actin-binding domain of spinophilin. Phosphorylation of spinophilin by PKA modulated the association between spinophilin and the actin cytoskeleton. phosphorylation of spinophilin reduced the stoichiometry of the spinophilin-actin interaction. In contrast, the ability of spinophilin to bind to PP1 remained unchanged.

SIGNOR-250035

P27361

Q9H9Z2

1

phosphorylation

down-regulates activity

0.277

Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200.

SIGNOR-277337

P63096

P48039

2

binding

up-regulates activity

0.476

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-256706

P32121

Q99835

2

binding

up-regulates

0.661

Grk2-mediated phosphorylation of vertebrate smo allows smo to bind to beta-arrestins 1 or 2

SIGNOR-132759

Q9H0K1

P27986

1

phosphorylation

up-regulates activity

0.322

The Regulatory Subunit of PI3K Is a Direct Catalytic Target of SIK2. These data confirm that p85α is a direct catalytic substrate of SIK2 and that SIK2 S154 phosphorylation significantly increases the activity of the PI3K/AKT pathway in ovarian cancer cells.

SIGNOR-277269

P22607

P05230

2

binding

up-regulates

0.801

Reports also show that fgf/fgfr3 signals mediate some of the effects of tgf-beta on embryonic bone formation

SIGNOR-195585

P29350

P06241

0

phosphorylation

up-regulates activity

0.551

By contrast, receptor multivalent aggregation induced a Fyn-dependent SHP-1 S591 phosphorylation (Fig.\u00a0 xref ).|Fyn simultaneously activates the PI3K-PKC\u03b1 pathway, leading to SHP-1 phosphorylation on serine 591.

SIGNOR-279716

Q04760

P35916

0

phosphorylation

up-regulates activity

0.2

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).

SIGNOR-276180

P17676

P35318

1

transcriptional regulation

up-regulates quantity by expression

0.245

These findings suggest that NF-IL6 and AP-2 sites in the promoter region are the functional elements in the transcriptional regulation of human AM gene in vascular endothelial cells.

SIGNOR-254047

Q5VWQ8

P98082

2

binding

up-regulates activity

0.521

In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation.

SIGNOR-254744

P12034

P21802

2

binding

up-regulates

0.702

Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2

SIGNOR-38995

P35222

P68400

0

phosphorylation

up-regulates activity

0.556

The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability.

SIGNOR-250849

Q03060

P27361

0

phosphorylation

down-regulates quantity by destabilization

0.41

The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway.

SIGNOR-275978

Q96L34

Q5BJF6

1

phosphorylation

up-regulates activity

0.516

Collectively, our data indicate that MARK4 interacts with ODF2 in vivo and phosphorylates ODF2 in vitro.|Collectively, our data support the model that MARK4 promotes ciliogenesis by acting upstream of ODF2.

SIGNOR-278961

P36897

P63000

1

null

up-regulates activity

0.28

Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity.

SIGNOR-227496

Q13424

P29475

1

relocalization

up-regulates

0.558

biochemical studies showed that the N-terminal PDZ domain of nNOS binds to a similar PDZ domain of syntrophin (Fig. 1), a dystrophin-associated protein

SIGNOR-236916

Q09472

P35222

2

binding

up-regulates

0.705

Ctnnb1 forms a ternary complex with lef1 and ep300 that is disrupted by ctnnbip1 binding

SIGNOR-76987

P24941

Q12834

1

phosphorylation

down-regulates activity

0.684

Here we show that cyclin A2-Cdk2 binds and phosphorylates Cdc20 in interphase and this inhibits APC/C-Cdc20 activity.|Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry.

SIGNOR-279322

P60484

P35568

1

dephosphorylation

down-regulates activity

0.576

In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser 307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon HCV infection occurred in a PTEN dependent manner.|In contrast, IRS-1 level were significantly decreased and phosphorylation of IRS-1 at Ser-307 was strongly enhanced by PTEN knockdown, suggesting that both reduction in IRS-1 level and increase in IRS-1 phosphorylation at Ser307 upon Hepatitis C virus infection occurred in a PTEN-dependent manner.

SIGNOR-277078

Q13829

P68400

0

phosphorylation

up-regulates

0.2

It was demonstrated that ck2 could phosphorylate tnfaip1 in vitro and in vivo, which facilitated the distribution of tnfaip1 in nucleus and enhanced its interaction with pcna. It is suggested that the phosphorylation of tnfaip1 may be required for its functions.

SIGNOR-188849

P30154

P67775

2

binding

up-regulates activity

0.943

Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity

SIGNOR-217872

Q86XK2

P41182

2

binding

down-regulates

0.49

Fbxo11 targets bcl6 for degradation

SIGNOR-177652

Q9BXS5

Q2M2I8

0

phosphorylation

up-regulates

0.2

Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis.

SIGNOR-115589

Q13009

P48729

0

phosphorylation

down-regulates quantity by destabilization

0.309

Phosphorylation of Ser329, Ser334, and Thr340 in Tiam1 is required for its interaction with βTrCP1. The proteolysis of Tiam1 is prevented by βTrCP silencing, inhibition of CK1 and MEK, or mutation of the Tiam1 degron site.

SIGNOR-276673

P19544

P00441

1

transcriptional regulation

up-regulates quantity by expression

0.265

The human copper-zinc superoxide dismutase gene (SOD1) proximal promoter is regulated by Sp1, Egr-1, and WT1 via non-canonical binding sites. Egr-1 and two splicing variants of the Egr-related protein WT1 were able to transactivate the SOD1 promoter in co-transfection experiments.

SIGNOR-253898

P10997

P29120

0

cleavage

up-regulates activity

0.446

The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule

SIGNOR-261782

P48431

Q9NQU5

0

phosphorylation

up-regulates quantity

0.2

PAK5 promotes the cell stemness ability by phosphorylating SOX2 in lung squamous cell carcinomas.|The absence of PAK5 abolishes self-renewal ability of LUSC cells by decreasing the expression and phosphorylation of SOX2 in vitro and in vivo.

SIGNOR-280060

Q15077

Q14344

2

binding

up-regulates activity

0.2

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

SIGNOR-257398

Q96P31

P29350

2

binding

up-regulates activity

0.39

Tyrosine phosphorylation of SPAP2a by c-Src and in vitro. Tyrosine-phosphorylated SPAP2 is specifically associated with SH2 domain-containing tyrosine kinases Syk and Zap70 and SH2 domain-containing tyrosine phosphatases SHP-1 and SHP-2. Site-specific mutagenesis studies revealed that tyrosyl residues 650 and 662 embedded in the ITIMs are responsible for the binding of Syk and Zap70 while tyrosyl residues 692 and 722 embedded in the ITIMs are involved in interactions with SHP-1 and SHP-2.

SIGNOR-274013

Q96HS1

P48163

1

dephosphorylation

up-regulates activity

0.2

PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation.

SIGNOR-275569

P15498

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.75

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-260580

P43378

P04626

1

dephosphorylation

down-regulates activity

0.304

Conversely, increasing expression of PTPN9 wild type (WT) inhibits tyrosyl phosphorylation of ErbB2 and EGFR.|Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells.

SIGNOR-277170

Q13233

P01116

2

binding

up-regulates

0.366

Mitogen-activated protein kinase kinase kinase (mekk1) is a serine-threonine kinase that regulates sequential protein kinase pathways involving stress-activated protein kinases and mitogen-activated protein kinases. Mekk1 is activated in response to growth factor stimulation of cells and by expression of activated ras. mekk1 directly binds ras.GTP. Thus, ras interacts with protein kinases of both the raf and mekk families.

SIGNOR-32620

P17706

O00401

1

dephosphorylation

down-regulates

0.29

Similarly, the t cell phosphatase has a 30-fold lower kcat/km toward autoinhibited p-n-wasp than toward the isolated p-gbd, and again this effect is largely reversed by that cdc42

SIGNOR-141652

Q6ZMZ0

P68036

2

binding

up-regulates activity

0.481

We demonstrated that both UbcH7 and UbcH8 bind to full-length NKLAM. We demonstrated decreased protein expression and enhanced ubiquitination of URKL-1 in the presence of NKLAM. These data indicate that NKLAM is a RING finger protein that binds Ubcs and

SIGNOR-271591

P43353

Q9NXK8

2

binding

down-regulates quantity by destabilization

0.32

We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members.

SIGNOR-272815

Q9NP62

Q9UKT8

2

binding

down-regulates quantity

0.538

FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system

SIGNOR-271524

Q03591

P08603

2

binding

down-regulates activity

0.504

Finally, we have been able to establish that CFHR1 can sterically inhibit the interaction that CFH/CFHL-1 SCR1-4 makes with C3b.|CFH regulates the alternative pathway of complement in both the fluid phase and on self-surfaces: It competes with complement factor B (CFB) for binding to C3b and C3(H2O) thereby blocking the formation of the pro-convertase complexes, C3bB and C3(H2O)B. It also accelerates the decay of any existing C3bBb or C3(H2O)Bb. |these data have allowed us to consolidate one possible model of CFHR1-mediated deregulation of CFH/CFHL-1 on an activating surface in which CFHR1 directly competes with or blocks both CFH-binding sites on C3b

SIGNOR-263476

P63092

Q14831

2

binding

up-regulates activity

0.357

MGluRs are members of the G-protein-coupled receptor (GPCR) superfamily, the most abundant receptor gene family in the human genome. GPCRs are membrane-bound proteins that are activated by extracellular ligands such as light, peptides, and neurotransmitters, and transduce intracellular signals via interactions with G proteins. The resulting change in conformation of the GPCR induced by ligand binding activates the G protein, which is composed of a heterotrimeric complex of α, β, and γ subunits.

SIGNOR-264080

Q9UKT8

Q9NP62

2

binding

down-regulates quantity

0.538

FBW2 targets GCMa to the ubiquitin-proteasome degradation system. Here, we report the identification of an SCF complex as the GCM ubiquitin-protein isopeptide ligase (E3) that regulates human GCMa (hGCMa) degradation. We found that SKP1 and CUL1, two key components of the SCF complex, associate with hGCMa in vivo. We further identify the human F-box protein FBW2 (hFBW2) as the substrate recognition subunit in the SCF E3 complex for hGCMa. We show that hFBW2 interacts with hGCMa in a phosphorylation-dependent manner and promotes hGCMa ubiquitination. Supporting a critical role for hFBW2 in hGCMa degradation, knockdown of hFBW2 expression by RNA interference leads to a reduction in hGCMa ubiquitination and a concomitant increase in hGCMa protein stability. Our study identifies the SCF(hFBW2) E3 complex as the key machinery that targets hGCMa to the ubiquitin-proteasome degradation system

SIGNOR-271524

Q16539

P10415

1

phosphorylation

down-regulates activity

0.334

Bcl-2 phosphorylation by p38 mapkin this study, we identify, by using mass spectrometry techniques and specific anti-phosphopeptide antibodies, ser(87) and thr(56) as the bcl-2 residues phosphorylated by p38 mapk and show that phosphorylation of these residues is always associated with a decrease in the antiapoptotic potential of bcl-2 protein.

SIGNOR-146786

P35354

Q12968

0

transcriptional regulation

up-regulates quantity by expression

0.279

NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration

SIGNOR-264028

Q02297

P04626

2

binding

up-regulates

0.792

Direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.

SIGNOR-26875

Q9BW19

Q13535

0

phosphorylation

up-regulates quantity by stabilization

0.257

ATM and ATR kinases phosphorylate KIFC1-S26 during DNA-damage conditions.KIFC1 was stabilized upon phosphorylation and thus promoted centrosome clustering, CIN, and tumor recurrence both in vivo and in vitro.

SIGNOR-277296

Q15722

Q03113

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-257196

P08754

O95136

2

binding

up-regulates activity

0.387

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-256871

P62256

P17542

0

transcriptional regulation

up-regulates quantity by expression

0.326

Tal1 expression activated UBE2H expression, whereas Tal1 knock-down reduced UBE2H expression and ubiquitin transfer activity.|Binding of Tal1 to UBE2H was confirmed by chromatin immunoprecipitation.

SIGNOR-269000

Q8TDB6

P62805

1

monoubiquitination

down-regulates activity

0.2

Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. In response to DNA damage, BBAP expression increases and the E3 ligase selectively monoubiquitylates H4K91. Disruption of BBAP-mediated monoubiquitylation of H4K91 is associated with loss of chromatin-associated PR-Set7/Set8 and mono- and dimethyl H4K20, delayed kinetics of 53BP1 foci formation and increased sensitivity to DNA damage.

SIGNOR-271897

Q96R06

P53350

0

phosphorylation

up-regulates activity

0.394

Phosphorylation of the astrin N-terminal domain by Plk1 contributes to kinetochore\u2013microtubule attachment stability.|Taken together with the localisation data in XREF_FIG B, these data suggest that the presence of the Plk1 phosphorylated astrin N-terminus promotes the accumulation of the astrin complex at attached kinetochores, without which attachments appear more prone to dissociate.

SIGNOR-279423

P05549

P54646

0

phosphorylation

up-regulates activity

0.307

Inhibition of AMPKalpha2 with either siRNA or compound C significantly suppressed the AngII- or nicotine enhanced AP-2alpha activity and the binding of AP-2alpha to DNA.|We report that nicotine, a major component of cigarette smoke, activates AMPK in VSMCs and that AMPKalpha2 phosphorylates AP-2alpha at serine 219 resulting in aberrant expression of MMP2 and consequent AAA formation.

SIGNOR-279648

P60510

Q9GZM8

1

dephosphorylation

down-regulates activity

0.395

Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation|PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome.|We next examined the ability of PP4c to dephosphorylate a Cdk1 phosphorylation site, phospho-T219

SIGNOR-248550

P08069

O14654

1

phosphorylation

up-regulates

0.657

Insulin-like growth factor i acting through its receptor was as effective as insulin in eliciting tyrosine phosphorylation of irs-4.

SIGNOR-56604

P81274

Q96KB5

0

phosphorylation

up-regulates

0.27

We found that the 450th threonine (thr450) of lgn/gpsm2 was phosphorylated by the serine/threonine kinase pbk/topk during mitosis. Western blot analysis indicated the highest expression and the phosphorylated form of lgn/gpsm2 protein in g2/m phase.

SIGNOR-166461

Q9HCK8

Q9HD90

1

transcriptional regulation

down-regulates quantity

0.2

Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells

SIGNOR-268918

Q15303

P62993

2

binding

up-regulates

0.83

Egfr and erbb4 had several docking sites for grb2, while erbb3 was characterized by six binding sites for pi3k. Egfr has six binding sites for the adapter protein grb2, and erbb4 has five, each with different binding strength.

SIGNOR-146876

Q13315

Q5XUX0

1

phosphorylation

up-regulates

0.406

We find that dna damage induced by gamma-irradiation results in increased fbxo31 levels, which requires phosphorylation of fbxo31 by the ddr-initiating kinase atm

SIGNOR-185635

Q7L7X3

Q13043

1

phosphorylation

up-regulates

0.368

In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.

SIGNOR-201324

O14965

Q9ULW0

1

phosphorylation

up-regulates activity

0.965

Here we show that TPX2, a microtubule-bundling protein and activator of Aurora A, plays an important role. TPX2 was phosphorylated by Aurora A during mitosis. Its phospho-null mutant caused short metaphase spindles coupled with low microtubule flux rate. Interestingly, phosphorylation of TPX2 regulated its interaction with CLASP1 but not Kif2a.|This suggests that TPX2 phosphorylation positively regulates the function of CLASP1.| This is in accord with a phosphoproteomics study that identified S121 and S125 as potential phosphorylation sites for Aurora A in mitotic HeLa cells

SIGNOR-265089

Q7Z2W4

Q14258

0

ubiquitination

up-regulates activity

0.398

Our data demonstrates that TRIM25 triggers ubiquitination of ZAP and enhances its antiviral activity through inhibition of viral translation, highlighting the importance of cofactors in the mechanisms of broadly antiviral proteins.

SIGNOR-278565

Q9H2X6

Q9NY61

1

phosphorylation

down-regulates quantity

0.346

HIPK2 phosphorylates Che-1.|Here we demonstrate that HIPK2, a proapoptotic kinase, is involved in Che-1 degradation.

SIGNOR-278942

P49662

Q63HK5

0

transcriptional regulation

down-regulates quantity by repression

0.27

Chromatin immunoprecipitation showed a direct interaction of FE65 and Teashirt3 with the promoter region of CASP4. The results were consistent with a model in which reduced expression of Teashirt3, mediated by genetic or other causes, increases caspase-4 expression, leading to progression of AD.

SIGNOR-264815

P01137

P35555

2

binding

up-regulates quantity

0.489

We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling.

SIGNOR-251888

P63000

Q8N1I0

0

guanine nucleotide exchange factor

up-regulates activity

0.586

DOCK4 (dedicator for cytokinesis 4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rac1, is one of few genes that are associated with both ASD and dyslexia.

SIGNOR-266823

P46527

O60674

0

phosphorylation

down-regulates activity

0.696

JAK2 phosphorylates tyrosine residue 88 (Y88) of p27(Kip1).

SIGNOR-278260

Q15303

P27361

0

phosphorylation

down-regulates activity

0.534

We also identified Ser-1026 as an ErbB4-specific ERK target site in the CYT-1 region. Moreover, double mutations (Thr-674/Ser-1026 to Ala) significantly upregulated ErbB4 activation, indicating that Thr-674 and Ser-1026 are cooperatively involved in negative feedback regulation.

SIGNOR-277448

Q13555

P07101

1

phosphorylation

up-regulates activity

0.332

In both isoforms, Ser-40 was found to be phosphorylated by PKA, and Ser-19 and Ser-40 were found to be phosphorylated by CaM-PK II. The putative phosphorylation site generated by alternative splicing (Ser-31) was phosphorylated specifically by CaM-PK II in TH-2 only. | Unlike TH-1, phosphorylation of TH-2 by CaM-PK II resulted in an increase of the Ki value for dopamine.

SIGNOR-250709

Q9Y253

P51587

2

binding

up-regulates

0.553

Palb2 and brca2 interact with pol_ and are required to sustain the recruitment of pol_ at blocked replication forks. Palb2 and brca2 stimulate pol_-dependent dna synthesis on d loop substrates

SIGNOR-204538

P62136

Q9UD71

2

binding

down-regulates activity

0.599

DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.â€šÂ

SIGNOR-264957

O43255

Q9Y6H5

1

ubiquitination

down-regulates

0.62

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

SIGNOR-140651

Q00722

P62873

2

binding

up-regulates

0.554

Activation of plc-beta 2 by beta gamma subunits may be an important mechanism by which pertussis toxin-sensitive g proteins stimulate plc.

SIGNOR-19447

P51812

P18846

1

phosphorylation

up-regulates activity

0.318

ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinase. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.|ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinases.

SIGNOR-280117

P38405

P30559

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-256936

P57059

Q6UUV9

1

phosphorylation

down-regulates

0.494

These results suggested that sik1 could phosphorylate all torcs and thereby repress their transactivation activities.

SIGNOR-147669

Q9Y5Z9

P01112

2

binding

down-regulates activity

0.2

This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells.

SIGNOR-256206

P25098

Q8IXH6

1

phosphorylation

down-regulates activity

0.2

In conclusion, experimental results demonstrate that GRK2 chronically downregulates DOR functional competence at the PM in peripheral sensory neurons, as well as peripheral DOR anti-nociception in vivo.|These data demonstrate that BK does not affect GRK2 mediated phosphorylation of DOR at its primary desensitization site.

SIGNOR-279739

Q13557

P13688

1

phosphorylation

up-regulates

0.2

Camkiid specifically phosphorylates thr-457 on ceacam1-sf, which in turn regulates the process of lumen formation via apoptosis of the central acinar cells.

SIGNOR-203402

Q13489

2

ubiquitination

down-regulates activity

0.2

Ciap1 and ciap2 undergo autoubiquitination and degradation upon binding to the iap antagonist second mitochondrial activator of caspases (smac)/direct iap-binding protein with low pi (diablo), which is released from the mitochondria.

SIGNOR-121880

Q00535

Q9Y490

1

phosphorylation

up-regulates

0.458

Cdk5 phosphorylated talin head at ser 425, inhibiting its binding to smurf1, thus preventing talin head ubiquitylation and degradation.

SIGNOR-185210

Q92968

O75381

2

binding

up-regulates activity

0.92

Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import

SIGNOR-253029

Q6P0Q8

P48764

1

phosphorylation

down-regulates activity

0.456

Coexpression of MAST205 inhibits the activity of Na +/H+ exchanger NHE3.|Consistent with these results, we found that MAST205 phosphorylated NHE3 under in vitro conditions.

SIGNOR-279229

Q12974

P24941

1

dephosphorylation

up-regulates

0.2

Cells overexpressing prl-2 exhibited enhanced cyclin-dependent kinase 2 (cdk2) activity

SIGNOR-119478

P46527

O15111

0

phosphorylation

down-regulates activity

0.372

Reduced nuclear p27 was also found in MCF7 human breast cancer cells that were transiently transfected with an IKKalpha expression vector; increased IKKalpha expression resulted in a dose dependent decrease in nuclear p27 and increased cytoplasmic p27 (XREF_FIG).|We found that IKKalpha phosphorylates p27 at S183 to cause its nuclear export.

SIGNOR-278438