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
O95760	Q01638	2	binding	up-regulates activity	0.925	We report a member of the IL-1 family, IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL-5, and IL-13 and leads to severe pathological changes in mucosal organs.The binding of IL-33 to cells that express ST2 results in the activation of NF-κB and MAP kinases. Administration of purified IL-33 either in vitro or in vivo leads to the production of TH2-associated cytokines.	SIGNOR-277711
Q04759	Q9UHD2	1	phosphorylation	up-regulates activity	0.2	TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation	SIGNOR-272472
Q12778	O00141	0	phosphorylation	down-regulates activity	0.607	We demonstrate that SGK1 affects differentiation by direct phosphorylation of Foxo1, thereby changing its cellular localization from the nucleus to the cytosol. In addition we show that SGK1-/- cells are unable to relocalize Foxo1 to the cytosol in response to dexamethasone.	SIGNOR-255925
O00763	Q8NHY2	0	ubiquitination	down-regulates quantity by destabilization	0.2	TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1. Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).	SIGNOR-271599
Q01973	P21860	1	phosphorylation	up-regulates activity	0.343	Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation.\|ROR1 knockdown decreased phosphorylations of ERBB3, c-Src, and AKT in NKX2-1 + / ROR1 + NCI-H1975, SK-LC-5, and NCI-H358 cells.	SIGNOR-279279
O15013	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.442	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-260536
P00519	Q05655	1	phosphorylation	up-regulates activity	0.384	Specifically, we have shown that nuclear targeting of PKCdelta is necessary and sufficient for epithelial cell apoptosis, and that nuclear translocation requires phosphorylation of PKCdelta at Y155 and Y64 by c-Abl and c-Src, respectively.	SIGNOR-279436
P62258	Q7Z3C6	2	binding	up-regulates activity	0.2	Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK.	SIGNOR-266368
P43403	O43561	1	phosphorylation	up-regulates activity	0.77	In the presence of the catalytically inactive LckK273R, the phosphorylation of LAT Y132 and Y191 residues by Zap70K362E were considerably increased	SIGNOR-274562
P49840	P12036	1	phosphorylation	down-regulates activity	0.254	Our results demonstrate that whereas GSK-3 alpha, GSK-3 beta, and cdk-5 will all phosphorylate NF-H, they generate different antibody reactivity profiles.	SIGNOR-279783
P16112	Q99542	0	cleavage	down-regulates quantity by destabilization	0.4	Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)\|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development.	SIGNOR-266978
Q9H3D4	P23443	0	phosphorylation	down-regulates	0.2	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180771
O43521	Q07817	2	binding	down-regulates activity	0.956	Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly.	SIGNOR-178679
Q15418	P84243	1	phosphorylation	down-regulates activity	0.2	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-70428
P37231	Q76L83	2	binding	up-regulates activity	0.2	ASXL2, which does not bind HP1, promotes differentiation by binding to PPARγ and increasing the level of methylated H3K4, leading to the elevation of PPARγ activity. Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ.	SIGNOR-260063
Q9P2S2	Q8N0W4	2	binding	up-regulates activity	0.768	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.\|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264155
P00519	P29323	1	phosphorylation	down-regulates	0.515	Two-hybrid screens identified regions of abl and arg that bind to the ephb2 and epha4 receptors, suggesting a novel signaling connection involving the two kinase families.The connection between EphB2 and Abl/Arg appears to be reciprocal. Activated EphB2 causes tyrosine phosphorylation of Abl and Arg, and vice versa. Interestingly, treatment of COS cells and B35 neuronal-like cells with ephrin-B1 to activate endogenous EphB2 decreased the kinase activity of endogenous Abl.	SIGNOR-109668
Q15139	O95863	1	phosphorylation	down-regulates activity	0.466	Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba.	SIGNOR-168537
Q99801	P60484	0	dephosphorylation	up-regulates quantity by stabilization	0.441	Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression.\|PTEN was also able to dephosphorylate NKX3.1 at threonine 179, a target of protein kinase C, but not threonine residues 89 and 93, targeted by casein kinase 2 .	SIGNOR-277026
O43426	Q00535	0	phosphorylation	down-regulates activity	0.505	Cdk5 phosphorylation inhibited the inositol 5-phosphatase activity of synaptojanin 1, whereas dephosphorylation by calcineurin stimulated such activity.\|The activity of synaptojanin 1 was also stimulated by its interaction with endophilin 1, its major binding partner at the synapse. Notably, Cdk5 phosphorylated serine 1144, which is adjacent to the endophilin binding site.	SIGNOR-279685
Q9UQL6	Q13950	1	deacetylation	down-regulates	0.458	Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation	SIGNOR-145983
Q14493	P0C5Z0	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265407
P43629	P48730	0	phosphorylation	up-regulates	0.2	In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.	SIGNOR-158125
Q8N3F0	Q9UHD2	2	binding	down-regulates activity	0.2	Here we report that viral infection induced upregulation of INKIT, an inhibitor for NF-κB and IRF3 that restricted innate antiviral responses by blocking phosphorylation of p65 and IRF3. Viral infection induced IKK-mediated phosphorylation of INKIT at Ser58, resulting in its dissociation from the IKKs. INKIT is associated with IKKα/β and TBK1/IKKɛ and inhibits the recruitment and phosphorylation of p65 and IRF3, respectively. IKKα and TBK1 phosphorylate INKIT at Ser58, which results in disassociation of INKIT from IKKα or TBK1 and thereby allows for the subsequent recruitment and phosphorylation of p65 and IRF3	SIGNOR-273664
Q9UEW8	Q96J92	0	phosphorylation	up-regulates activity	0.507	Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.\| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1	SIGNOR-264641
P17858	O60502	0	deglycosylation	up-regulates activity	0.2	Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity\|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively.	SIGNOR-267608
P01106	P62633	0	transcriptional regulation	down-regulates quantity by repression	0.303	These data verified that the binding of CNBP with c-myc promoter G-quadruplex can indeed down-regulate its associated gene expression for a certain period of time. This result with human CNBP is somehow consistent with previous reports that c-myc G-quadruplex serves as a silencer of c-myc transcription [7] and CNBP promotes the formation of c-myc G-quadruplex.	SIGNOR-261571
P40763	P18031	0	dephosphorylation	down-regulates activity	0.552	PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.	SIGNOR-248427
Q96QK1	Q96NR3	2	binding	up-regulates quantity	0.2	Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus	SIGNOR-266653
O75044	P60953	1	gtpase-activating protein	down-regulates activity	0.604	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-260517
Q16695	Q9Y4C1	0	demethylation	up-regulates activity	0.2	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.	SIGNOR-276846
P12830	Q9UI47	0	relocalization	up-regulates quantity	0.567	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-265492
P12931	Q05209	0	dephosphorylation	up-regulates activity	0.542	PTP-PEST increases dephosphorylation of Src at Y527 and activates it.\|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src).	SIGNOR-277086
Q16828	Q12778	1	dephosphorylation	up-regulates activity	0.428	It has been previously demonstrated that MKP-3 dephosphorylates FOXO1 on Ser256 and promotes nuclear translocation of FOXO1 , which subsequentially binds to the promoters of gluconeogenic genes and turns on the gluconeogenic program.\|We also reported that MKP-3 can activate FOXO1 by at least dephosphorylating Ser 256, one of the Akt phosphorylation sites xref .	SIGNOR-276983
P67775	P08047	1	dephosphorylation	up-regulates activity	0.264	These results indicate that the signals from TCDD or OP caused PP2A-mediated dephosphorylation of Sp1 at Ser-59 and induced CYP1A1 transcription	SIGNOR-248223
P10275	Q99801	2	transcriptional regulation	up-regulates quantity by expression	0.502	Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events.	SIGNOR-251546
P19838	Q5XPI4	0	polyubiquitination	down-regulates quantity by destabilization	0.397	Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling.	SIGNOR-272221
Q52LA3	Q13627	0	phosphorylation	up-regulates activity	0.681	Here we report that DYRK1A can specifically phosphorylate LIN52 on serine residue 28, and that this phosphorylation is required for DREAM assembly.	SIGNOR-262846
P17612	Q15256	1	phosphorylation	down-regulates activity	0.343	The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue. treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.‚	SIGNOR-250038
P28482	Q86UR1	1	phosphorylation	down-regulates	0.326	These results demonstrated a critical role of noxa1 phosphorylation on ser-282 and ser-172 in preventing nox1 hyperactivation through the decrease of noxa1 interaction to nox1 and rac1.	SIGNOR-163659
P45983	Q13464	0	phosphorylation	up-regulates activity	0.296	Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter.	SIGNOR-123717
Q9UQQ2	P43403	0	phosphorylation	up-regulates	0.363	In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation.	SIGNOR-48854
P49841	Q9NQX3	1	phosphorylation	down-regulates	0.283	Identification of gsk3_ as the kinase targeting ser-270 /phosphorylation at ser-270 promotes gephyrin processing by calpain	SIGNOR-200957
Q9H0Z9	P38936	1	post transcriptional regulation	up-regulates quantity by stabilization	0.318	Here, we found that RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript.	SIGNOR-275391
Q8IZL8	P24941	0	phosphorylation	up-regulates	0.367	We identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we conclude that pelp1 is a novel substrate of interphase cdks and that its phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function.	SIGNOR-167766
O14867	O60675	2	binding	up-regulates activity	0.474	Bach1 forms a heterodimer with the small Maf oncoproteins and binds to the Maf-recognition element (MARE) to inhibit target genes	SIGNOR-226409
Q02156	P61764	1	phosphorylation	down-regulates quantity	0.273	These results show that nPKC\u03b5 induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKC\u03b5 downregulates Munc18-1 levels, induced by the nerve stimulation.\|These results show that nPKCepsilon induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKCepsilon downregulates Munc18-1 levels, induced by the nerve stimulation.	SIGNOR-279479
P30279	Q9UKC9	2	binding	down-regulates quantity by destabilization	0.421	F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation. Purified SCF complex components were incubated with V5-cyclin D2 and the full complement of ubiquitination reaction components (second lane from left) showing polyubiquitinated cyclin D2.	SIGNOR-272006
Q13156	P54727	2	binding	up-regulates activity	0.26	GG-NER is initiated by the GG-NER specific factor XPC-RAD23B, in some cases with the help of UV-DDB (UV-damaged DNA-binding protein). TC-NER is initiated by RNA polymerase stalled at a lesion with the help of TC-NER specific factors CSA, CSB, and XAB2. Both pathways require the core NER factors to complete the excision process\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000).\|The core NER dual incision reaction has been reconstituted in vitro with purified factors using XPC-RAD23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF (Aboussekhra et al. 1995; Mu et al. 1995; Araujo et al. 2000). Functional studies revealed that XPC-RAD23B is the initial damage recognition factor in this system, as the presence of XPC-RAD23B is required for assembly of the other core NER factors and progression through the NER pathway both in vitro and in vivo	SIGNOR-275701
Q9H4A3	Q9Y3S1	0	phosphorylation	up-regulates activity	0.546	WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). \| We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro.	SIGNOR-260790
P03952	P26927	1	cleavage	up-regulates activity	0.325	Proteolytic cleavage of pro-MSP at a single site yields active MSP, a disulfide-linked alphabeta-chain heterodimer. human kallikrein cleaved only at Arg483–Val484, the cleavage site for formation of a- and b-chains.	SIGNOR-256511
Q14980	Q6PEY2	2	binding	up-regulates	0.248	Direct binding of numa to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules.	SIGNOR-116738
O00444	Q969U6	1	phosphorylation	down-regulates activity	0.543	The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6.	SIGNOR-275476
O43791	O75367	2	binding	up-regulates activity	0.2	Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex.	SIGNOR-272657
Q8IWR1	O75367	1	polyubiquitination	down-regulates quantity by destabilization	0.2	Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity.	SIGNOR-272931
Q16539	Q16644	1	phosphorylation	up-regulates activity	0.714	These results, taken together, suggest the importance of the docking interaction in the efficient phosphorylation and activation of 3pk by p38.	SIGNOR-235451
Q7KZI7	Q9UQB8	1	phosphorylation	down-regulates activity	0.462	Par1b directly phosphorylates IRSp53 on S366 in cell lysates and stimulates phosphorylation on S453/3/5 via an indirect mechanism.\|These data are consistent with a scenario in which Par1b phosphorylation inhibits IRSp53 function.	SIGNOR-278411
P06239	O43561	1	phosphorylation	up-regulates	0.758	Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation.	SIGNOR-149182
Q9P1W9	P30304	1	phosphorylation	down-regulates quantity by destabilization	0.361	The proteasome-dependent degradation of CDC25A, seen in this study upon PIM-2 over-expression, suggests that PIM-2 promotes CDC25A phosphorylation that triggers its ubiquitylation.	SIGNOR-279750
Q96Q27	P28482	0	phosphorylation	up-regulates activity	0.265	Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. \|Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation.	SIGNOR-272240
Q05655	P42224	1	phosphorylation	up-regulates	0.589	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154791
Q9UJU2	P23760	2	binding	up-regulates activity	0.427	Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1.	SIGNOR-162100
Q9P1W9	O95644	1	phosphorylation	up-regulates activity	0.261	In addition to PIM1, also PIM2 and PIM3 were able to phosphorylate WT, but not MM NFATC1 in vitro (Fig. (Fig.22c).	SIGNOR-276772
P15884	P05412	2	binding	up-regulates	0.392	Phosphorylation-dependent interaction between c-jun and tcf4;c-jun and tcf4 cooperatively activated the c-jun promoter in reporter assays	SIGNOR-138544
P46531	P84022	2	binding	up-regulates	0.543	Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd	SIGNOR-119374
Q06187	P23470	0	dephosphorylation	down-regulates activity	0.262	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254694
P63000	Q9C0H5	0	gtpase-activating protein	down-regulates activity	0.501	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-260494
O00308	Q07912	0	phosphorylation	up-regulates activity	0.342	ACK1 phosphorylates WWP2 at the 2, 3-linker and partially activates the ubiquitination ligase activity.\|Activation of E3 ubiquitin ligase WWP2 by non-receptor tyrosine kinase ACK1.	SIGNOR-279302
P16949	P28482	0	phosphorylation	down-regulates	0.452	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily.	SIGNOR-166686
P41968	P50148	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-257230
P22223	Q9UQB3	2	binding	up-regulates quantity by stabilization	0.294	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252130
Q9NTG7	P06493	0	phosphorylation	up-regulates activity	0.315	Both SIRT3 T150 and S159 phosphorylated by CDK1 indicates that CDK1-SIRT3 pathway may play a role in the overall mitochondrial protein acetylation involved in mitochondrial homeostasis and apoptosis.	SIGNOR-279395
P16520	Q9NPG1	2	binding	up-regulates	0.385	In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor.	SIGNOR-152603
P17252	Q99623	1	phosphorylation	down-regulates activity	0.2	PKC\u03b1 phosphorylates PHB2-S39.	SIGNOR-279256
Q9UPG8	Q09472	0	acetylation	up-regulates	0.2	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140947
P05000	P48551	2	binding	up-regulates	0.758	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-105982
P46527	P28482	0	phosphorylation	up-regulates	0.346	Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.	SIGNOR-77651
P28482	Q02750	2	phosphorylation	down-regulates activity	0.75	We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling.	SIGNOR-236335
P41968	P08754	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-256891
Q9H1J5	Q9Y5W5	2	binding	down-regulates	0.56	Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities.	SIGNOR-66892
A7MCY6	Q9UHD2	1	relocalization	up-regulates activity	0.603	TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation	SIGNOR-272469
P06493	Q02750	1	phosphorylation	down-regulates	0.496	P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well	SIGNOR-36116
Q9UKB1	O15111	2	binding	down-regulates quantity by destabilization	0.441	We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.	SIGNOR-272545
Q969G2	P28069	1	transcriptional regulation	up-regulates quantity by expression	0.514	We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression.	SIGNOR-266056
Q14005	P68400	0	phosphorylation	up-regulates activity	0.326	We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. \| Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation.	SIGNOR-250905
Q15796	Q9GZU7	0	dephosphorylation	down-regulates activity	0.515	SCP1 Dephosphorylates Smad2/3 in the Linkers\|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248795
Q9NPD5	P10276	0	transcriptional regulation	up-regulates quantity by expression	0.2	Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter.	SIGNOR-268989
P18507	Q02156	0	phosphorylation	down-regulates activity	0.233	Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol.	SIGNOR-263174
P63096	Q9Y4H4	2	binding	down-regulates activity	0.492	GPSM3 acts through its two GoLoco motifs to exert GDP dissociation inhibitor activity over Galpha(i) subunits\|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET.	SIGNOR-264864
P01106	P49591	2	binding	down-regulates activity	0.2	Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation.	SIGNOR-259368
P68400	O60341	1	phosphorylation	up-regulates activity	0.318	We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.	SIGNOR-276903
Q00535	P56817	1	phosphorylation	up-regulates activity	0.44	BACE1 is phosphorylated by p25 and Cdk5 at Thr252.\|Our finding that p25/Cdk5 stimulates BACE1 activity supports that p25/Cdk5 may represent a promising target for the development of drugs to treat Alzheimer's disease.	SIGNOR-278249
Q9Y5F9	Q9Y5H9	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265684
P48729	Q99835	1	phosphorylation	up-regulates	0.521	We demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation.	SIGNOR-174542
P25963	Q9UHD2	0	phosphorylation	down-regulates quantity by destabilization	0.456	Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha.	SIGNOR-246643
Q9BWU1	P46531	1	phosphorylation	down-regulates quantity by destabilization	0.302	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273135
P07948	P12318	1	phosphorylation	up-regulates activity	0.608	Phosphorylation of FcgammaRIIa/c by Lyn is clearly dependent on the presence of Y-298, since all mutants lacking this residue are not phosphorylated by this PTK. This result suggests that Y-298 might be the only tyrosine residue of FcgammaRIIa/c phos- phorylated by Lyn.	SIGNOR-249379
Q03135	P17096	1	relocalization	up-regulates activity	0.265	CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization.	SIGNOR-254428
Q9UBR4	Q15319	0	transcriptional regulation	up-regulates quantity by expression	0.398	Using oligonucleotide microarrays to generate expression profiles of inner ears of Pou4f3(ddl/ddl) mutant and wild-type mice, we have identified and validated Lhx3, a LIM domain transcription factor, as an in vivo target gene regulated by Pou4f3. Lhx3 is a hair cell-specific gene expressed in all hair cells of the auditory and vestibular system as early as embryonic day 16. The level of Lhx3 mRNA is greatly reduced in the inner ears of embryonic Pou4f3 mutant mice. Our data also show that the expression of Lhx3 is regulated differently in auditory and vestibular hair cells.	SIGNOR-262586
P40763	P51617	0	phosphorylation	up-regulates	0.55	Irak1 can directly use stat3 as a substrate and cause stat3 serine 727 phosphorylation.	SIGNOR-129685

O95760

Q01638

2

binding

up-regulates activity

0.925

We report a member of the IL-1 family, IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL-5, and IL-13 and leads to severe pathological changes in mucosal organs.The binding of IL-33 to cells that express ST2 results in the activation of NF-κB and MAP kinases. Administration of purified IL-33 either in vitro or in vivo leads to the production of TH2-associated cytokines.

SIGNOR-277711

Q04759

Q9UHD2

1

phosphorylation

up-regulates activity

0.2

TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation

SIGNOR-272472

Q12778

O00141

0

phosphorylation

down-regulates activity

0.607

We demonstrate that SGK1 affects differentiation by direct phosphorylation of Foxo1, thereby changing its cellular localization from the nucleus to the cytosol. In addition we show that SGK1-/- cells are unable to relocalize Foxo1 to the cytosol in response to dexamethasone.

SIGNOR-255925

O00763

Q8NHY2

0

ubiquitination

down-regulates quantity by destabilization

0.2

TRB3 appears to inhibit ACC activity by functioning as an adaptor for COP1. Taken together, these results suggest that TRB3 may promote loss of fat by mediating the COP1-dependent ubiquitination and inactivation of ACC. Taking these results together, we propose that TRB3 may protect against diet-induced obesity by stimulating fatty acid oxidation in adipose during fasting through the COP1-mediated ubiquitination and degradation of ACC (Fig. 4D).

SIGNOR-271599

Q01973

P21860

1

phosphorylation

up-regulates activity

0.343

Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation.|ROR1 knockdown decreased phosphorylations of ERBB3, c-Src, and AKT in NKX2-1 + / ROR1 + NCI-H1975, SK-LC-5, and NCI-H358 cells.

SIGNOR-279279

O15013

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.442

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-260536

P00519

Q05655

1

phosphorylation

up-regulates activity

0.384

Specifically, we have shown that nuclear targeting of PKCdelta is necessary and sufficient for epithelial cell apoptosis, and that nuclear translocation requires phosphorylation of PKCdelta at Y155 and Y64 by c-Abl and c-Src, respectively.

SIGNOR-279436

P62258

Q7Z3C6

2

binding

up-regulates activity

0.2

Our data suggest that the localization of mammalian Atg9A to autophagosomes requires phosphorylation on the C terminus of Atg9A at S761, which creates a 14-3-3ζ docking site. Under basal conditions, this phosphorylation is maintained at a low level and is dependent on both ULK1 and AMPK.

SIGNOR-266368

P43403

O43561

1

phosphorylation

up-regulates activity

0.77

In the presence of the catalytically inactive LckK273R, the phosphorylation of LAT Y132 and Y191 residues by Zap70K362E were considerably increased

SIGNOR-274562

P49840

P12036

1

phosphorylation

down-regulates activity

0.254

Our results demonstrate that whereas GSK-3 alpha, GSK-3 beta, and cdk-5 will all phosphorylate NF-H, they generate different antibody reactivity profiles.

SIGNOR-279783

P16112

Q99542

0

cleavage

down-regulates quantity by destabilization

0.4

Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development.

SIGNOR-266978

Q9H3D4

P23443

0

phosphorylation

down-regulates

0.2

Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively

SIGNOR-180771

O43521

Q07817

2

binding

down-regulates activity

0.956

Bim can induce apoptosis by interacting with anti-apoptotic members of the bcl2 family, including bcl2, bcl-xl and mcl-1.Bim binds bcl-2, bcl2l1, bcl2l2, mcl1 and a1 tightly.

SIGNOR-178679

Q15418

P84243

1

phosphorylation

down-regulates activity

0.2

Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.

SIGNOR-70428

P37231

Q76L83

2

binding

up-regulates activity

0.2

ASXL2, which does not bind HP1, promotes differentiation by binding to PPARγ and increasing the level of methylated H3K4, leading to the elevation of PPARγ activity. Our genome-wide analysis confirmed the physiological roles of ASXL1 and ASXL2 in adipogenesis at the molecular level, supporting the hypothesis that ASXL1 is an authentic corepressor of PPARγ, whereas ASXL2 is a PPARγ coactivator, and that together ASXL1 and ASXL2 fine-tune adipogenesis via differential regulation of PPARγ.

SIGNOR-260063

Q9P2S2

Q8N0W4

2

binding

up-regulates activity

0.768

Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)

SIGNOR-264155

P00519

P29323

1

phosphorylation

down-regulates

0.515

Two-hybrid screens identified regions of abl and arg that bind to the ephb2 and epha4 receptors, suggesting a novel signaling connection involving the two kinase families.The connection between EphB2 and Abl/Arg appears to be reciprocal. Activated EphB2 causes tyrosine phosphorylation of Abl and Arg, and vice versa. Interestingly, treatment of COS cells and B35 neuronal-like cells with ephrin-B1 to activate endogenous EphB2 decreased the kinase activity of endogenous Abl.

SIGNOR-109668

Q15139

O95863

1

phosphorylation

down-regulates activity

0.466

Pkd1 phosphorylates ser(11) (s11) on transcription factor snail, a master emt regulator and repressor of e-cadherin expression, triggering nuclear export of snail via 14-3-3_ binding. Pkd1 regulates the expression of e-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor snai1. Pkd1-mediated phosphorylation of snai1 occurs in the nucleus and generates a nuclear, inactive dna/snai1 complex that shows decreased interaction with its co-repressor ajuba.

SIGNOR-168537

Q99801

P60484

0

dephosphorylation

up-regulates quantity by stabilization

0.441

Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression.|PTEN was also able to dephosphorylate NKX3.1 at threonine 179, a target of protein kinase C, but not threonine residues 89 and 93, targeted by casein kinase 2 .

SIGNOR-277026

O43426

Q00535

0

phosphorylation

down-regulates activity

0.505

Cdk5 phosphorylation inhibited the inositol 5-phosphatase activity of synaptojanin 1, whereas dephosphorylation by calcineurin stimulated such activity.|The activity of synaptojanin 1 was also stimulated by its interaction with endophilin 1, its major binding partner at the synapse. Notably, Cdk5 phosphorylated serine 1144, which is adjacent to the endophilin binding site.

SIGNOR-279685

Q9UQL6

Q13950

1

deacetylation

down-regulates

0.458

Hdac4 and hdac5 deacetylate runx2 and lead to a smurf-mediated degradation

SIGNOR-145983

Q14493

P0C5Z0

1

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265407

P43629

P48730

0

phosphorylation

up-regulates

0.2

In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.

SIGNOR-158125

Q8N3F0

Q9UHD2

2

binding

down-regulates activity

0.2

Here we report that viral infection induced upregulation of INKIT, an inhibitor for NF-κB and IRF3 that restricted innate antiviral responses by blocking phosphorylation of p65 and IRF3. Viral infection induced IKK-mediated phosphorylation of INKIT at Ser58, resulting in its dissociation from the IKKs. INKIT is associated with IKKα/β and TBK1/IKKɛ and inhibits the recruitment and phosphorylation of p65 and IRF3, respectively. IKKα and TBK1 phosphorylate INKIT at Ser58, which results in disassociation of INKIT from IKKα or TBK1 and thereby allows for the subsequent recruitment and phosphorylation of p65 and IRF3

SIGNOR-273664

Q9UEW8

Q96J92

0

phosphorylation

up-regulates activity

0.507

Vitari et al. (76) and Moriguchi et al. (52) demonstrated that WNK4 bound and phosphorylated PASK at Thr-233 and Ser-373 in mammalian cells.| this phosphorylation event activates PASK, which in turn phosphorylates and activates NKCC1

SIGNOR-264641

P17858

O60502

0

deglycosylation

up-regulates activity

0.2

Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively.

SIGNOR-267608

P01106

P62633

0

transcriptional regulation

down-regulates quantity by repression

0.303

These data verified that the binding of CNBP with c-myc promoter G-quadruplex can indeed down-regulate its associated gene expression for a certain period of time. This result with human CNBP is somehow consistent with previous reports that c-myc G-quadruplex serves as a silencer of c-myc transcription [7] and CNBP promotes the formation of c-myc G-quadruplex.

SIGNOR-261571

P40763

P18031

0

dephosphorylation

down-regulates activity

0.552

PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.

SIGNOR-248427

Q96QK1

Q96NR3

2

binding

up-regulates quantity

0.2

Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus

SIGNOR-266653

O75044

P60953

1

gtpase-activating protein

down-regulates activity

0.604

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-260517

Q16695

Q9Y4C1

0

demethylation

up-regulates activity

0.2

Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.

SIGNOR-276846

P12830

Q9UI47

0

relocalization

up-regulates quantity

0.567

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-265492

P12931

Q05209

0

dephosphorylation

up-regulates activity

0.542

PTP-PEST increases dephosphorylation of Src at Y527 and activates it.|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src).

SIGNOR-277086

Q16828

Q12778

1

dephosphorylation

up-regulates activity

0.428

It has been previously demonstrated that MKP-3 dephosphorylates FOXO1 on Ser256 and promotes nuclear translocation of FOXO1 , which subsequentially binds to the promoters of gluconeogenic genes and turns on the gluconeogenic program.|We also reported that MKP-3 can activate FOXO1 by at least dephosphorylating Ser 256, one of the Akt phosphorylation sites xref .

SIGNOR-276983

P67775

P08047

1

dephosphorylation

up-regulates activity

0.264

These results indicate that the signals from TCDD or OP caused PP2A-mediated dephosphorylation of Sp1 at Ser-59 and induced CYP1A1 transcription

SIGNOR-248223

P10275

Q99801

2

transcriptional regulation

up-regulates quantity by expression

0.502

Whereas androgen receptor (AR) positively regulates NKX3.1 expression, NKX3.1 negatively modulates AR transcription and consequently the AR-associated signaling events.

SIGNOR-251546

P19838

Q5XPI4

0

polyubiquitination

down-regulates quantity by destabilization

0.397

Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling.

SIGNOR-272221

Q52LA3

Q13627

0

phosphorylation

up-regulates activity

0.681

Here we report that DYRK1A can specifically phosphorylate LIN52 on serine residue 28, and that this phosphorylation is required for DREAM assembly.

SIGNOR-262846

P17612

Q15256

1

phosphorylation

down-regulates activity

0.343

The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue. treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.‚

SIGNOR-250038

P28482

Q86UR1

1

phosphorylation

down-regulates

0.326

These results demonstrated a critical role of noxa1 phosphorylation on ser-282 and ser-172 in preventing nox1 hyperactivation through the decrease of noxa1 interaction to nox1 and rac1.

SIGNOR-163659

P45983

Q13464

0

phosphorylation

up-regulates activity

0.296

Instead, we found that rock activates jnk, which then phosphorylates c-jun and atf2 when bound to the c-jun promoter.

SIGNOR-123717

Q9UQQ2

P43403

0

phosphorylation

up-regulates

0.363

In vitro tyrosine phosphorylation of lnk by lck and zap-70. Tyrosine 297 would appear to be an attractive target for phosphorylation within the c-terminal domain. Our studies suggest that although lnk may participate in tcr signaling, its functions are in no way limiting during t cell development or activation.

SIGNOR-48854

P49841

Q9NQX3

1

phosphorylation

down-regulates

0.283

Identification of gsk3_ as the kinase targeting ser-270 /phosphorylation at ser-270 promotes gephyrin processing by calpain

SIGNOR-200957

Q9H0Z9

P38936

1

post transcriptional regulation

up-regulates quantity by stabilization

0.318

Here, we found that RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript.

SIGNOR-275391

Q8IZL8

P24941

0

phosphorylation

up-regulates

0.367

We identified ser(477) and ser(991) of pelp1 as cdk phosphorylation sites. we conclude that pelp1 is a novel substrate of interphase cdks and that its phosphorylation is important for the proper function of pelp1 in modulating hormone-driven cell cycle progression and also for optimal e2f transactivation function.

SIGNOR-167766

O14867

O60675

2

binding

up-regulates activity

0.474

Bach1 forms a heterodimer with the small Maf oncoproteins and binds to the Maf-recognition element (MARE) to inhibit target genes

SIGNOR-226409

Q02156

P61764

1

phosphorylation

down-regulates quantity

0.273

These results show that nPKC\u03b5 induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKC\u03b5 downregulates Munc18-1 levels, induced by the nerve stimulation.|These results show that nPKCepsilon induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKCepsilon downregulates Munc18-1 levels, induced by the nerve stimulation.

SIGNOR-279479

P30279

Q9UKC9

2

binding

down-regulates quantity by destabilization

0.421

F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation. Purified SCF complex components were incubated with V5-cyclin D2 and the full complement of ubiquitination reaction components (second lane from left) showing polyubiquitinated cyclin D2.

SIGNOR-272006

Q13156

P54727

2

binding

up-regulates activity

0.26

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

SIGNOR-275701

Q9H4A3

Q9Y3S1

0

phosphorylation

up-regulates activity

0.546

WNK1, which is activated in response to osmotic stress by phosphorylation of its T-loop residue (Ser382). | We found that wild-type WNK2 (Figure 8A) or WNK3 (Figure 8B) phosphorylated kinase-inactive WNK1 (1–667, D368A) at Ser382 in vitro.

SIGNOR-260790

P03952

P26927

1

cleavage

up-regulates activity

0.325

Proteolytic cleavage of pro-MSP at a single site yields active MSP, a disulfide-linked alphabeta-chain heterodimer. human kallikrein cleaved only at Arg483–Val484, the cleavage site for formation of a- and b-chains.

SIGNOR-256511

Q14980

Q6PEY2

2

binding

up-regulates

0.248

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

SIGNOR-116738

O00444

Q969U6

1

phosphorylation

down-regulates activity

0.543

The activity of SCF-FBXW5 is in turn negatively regulated by Polo-like kinase 4 (PLK4), which phosphorylates FBXW5 at Ser 151 to suppress its ability to ubiquitylate HsSAS-6.

SIGNOR-275476

O43791

O75367

2

binding

up-regulates activity

0.2

Here, we describe an E3 ubiquitin ligase consisting of SPOP and CULLIN3 that is able to ubiquitinate the PcG protein BMI1 and the variant histone MACROH2A1. BMI1 and MACROH2A1 interact with and are ubiquitinated by the CULLIN3 and SPOP ligase complex.

SIGNOR-272657

Q8IWR1

O75367

1

polyubiquitination

down-regulates quantity by destabilization

0.2

Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity.

SIGNOR-272931

Q16539

Q16644

1

phosphorylation

up-regulates activity

0.714

These results, taken together, suggest the importance of the docking interaction in the efficient phosphorylation and activation of 3pk by p38.

SIGNOR-235451

Q7KZI7

Q9UQB8

1

phosphorylation

down-regulates activity

0.462

Par1b directly phosphorylates IRSp53 on S366 in cell lysates and stimulates phosphorylation on S453/3/5 via an indirect mechanism.|These data are consistent with a scenario in which Par1b phosphorylation inhibits IRSp53 function.

SIGNOR-278411

P06239

O43561

1

phosphorylation

up-regulates

0.758

Evidence of lat as a dual substrate for lck and syk in t lymphocytes.Lat is a linker protein essential for activation of t lymphocytes. Its rapid tyrosine-phosphorylation upon t cell receptor (tcr) stimulation recruits downstream signaling molecules for membrane targeting and activation.

SIGNOR-149182

Q9P1W9

P30304

1

phosphorylation

down-regulates quantity by destabilization

0.361

The proteasome-dependent degradation of CDC25A, seen in this study upon PIM-2 over-expression, suggests that PIM-2 promotes CDC25A phosphorylation that triggers its ubiquitylation.

SIGNOR-279750

Q96Q27

P28482

0

phosphorylation

up-regulates activity

0.265

Indeed, using mass spectrometry, we showed for the first time that ASB2a is phosphorylated and that phosphorylation of serine-323 (Ser-323) of ASB2a is crucial for the targeting of the actin-binding protein filamin A (FLNa) to degradation. |Moreover, inhibition of the extracellular signal-regulated kinases 1 and 2 (Erk1/2) activity reduced ASB2a-mediated FLNa degradation.

SIGNOR-272240

Q05655

P42224

1

phosphorylation

up-regulates

0.589

All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).

SIGNOR-154791

Q9UJU2

P23760

2

binding

up-regulates activity

0.427

Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1.

SIGNOR-162100

Q9P1W9

O95644

1

phosphorylation

up-regulates activity

0.261

In addition to PIM1, also PIM2 and PIM3 were able to phosphorylate WT, but not MM NFATC1 in vitro (Fig. (Fig.22c).

SIGNOR-276772

P15884

P05412

2

binding

up-regulates

0.392

Phosphorylation-dependent interaction between c-jun and tcf4;c-jun and tcf4 cooperatively activated the c-jun promoter in reporter assays

SIGNOR-138544

P46531

P84022

2

binding

up-regulates

0.543

Nicd and smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and smad3 could be recruited to csl-binding sites on dna in the presence of csl and nicd

SIGNOR-119374

Q06187

P23470

0

dephosphorylation

down-regulates activity

0.262

PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.

SIGNOR-254694

P63000

Q9C0H5

0

gtpase-activating protein

down-regulates activity

0.501

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-260494

O00308

Q07912

0

phosphorylation

up-regulates activity

0.342

ACK1 phosphorylates WWP2 at the 2, 3-linker and partially activates the ubiquitination ligase activity.|Activation of E3 ubiquitin ligase WWP2 by non-receptor tyrosine kinase ACK1.

SIGNOR-279302

P16949

P28482

0

phosphorylation

down-regulates

0.452

Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. The kinases involved in phosphorylating stmn ser-16 and ser-63 include camp-dependent protein kinase (pka) and pak1, whereas stmn ser-25 and ser-38 have been shown to be targets for proline-directed serine/threonine kinases such as cyclin-dependent kinases, erk1/2, and members of the p38 mapk subfamily.

SIGNOR-166686

P41968

P50148

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-257230

P22223

Q9UQB3

2

binding

up-regulates quantity by stabilization

0.294

To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.

SIGNOR-252130

Q9NTG7

P06493

0

phosphorylation

up-regulates activity

0.315

Both SIRT3 T150 and S159 phosphorylated by CDK1 indicates that CDK1-SIRT3 pathway may play a role in the overall mitochondrial protein acetylation involved in mitochondrial homeostasis and apoptosis.

SIGNOR-279395

P16520

Q9NPG1

2

binding

up-regulates

0.385

In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor.

SIGNOR-152603

P17252

Q99623

1

phosphorylation

down-regulates activity

0.2

PKC\u03b1 phosphorylates PHB2-S39.

SIGNOR-279256

Q9UPG8

Q09472

0

acetylation

up-regulates

0.2

Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.

SIGNOR-140947

P05000

P48551

2

binding

up-regulates

0.758

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-105982

P46527

P28482

0

phosphorylation

up-regulates

0.346

Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.

SIGNOR-77651

P28482

Q02750

2

phosphorylation

down-regulates activity

0.75

We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling.

SIGNOR-236335

P41968

P08754

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-256891

Q9H1J5

Q9Y5W5

2

binding

down-regulates

0.56

Here we describe wnt-inhibitory factor-1 (wif-1), a secreted protein that binds to wnt proteins and inhibits their activities.

SIGNOR-66892

A7MCY6

Q9UHD2

1

relocalization

up-regulates activity

0.603

TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation

SIGNOR-272469

P06493

Q02750

1

phosphorylation

down-regulates

0.496

P34cdc2 catalyzes the in vitro phosphorylation of mkk1 on both of these threonine residues and inactivates mkk1 enzymatic activity. Both sites are phosphorylated in vivo as well

SIGNOR-36116

Q9UKB1

O15111

2

binding

down-regulates quantity by destabilization

0.441

We identified a human F-box/WD40 repeats protein (HOS), which is homologous to Slimb/h betaTrCP. Being a part of SCF complex with Skp1 and Cullin1, HOS specifically interacted with the phosphorylated IkappaB and beta-catenin, targeting these proteins for proteasome-dependent degradation in vivo.

SIGNOR-272545

Q969G2

P28069

1

transcriptional regulation

up-regulates quantity by expression

0.514

We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression.

SIGNOR-266056

Q14005

P68400

0

phosphorylation

up-regulates activity

0.326

We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation.

SIGNOR-250905

Q15796

Q9GZU7

0

dephosphorylation

down-regulates activity

0.515

SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity

SIGNOR-248795

Q9NPD5

P10276

0

transcriptional regulation

up-regulates quantity by expression

0.2

Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter.

SIGNOR-268989

P18507

Q02156

0

phosphorylation

down-regulates activity

0.233

Protein kinase C epsilon regulates gamma-aminobutyrate type A receptor sensitivity to ethanol and benzodiazepines through phosphorylation of gamma2 subunits. Our findings indicate that PKCepsilon phosphorylation of gamma2 regulates the response of GABA(A) receptors to specific allosteric modulators, and, in particular, PKCepsilon inhibition renders these receptors sensitive to low intoxicating concentrations of ethanol.

SIGNOR-263174

P63096

Q9Y4H4

2

binding

down-regulates activity

0.492

GPSM3 acts through its two GoLoco motifs to exert GDP dissociation inhibitor activity over Galpha(i) subunits|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET.

SIGNOR-264864

P01106

P49591

2

binding

down-regulates activity

0.2

Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation.

SIGNOR-259368

P68400

O60341

1

phosphorylation

up-regulates activity

0.318

We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.

SIGNOR-276903

Q00535

P56817

1

phosphorylation

up-regulates activity

0.44

BACE1 is phosphorylated by p25 and Cdk5 at Thr252.|Our finding that p25/Cdk5 stimulates BACE1 activity supports that p25/Cdk5 may represent a promising target for the development of drugs to treat Alzheimer's disease.

SIGNOR-278249

Q9Y5F9

Q9Y5H9

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265684

P48729

Q99835

1

phosphorylation

up-regulates

0.521

We demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation.

SIGNOR-174542

P25963

Q9UHD2

0

phosphorylation

down-regulates quantity by destabilization

0.456

Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkapapB. TBK-1 and IKK-i phosphorylate Ser36 of IkappaBalpha.

SIGNOR-246643

Q9BWU1

P46531

1

phosphorylation

down-regulates quantity by destabilization

0.302

Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues

SIGNOR-273135

P07948

P12318

1

phosphorylation

up-regulates activity

0.608

Phosphorylation of FcgammaRIIa/c by Lyn is clearly dependent on the presence of Y-298, since all mutants lacking this residue are not phosphorylated by this PTK. This result suggests that Y-298 might be the only tyrosine residue of FcgammaRIIa/c phos- phorylated by Lyn.

SIGNOR-249379

Q03135

P17096

1

relocalization

up-regulates activity

0.265

CAV1 was shown to stimulate GLUT3 transcription via an HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization.

SIGNOR-254428

Q9UBR4

Q15319

0

transcriptional regulation

up-regulates quantity by expression

0.398

Using oligonucleotide microarrays to generate expression profiles of inner ears of Pou4f3(ddl/ddl) mutant and wild-type mice, we have identified and validated Lhx3, a LIM domain transcription factor, as an in vivo target gene regulated by Pou4f3. Lhx3 is a hair cell-specific gene expressed in all hair cells of the auditory and vestibular system as early as embryonic day 16. The level of Lhx3 mRNA is greatly reduced in the inner ears of embryonic Pou4f3 mutant mice. Our data also show that the expression of Lhx3 is regulated differently in auditory and vestibular hair cells.

SIGNOR-262586

P40763

P51617

0

phosphorylation

up-regulates

0.55

Irak1 can directly use stat3 as a substrate and cause stat3 serine 727 phosphorylation.

SIGNOR-129685