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
P45983	Q6JBY9	1	phosphorylation	down-regulates activity	0.286	CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263085
Q92993	P15172	2	binding	up-regulates activity	0.365	Tip60 regulates myoblast differentiation by enhancing the transcriptional activity of MyoD via their physical interactions.	SIGNOR-237675
Q96CW1	Q5S007	0	phosphorylation	up-regulates activity	0.259	These data confirmed that LRRK2 phosphorylates AP2M1 at Thr 156 in vitro.	SIGNOR-278183
Q02156	P21802	1	phosphorylation	up-regulates	0.2	Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation	SIGNOR-201675
P08913	P08754	2	binding	up-regulates activity	0.469	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-256841
P04818	P01106	0	transcriptional regulation	up-regulates quantity by expression	0.337	Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.	SIGNOR-267374
Q07889	Q9UNS2	2	binding	up-regulates quantity by stabilization	0.2	Our observations characterizing the interaction between CSN3 and the Sos1 HD suggest that this domain not only functions regulating Sos-GEF autoinhibition but is also involved in other functional roles, such as the control of Sos protein stability and homeostasis by modulating the degradation and intracellular levels of Sos1.	SIGNOR-256217
Q03135	P04150	2	binding	up-regulates	0.38	He mGR appears to reside in caveolae and its association with caveolin-1 (Cav-1) was clearly detected in two of the four cell lines investigated using double recognition proximity ligation assay.	SIGNOR-251683
P06748	P06493	0	phosphorylation	down-regulates activity	0.518	However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation.	SIGNOR-89605
Q16671	Q04771	2	binding	up-regulates	0.553	See table2	SIGNOR-121593
Q9BYW2	P42224	1	methylation	up-regulates activity	0.266	SETD2 enhances antiviral immunity by directly methylating STAT1 on K525. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response.	SIGNOR-269091
P28698	P57086	2	binding	up-regulates activity	0.365	Co-immunoprecipitation and yeast two-hybrid analyses demonstrate that MZF1B and RAZ1 associate in vitro via a SCAN box-dependent mechanism. The interaction between MZF1B and RAZ1 might be necessary for mediating MZF1B function	SIGNOR-221561
Q14393	P38435	0	carboxylation	up-regulates activity	0.525	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265923
Q14689	P04179	2	binding	up-regulates activity	0.2	DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain.	SIGNOR-266592
P31268	O15550	0	transcriptional regulation	up-regulates quantity by expression	0.275	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260024
P32248	Q99731	2	binding	up-regulates activity	0.784	CCL19 and CCL21 are endogenous agonists for the seven-trans membrane receptor CCR7.	SIGNOR-278123
P49841	Q96G01	1	phosphorylation	up-regulates activity	0.331	Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein.	SIGNOR-262744
P04637	P17252	0	phosphorylation	up-regulates activity	0.437	Here, we demonstrate that cotransfection of p53 with either PKC alpha or PKC zeta increases p53's transcriptional activity. Mutagenesis of p53 indicates that serine 371 is the major site for phosphorylation by PKC alpha in vitro.	SIGNOR-248999
Q99607	Q9UHD2	0	phosphorylation	up-regulates activity	0.361	Taken together, these results suggest that in response to viral infection, ELF4 was phosphorylated by TBK1 and translocated to the nucleus in a MAVS- and STING dependent manner.\|We speculate that overexpressed ELF4 may recruit and be activated by TBK1.	SIGNOR-279130
P63208	Q13616	2	binding	up-regulates	0.959	The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin.	SIGNOR-64511
Q8TCJ0	Q05655	0	phosphorylation	up-regulates activity	0.271	FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.\|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells,	SIGNOR-275561
O15503	Q13131	0	phosphorylation	up-regulates quantity by stabilization	0.256	Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPKα1 subunit associates with Insig-1 in a dose-dependent manner.	SIGNOR-277430
Q13315	Q7L7X3	1	phosphorylation	up-regulates	0.42	The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells.	SIGNOR-154171
P67775	P24071	1	dephosphorylation	up-regulates activity	0.323	Furthermore, FcalphaRI activation is induced by protein phosphatase 2A (PP2A) after it dephosphorylates a single serine residue (S263) in the FcalphaRI intracellular tail	SIGNOR-264858
Q9Y5S8	Q86UR1	2	binding	up-regulates activity	0.751	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner\|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein\|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264710
P43320	P43320	2	binding	up-regulates activity	0.2	βB2-crystallin is the major component of β-crystallin and is a dimer at low concentrations. At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency.	SIGNOR-252154
Q9H6Z9	O43521-1	1	hydroxylation	up-regulates quantity by stabilization	0.254	EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance\|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues	SIGNOR-262003
Q8TAT6	Q92890	2	binding	up-regulates activity	0.2	These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes.	SIGNOR-252422
Q9NRC8	Q9NR31	1	deacetylation	up-regulates activity	0.2	SIRT7 interacts with the helicase DDX21. Deacetylation by SIRT7 is required for DDX21 activity and R-loop unwinding	SIGNOR-260978
P17612	Q9BY41	1	phosphorylation	down-regulates	0.494	Negative regulation of histone deacetylase 8 activity by cyclic amp-dependent protein kinase athe pka phosphoacceptor site of hdac8 is ser(39)	SIGNOR-120643
P18031	P35968	1	dephosphorylation	down-regulates activity	0.418	This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y 1175 , the site involved in activating ERK signaling.	SIGNOR-277011
Q96GX5	Q9Y5B0	0	dephosphorylation	down-regulates activity	0.433	Taken together, these data suggest that Fcp1 bound and dephosphorylated Gwl at S90 and S453, and possibly at other Cdk1 dependent sites, during mitosis exit and that Fcp1 catalyzed dephosphorylation lowered Gwl activity towards Ensa and ARPP19, allowing PP2A-B55 to autoactivate.\|Together, these data indicate that Fcp1 dependent dephosphorylation greatly reduces S67-Ensa kinase activity of Gwl and that, downstream inactivation of Cdk1, Fcp1 deficit substantially blunts inactivation of Gwl.	SIGNOR-276971
Q92686	P05771	0	phosphorylation	up-regulates activity	0.361	Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM.	SIGNOR-248914
Q9NS91	Q12888	1	ubiquitination	up-regulates activity	0.611	RAD18 associates with 53BP1 and is recruited to DSB sites in a 53BP1 dependent manner specifically during G1-phase, RAD18 monoubiquitinates KBD domain of 53BP1 at lysine 1268 in vitro.\|These results suggest that RAD18 directed modification at Lysine 1268 of 53BP1 promotes the retention of 53BP1 at DSBs.	SIGNOR-278593
Q04206	Q96EB6	0	deacetylation	down-regulates activity	0.722	SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310.	SIGNOR-238817
Q04727	Q02548	2	binding	down-regulates activity	0.563	Grg4 efficiently represses the transcriptional activity of Pax5 in an octapeptide-dependent manner. Similar protein interactions resulting in transcriptional repression were also observed between distantly related members of both the Pax2/5/8 and Groucho protein families	SIGNOR-269083
P35222	P48730	0	phosphorylation	down-regulates	0.626	However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo.	SIGNOR-87441
P23246	P49841	0	phosphorylation	down-regulates	0.345	Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687	SIGNOR-168392
P68431	P41229	0	demethylation	up-regulates activity	0.2	KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.	SIGNOR-264305
P20023	P15391	2	binding	up-regulates activity	0.783	Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling.	SIGNOR-266642
P24864	Q13309	2	binding	down-regulates quantity by destabilization	0.707	Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3.	SIGNOR-272566
Q05655	Q99986	1	phosphorylation	down-regulates activity	0.285	PKC\u03b4 phosphorylates VRK1 on Ser-355 in vitro.\|PKCdelta negatively regulates VRK1 kinase activity in vitro.	SIGNOR-278219
P50406	P38405	2	binding	up-regulates activity	0.375	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-256944
Q12834	O43683	0	phosphorylation	down-regulates activity	0.992	Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.	SIGNOR-250606
Q9H159	P35222	2	binding	up-regulates activity	0.315	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265858
P09544	O75581	2	binding	up-regulates	0.673	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131730
P63244	P12931	0	phosphorylation	up-regulates	0.2	We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246	SIGNOR-94800
Q13043	Q7L9L4	1	phosphorylation	up-regulates	0.851	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.	SIGNOR-175841
P35968	P29353	1	relocalization	up-regulates activity	0.711	In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.	SIGNOR-261949
Q14498	P00519	0	phosphorylation	up-regulates activity	0.322	In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner.	SIGNOR-262609
Q14344	Q08881	0	phosphorylation	up-regulates activity	0.2	This ability of Itk to phosphorylate Galpha13 was abolished in Itk mutants R29C (no longer able to interact with the membrane, and thus unable to interact with Galpha13) and K391M (no kinase activity) (XREF_FIG).\|To determine whether Itk is a downstream mediator of Galpha13, we examined whether Galpha13 could interact with Itk when locked in the GDP bound or GTP bound state.	SIGNOR-279623
Q13554	P14921	1	phosphorylation	down-regulates activity	0.309	Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites \| Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1	SIGNOR-250684
Q6ZN28	O15075	0	phosphorylation	up-regulates activity	0.2	Subsequently, MACC1 gets phosphorylated by DCLK1.\|This might be attributed to the higher activation of MACC1 by DCLK1 in the MACC1-positive cell lines SW620/Control and SW480/MACC1 used in this study.	SIGNOR-279031
O00398	Q03113	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-257287
O15111	P24385	1	phosphorylation	down-regulates	0.379	Ikkalpha regulates subcellular localization and proteolysis of cyclin d1 by phosphorylation of cyclin d1 at thr286.	SIGNOR-139570
Q13464	Q9Y613	1	phosphorylation	up-regulates	0.309	Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres.	SIGNOR-160548
P36956	Q8N6T7	2	binding	up-regulates activity	0.371	SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids.	SIGNOR-268158
P06241	P04629	1	phosphorylation	up-regulates activity	0.254	Here, we demonstrate that Fyn can directly phosphorylate the intracellular domain of TrkA and that its kinase activity towards Trk is increased by GPCR stimulation ( Fig. 4 ).	SIGNOR-279410
P26651	P49137	0	phosphorylation	down-regulates activity	0.699	We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.	SIGNOR-250153
P06493	Q53EZ4	1	phosphorylation	down-regulates	0.45	Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.	SIGNOR-140882
Q9NZJ5	P18031	0	dephosphorylation	down-regulates activity	0.267	Finally, we demonstrated that wild-type PTP1B directly dephosphorylated myc-tagged PERK that had been isolated from tunicamycin-treated HEK293T cells by immunoprecipitation ( xref ).\|The ability of PTP1B to dephosphorylate Tyr619 and inactivate PERK is fine tuned by the production of H 2 S by CSE in response to ER stress.	SIGNOR-277051
P00533	Q7Z699	1	phosphorylation	down-regulates activity	0.272	We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions.	SIGNOR-273638
P32245	P17612	0	phosphorylation	down-regulates activity	0.308	Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA	SIGNOR-250016
P13807	Q16821	0	dephosphorylation	up-regulates	0.502	In skeletal muscle, the activation of glycogen synthase by insulin involves the dephosphorylation of serine residues that are phosphorylated by gsk3 and dephosphorylated by the glycogen-associated form of protein phosphatase-l (pp1g).	SIGNOR-37301
Q9Y4K3	Q8N2H9	0	ubiquitination	down-regulates quantity	0.63	Finally, we used coexpression studies to directly demonstrate that Pellino3 inhibits the ability of wild-type TRAF6 to stabilize HIF-1alpha but not the stabilizing effects of the K124A TRAF6 mutant that is resistant to ubiquitination.\|In the present study, Pellino3 ubiquitinates TRAF6 with lysine 63-linked polyubiquitin chains to block the interaction of TRAF6 with HIF-1\u03b1.	SIGNOR-278707
P35558	Q12778	0	transcriptional regulation	up-regulates quantity by expression	0.428	Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase).	SIGNOR-197200
P45984	Q13115	0	dephosphorylation	down-regulates	0.606	We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. . Mkp-2 had detectable activity against jnk2, although full inactivation of jnk2 was not observed even at the higher phosphatase concentration.	SIGNOR-40929
P06493	Q07817	1	phosphorylation	down-regulates activity	0.537	Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis\|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis.	SIGNOR-267986
Q9UN86	P25963	1	relocalization	down-regulates activity	0.342	IkappaBalpha interacts with G3BP2 both in vivo and in vitrothrough the IkappaBalpha CRS. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm.	SIGNOR-260985
Q8NFH5	P06493	0	phosphorylation	down-regulates activity	0.563	Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.\|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association.	SIGNOR-278917
P26599	P17612	0	phosphorylation	down-regulates activity	0.309	PKA directly phosphorylates PTB on conserved Ser-16, and PKA activation in PC12 cells induces Ser-16 phosphorylation. PTB carrying a Ser-16 to alanine mutation accumulates normally in the nucleus. However, export of this mutant protein from the nucleus is greatly reduced in heterokaryon shuttling assays. Conversely, hyperphosphorylation of PTB by coexpression with the catalytic subunit of PKA results in the accumulation of PTB in the cytoplasm.	SIGNOR-263149
P01112	Q8N431	2	binding	up-regulates	0.2	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-161505
P48735	P24752	0	acetylation	down-regulates activity	0.287	Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2\|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers	SIGNOR-267627
P49841	O75122	1	phosphorylation	down-regulates activity	0.515	GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.\| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells	SIGNOR-264826
P11168	P17612	0	phosphorylation	down-regulates activity	0.309	GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity.	SIGNOR-250050
Q05209	Q05397	1	dephosphorylation	down-regulates activity	0.538	We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.\| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis.	SIGNOR-248661
Q92542	P49768	2	binding	up-regulates	0.965	Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2.	SIGNOR-118852
Q9UPX8	Q15398	0	relocalization	up-regulates activity	0.452	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264599
Q9UHD2	P25963	1	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
Q12857	Q01664	2	binding	up-regulates activity	0.266	We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.	SIGNOR-226586
P35222	P19022	2	binding	up-regulates activity	0.818	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265864
P62979	Q93009	0	cleavage	up-regulates quantity	0.654	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270824
P23396	P27361	0	phosphorylation	up-regulates	0.351	Erk phosphorylates threonine 42 residue of ribosomal protein s3.	SIGNOR-137175
O15550	P31273	1	transcriptional regulation	up-regulates quantity by expression	0.307	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260029
P19838	P25963	2	binding	down-regulates activity	0.74	Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b	SIGNOR-17688
P17252	P52566	1	phosphorylation	down-regulates	0.2	These results reveal a mechanism of downregulation of rhogdi2 activity through pkc-mediated phosphorylation of ser31.	SIGNOR-196765
Q6NUN9	Q9BXM7	0	phosphorylation	up-regulates activity	0.37	PINK1 directly phosphorylates PARIS at S322 and S613, priming it for ubiquitination by Parkin, which interacts with the C-terminus zinc finger of PARIS and tags it for destruction [ xref \u2013 xref , xref ].\|Thus, by tagging PARIS for destruction, PINK1/Parkin drive the generation of new mitochondria by increasing PGC-1\u03b1 levels (Fig. 1d).	SIGNOR-278268
P18031	Q16620	1	dephosphorylation	down-regulates activity	0.38	Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.\| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling	SIGNOR-264554
P37173	Q13347	2	binding	up-regulates	0.324	Another receptor-associated protein is trip-1, which interacts with and is phosphorylated by tbrii and contains five wd-40 repeats. The association of wd-40 repeat proteins may then allow them to play a role in signaling by the serine/threonine kinase receptors.	SIGNOR-60700
Q04759	P41594	1	phosphorylation	up-regulates activity	0.291	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249290
Q04206	P11309	0	phosphorylation	up-regulates	0.2	In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276.	SIGNOR-189125
P63092	Q13258	2	binding	up-regulates activity	0.593	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256755
P67809	Q7Z6M2	2	binding	down-regulates quantity by destabilization	0.381	Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions. FBX33 recruits Skp-1/Cul1 to YB-1	SIGNOR-271604
Q9GZQ8	Q8TD19	0	phosphorylation	down-regulates activity	0.2	LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1).	SIGNOR-273904
P23467	P12931	1	dephosphorylation	down-regulates activity	0.445	Collectively, these results suggest that PTPRB inhibits Src activation and down -- regulation of PTPRB activates Src signalling pathway required for cell invasion in A549 cells.\|Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2.	SIGNOR-277132
P36894	A6ND36	1	phosphorylation	up-regulates activity	0.374	These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. \|Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway.	SIGNOR-264766
Q5SQI0	Q9NY65	1	acetylation	up-regulates quantity by stabilization	0.244	Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.\|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules	SIGNOR-272250
O96017	P40337	1	phosphorylation	up-regulates	0.455	We demonstrated that checkpoint kinase-2 (chk2) binds to the beta-domain of pvhl and phosphorylates ser 111 on dna damage. Notably, this modification enhances pvhl-mediated transactivation of p53 by recruiting p300 and tip60 to the chromatin of p53 target gene	SIGNOR-177091
O00429	Q00535	0	phosphorylation	up-regulates activity	0.464	CDK5 activates DRP1 in BTICs.\|To determine if CDK5 could directly phosphorylate DRP1, we performed an in vitro kinase assay with CDK5, its regulatory partner p25 and GST-DRP1 (wild type or S616A mutant) and found that CDK5 directly phosphorylates DRP1 on the S616 site (Fig. 7d).	SIGNOR-278275
P10721	Q13239	2	phosphorylation	down-regulates activity	0.2	Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity	SIGNOR-263141

P45983

Q6JBY9

1

phosphorylation

down-regulates activity

0.286

CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.

SIGNOR-263085

Q92993

P15172

2

binding

up-regulates activity

0.365

Tip60 regulates myoblast differentiation by enhancing the transcriptional activity of MyoD via their physical interactions.

SIGNOR-237675

Q96CW1

Q5S007

0

phosphorylation

up-regulates activity

0.259

These data confirmed that LRRK2 phosphorylates AP2M1 at Thr 156 in vitro.

SIGNOR-278183

Q02156

P21802

1

phosphorylation

up-regulates

0.2

Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation

SIGNOR-201675

P08913

P08754

2

binding

up-regulates activity

0.469

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-256841

P04818

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.337

Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.

SIGNOR-267374

Q07889

Q9UNS2

2

binding

up-regulates quantity by stabilization

0.2

Our observations characterizing the interaction between CSN3 and the Sos1 HD suggest that this domain not only functions regulating Sos-GEF autoinhibition but is also involved in other functional roles, such as the control of Sos protein stability and homeostasis by modulating the degradation and intracellular levels of Sos1.

SIGNOR-256217

Q03135

P04150

2

binding

up-regulates

0.38

He mGR appears to reside in caveolae and its association with caveolin-1 (Cav-1) was clearly detected in two of the four cell lines investigated using double recognition proximity ligation assay.

SIGNOR-251683

P06748

P06493

0

phosphorylation

down-regulates activity

0.518

However, under the experimental conditions used here, the t199 residue was the most likely candidate to be phosphorylated by cyclin b/cdc2 these results strongly support the concept that the rna binding activity of b23.1 is inactivated by cyclin b/cdc2-mediated phosphorylation.

SIGNOR-89605

Q16671

Q04771

2

binding

up-regulates

0.553

See table2

SIGNOR-121593

Q9BYW2

P42224

1

methylation

up-regulates activity

0.266

SETD2 enhances antiviral immunity by directly methylating STAT1 on K525. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response.

SIGNOR-269091

P28698

P57086

2

binding

up-regulates activity

0.365

Co-immunoprecipitation and yeast two-hybrid analyses demonstrate that MZF1B and RAZ1 associate in vitro via a SCAN box-dependent mechanism. The interaction between MZF1B and RAZ1 might be necessary for mediating MZF1B function

SIGNOR-221561

Q14393

P38435

0

carboxylation

up-regulates activity

0.525

Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.

SIGNOR-265923

Q14689

P04179

2

binding

up-regulates activity

0.2

DIP2a is associated with SOD in the mitochondria of mouse brain. DIP2a knockout inhibited SOD activity. In this paper, we analyzed the interacting proteins of DIP2A by mass spectrum analysis and found that DIP2A was correlated with superoxide dismutase (SOD), SOD1 and SOD2. Knockout of DIP2A decreased SOD activity and increased the level of ROS in the mouse brain.

SIGNOR-266592

P31268

O15550

0

transcriptional regulation

up-regulates quantity by expression

0.275

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260024

P32248

Q99731

2

binding

up-regulates activity

0.784

CCL19 and CCL21 are endogenous agonists for the seven-trans membrane receptor CCR7.

SIGNOR-278123

P49841

Q96G01

1

phosphorylation

up-regulates activity

0.331

Therefore, at least Ser585 and Thr597 in BICD1 are important phosphorylation sites for BICD1 to exert its functions, and GSK-3β-dependent phosphorylation is required for the interaction of BICD1 with dynein.

SIGNOR-262744

P04637

P17252

0

phosphorylation

up-regulates activity

0.437

Here, we demonstrate that cotransfection of p53 with either PKC alpha or PKC zeta increases p53's transcriptional activity. Mutagenesis of p53 indicates that serine 371 is the major site for phosphorylation by PKC alpha in vitro.

SIGNOR-248999

Q99607

Q9UHD2

0

phosphorylation

up-regulates activity

0.361

Taken together, these results suggest that in response to viral infection, ELF4 was phosphorylated by TBK1 and translocated to the nucleus in a MAVS- and STING dependent manner.|We speculate that overexpressed ELF4 may recruit and be activated by TBK1.

SIGNOR-279130

P63208

Q13616

2

binding

up-regulates

0.959

The human f box protein beta-trcp associates with the cul1/skp1 complex and regulates the stability of beta-catenin.

SIGNOR-64511

Q8TCJ0

Q05655

0

phosphorylation

up-regulates activity

0.271

FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cdelta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1.|Accordingly, PRKCD-induced phosphorylation of Hax-1 at Ser210 and Fbxo25 at Ser178 was associated with decreased expression of Hax-1 in control cells,

SIGNOR-275561

O15503

Q13131

0

phosphorylation

up-regulates quantity by stabilization

0.256

Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPKα1 subunit associates with Insig-1 in a dose-dependent manner.

SIGNOR-277430

Q13315

Q7L7X3

1

phosphorylation

up-regulates

0.42

The dna damage kinase ataxia telangiectasia mutated (atm) phosphorylates taos in vitro;radiation induces phosphorylation of tao on a consensus site for phosphorylation by the atmprotein kinase in cells.

SIGNOR-154171

P67775

P24071

1

dephosphorylation

up-regulates activity

0.323

Furthermore, FcalphaRI activation is induced by protein phosphatase 2A (PP2A) after it dephosphorylates a single serine residue (S263) in the FcalphaRI intracellular tail

SIGNOR-264858

Q9Y5S8

Q86UR1

2

binding

up-regulates activity

0.751

Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation

SIGNOR-264710

P43320

2

binding

up-regulates activity

0.2

βB2-crystallin is the major component of β-crystallin and is a dimer at low concentrations. At high concentrations or in the lens, βB2-crystallin forms hetero-oligomers with other β-crystallins. These oligomeric β-crystallins further participate in the formation of a supramolecular assembly that is important in lens function-lens transparency.

SIGNOR-252154

Q9H6Z9

O43521-1

1

hydroxylation

up-regulates quantity by stabilization

0.254

EglN3 hydroxylase stabilizes BIM-EL linking VHL type 2C mutations to pheochromocytoma pathogenesis and chemotherapy resistance|EglN3 Hydroxylates BIM-EL at the Proline67/70 Residues

SIGNOR-262003

Q8TAT6

Q92890

2

binding

up-regulates activity

0.2

These findings ascribe specific functions to each of the components of the VCP-UFD1L-NPL4 complex in Vpu-mediated CD4 degradation: VCP energizes the process through ATP binding and hydrolysis, UFD1L binds ubiquitinated CD4 through recognition of K48 Ub chains, and NPL4 stabilizes UFD1L. VCP is thus likely to provide the energy required for extraction of CD4 from membranes.

SIGNOR-252422

Q9NRC8

Q9NR31

1

deacetylation

up-regulates activity

0.2

SIRT7 interacts with the helicase DDX21. Deacetylation by SIRT7 is required for DDX21 activity and R-loop unwinding

SIGNOR-260978

P17612

Q9BY41

1

phosphorylation

down-regulates

0.494

Negative regulation of histone deacetylase 8 activity by cyclic amp-dependent protein kinase athe pka phosphoacceptor site of hdac8 is ser(39)

SIGNOR-120643

P18031

P35968

1

dephosphorylation

down-regulates activity

0.418

This led to increased PTPN1 (PTP1b)-mediated dephosphorylation of VEGFR2 at Y 1175 , the site involved in activating ERK signaling.

SIGNOR-277011

Q96GX5

Q9Y5B0

0

dephosphorylation

down-regulates activity

0.433

Taken together, these data suggest that Fcp1 bound and dephosphorylated Gwl at S90 and S453, and possibly at other Cdk1 dependent sites, during mitosis exit and that Fcp1 catalyzed dephosphorylation lowered Gwl activity towards Ensa and ARPP19, allowing PP2A-B55 to autoactivate.|Together, these data indicate that Fcp1 dependent dephosphorylation greatly reduces S67-Ensa kinase activity of Gwl and that, downstream inactivation of Cdk1, Fcp1 deficit substantially blunts inactivation of Gwl.

SIGNOR-276971

Q92686

P05771

0

phosphorylation

up-regulates activity

0.361

Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM.

SIGNOR-248914

Q9NS91

Q12888

1

ubiquitination

up-regulates activity

0.611

RAD18 associates with 53BP1 and is recruited to DSB sites in a 53BP1 dependent manner specifically during G1-phase, RAD18 monoubiquitinates KBD domain of 53BP1 at lysine 1268 in vitro.|These results suggest that RAD18 directed modification at Lysine 1268 of 53BP1 promotes the retention of 53BP1 at DSBs.

SIGNOR-278593

Q04206

Q96EB6

0

deacetylation

down-regulates activity

0.722

SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310.

SIGNOR-238817

Q04727

Q02548

2

binding

down-regulates activity

0.563

Grg4 efficiently represses the transcriptional activity of Pax5 in an octapeptide-dependent manner. Similar protein interactions resulting in transcriptional repression were also observed between distantly related members of both the Pax2/5/8 and Groucho protein families

SIGNOR-269083

P35222

P48730

0

phosphorylation

down-regulates

0.626

However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo.

SIGNOR-87441

P23246

P49841

0

phosphorylation

down-regulates

0.345

Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687

SIGNOR-168392

P68431

P41229

0

demethylation

up-regulates activity

0.2

KDM5 subfamily is capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4). Depending on the methylation site, its effect on transcription can be either activating or repressing.

SIGNOR-264305

P20023

P15391

2

binding

up-regulates activity

0.783

Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling.

SIGNOR-266642

P24864

Q13309

2

binding

down-regulates quantity by destabilization

0.707

Biochemical studies showed that Skp2 interacts specifically with cyclin E and thereby promotes its ubiquitylation and degradation both in vivo and in vitro. These results suggest that specific degradation of cyclin E and p27(Kip1) is mediated by the SCF(Skp2) ubiquitin ligase complex, and that Skp2 may control chromosome replication and centrosome duplication by determining the abundance of cell cycle regulators. Skp2 was associated with Cul1, but not Cul3.

SIGNOR-272566

Q05655

Q99986

1

phosphorylation

down-regulates activity

0.285

PKC\u03b4 phosphorylates VRK1 on Ser-355 in vitro.|PKCdelta negatively regulates VRK1 kinase activity in vitro.

SIGNOR-278219

P50406

P38405

2

binding

up-regulates activity

0.375

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-256944

Q12834

O43683

0

phosphorylation

down-regulates activity

0.992

Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically. A Cdc20 mutant with all six Bub1 phosphorylation sites removed is refractory to Bub1-mediated phosphorylation and inhibition in vitro.

SIGNOR-250606

Q9H159

P35222

2

binding

up-regulates activity

0.315

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

SIGNOR-265858

P09544

O75581

2

binding

up-regulates

0.673

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131730

P63244

P12931

0

phosphorylation

up-regulates

0.2

We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246

SIGNOR-94800

Q13043

Q7L9L4

1

phosphorylation

up-regulates

0.851

Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2mob1 interaction.

SIGNOR-175841

P35968

P29353

1

relocalization

up-regulates activity

0.711

In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.

SIGNOR-261949

Q14498

P00519

0

phosphorylation

up-regulates activity

0.322

In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner.

SIGNOR-262609

Q14344

Q08881

0

phosphorylation

up-regulates activity

0.2

This ability of Itk to phosphorylate Galpha13 was abolished in Itk mutants R29C (no longer able to interact with the membrane, and thus unable to interact with Galpha13) and K391M (no kinase activity) (XREF_FIG).|To determine whether Itk is a downstream mediator of Galpha13, we examined whether Galpha13 could interact with Itk when locked in the GDP bound or GTP bound state.

SIGNOR-279623

Q13554

P14921

1

phosphorylation

down-regulates activity

0.309

Increased Transactivation of the GM-CSF Promoter/Enhancer by Ets1 with Mutated CaMK II Sites | Significantly, phosphorylation of Ets1 by Ca2+-dependent pathways is thought to inhibit DNA binding in vitro. To analyze the role of these four serines, S251, S257, S282, and S285, in transcription, we constructed three mutant derivatives of human Ets1

SIGNOR-250684

Q6ZN28

O15075

0

phosphorylation

up-regulates activity

0.2

Subsequently, MACC1 gets phosphorylated by DCLK1.|This might be attributed to the higher activation of MACC1 by DCLK1 in the MACC1-positive cell lines SW620/Control and SW480/MACC1 used in this study.

SIGNOR-279031

O00398

Q03113

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-257287

O15111

P24385

1

phosphorylation

down-regulates

0.379

Ikkalpha regulates subcellular localization and proteolysis of cyclin d1 by phosphorylation of cyclin d1 at thr286.

SIGNOR-139570

Q13464

Q9Y613

1

phosphorylation

up-regulates

0.309

Rock phosphorylates the c-terminal residues ser1131, ser1137, and thr1141 of formin homology domain protein 1 (fhod1). Phosphorylation of fhod1 at the three residues fully disrupts the autoinhibitory interaction, which culminates in formation of stress fibres.

SIGNOR-160548

P36956

Q8N6T7

2

binding

up-regulates activity

0.371

SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids.

SIGNOR-268158

P06241

P04629

1

phosphorylation

up-regulates activity

0.254

Here, we demonstrate that Fyn can directly phosphorylate the intracellular domain of TrkA and that its kinase activity towards Trk is increased by GPCR stimulation ( Fig. 4 ).

SIGNOR-279410

P26651

P49137

0

phosphorylation

down-regulates activity

0.699

We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.

SIGNOR-250153

P06493

Q53EZ4

1

phosphorylation

down-regulates

0.45

Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.

SIGNOR-140882

Q9NZJ5

P18031

0

dephosphorylation

down-regulates activity

0.267

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

SIGNOR-277051

P00533

Q7Z699

1

phosphorylation

down-regulates activity

0.272

We show that oncogenic EGFR(L858R) signaling leads to the phosphorylation of SPRED1 on serine 105, disrupting the SPRED1-neurofibromin complex. The structural, biochemical, and biological results provide new mechanistic insights about how SPRED1 interacts with neurofibromin and regulates active KRAS levels in normal and pathologic conditions.

SIGNOR-273638

P32245

P17612

0

phosphorylation

down-regulates activity

0.308

Activation of MC4R by agonist is associated with protein kinase A (PKA) and GRK phosphorylation of serine/threonine residues in the C-terminal tail of MC4R, followed by -arrestin and dynamin-dependent internalization of the receptor. Thr312 and Ser329/330 in the C-terminal tail of MC4R are potential sites for PKA

SIGNOR-250016

P13807

Q16821

0

dephosphorylation

up-regulates

0.502

In skeletal muscle, the activation of glycogen synthase by insulin involves the dephosphorylation of serine residues that are phosphorylated by gsk3 and dephosphorylated by the glycogen-associated form of protein phosphatase-l (pp1g).

SIGNOR-37301

Q9Y4K3

Q8N2H9

0

ubiquitination

down-regulates quantity

0.63

Finally, we used coexpression studies to directly demonstrate that Pellino3 inhibits the ability of wild-type TRAF6 to stabilize HIF-1alpha but not the stabilizing effects of the K124A TRAF6 mutant that is resistant to ubiquitination.|In the present study, Pellino3 ubiquitinates TRAF6 with lysine 63-linked polyubiquitin chains to block the interaction of TRAF6 with HIF-1\u03b1.

SIGNOR-278707

P35558

Q12778

0

transcriptional regulation

up-regulates quantity by expression

0.428

Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase).

SIGNOR-197200

P45984

Q13115

0

dephosphorylation

down-regulates

0.606

We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. . Mkp-2 had detectable activity against jnk2, although full inactivation of jnk2 was not observed even at the higher phosphatase concentration.

SIGNOR-40929

P06493

Q07817

1

phosphorylation

down-regulates activity

0.537

Cyclin-Dependent Kinase 1-Mediated Bcl-xL/Bcl-2 Phosphorylation Acts as a Functional Link Coupling Mitotic Arrest and Apoptosis|These findings suggest a model whereby a switch in the duration of CDK1 activation, from transient during mitosis to sustained during mitotic arrest, dramatically increases the extent of Bcl-xL/Bcl-2 phosphorylation, resulting in inactivation of their antiapoptotic function. Thus, phosphorylation of antiapoptotic Bcl-2 proteins acts as a sensor for CDK1 signal duration and as a functional link coupling mitotic arrest to apoptosis.

SIGNOR-267986

Q9UN86

P25963

1

relocalization

down-regulates activity

0.342

IkappaBalpha interacts with G3BP2 both in vivo and in vitrothrough the IkappaBalpha CRS. Overexpression of G3BP2 directly promotes retention of IkappaBalpha in the cytoplasm.

SIGNOR-260985

Q8NFH5

P06493

0

phosphorylation

down-regulates activity

0.563

Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association.

SIGNOR-278917

P26599

P17612

0

phosphorylation

down-regulates activity

0.309

PKA directly phosphorylates PTB on conserved Ser-16, and PKA activation in PC12 cells induces Ser-16 phosphorylation. PTB carrying a Ser-16 to alanine mutation accumulates normally in the nucleus. However, export of this mutant protein from the nucleus is greatly reduced in heterokaryon shuttling assays. Conversely, hyperphosphorylation of PTB by coexpression with the catalytic subunit of PKA results in the accumulation of PTB in the cytoplasm.

SIGNOR-263149

P01112

Q8N431

2

binding

up-regulates

0.2

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

SIGNOR-161505

P48735

P24752

0

acetylation

down-regulates activity

0.287

Mitochondrial acetyltransferase ACAT1 and deacetylase SIRT3 are responsible for acetylation and deacetylation, respectively, at K413 of mIDH2|K413 acetylation inhibits mIDH2 by simultaneously attenuating dimer formation from monomers and destabilizing dimers for conversion to monomers

SIGNOR-267627

P49841

O75122

1

phosphorylation

down-regulates activity

0.515

GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells

SIGNOR-264826

P11168

P17612

0

phosphorylation

down-regulates activity

0.309

GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity.

SIGNOR-250050

Q05209

Q05397

1

dephosphorylation

down-regulates activity

0.538

We demonstrate here that activated Ras induces tyrosine dephosphorylation and inhibition of FAK mediated by the Ras downstream Fgd1-Cdc42-PAK1-MEK-ERK signaling cascade.| PIN1 binding and prolyl isomerization of FAK cause PTP-PEST to interact with and dephosphorylate FAK Y397. Inhibition of FAK mediated by this signal relay promotes Ras-induced cell migration, invasion, and metastasis.

SIGNOR-248661

Q92542

P49768

2

binding

up-regulates

0.965

Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2.

SIGNOR-118852

Q9UPX8

Q15398

0

relocalization

up-regulates activity

0.452

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

SIGNOR-264599

Q9UHD2

P25963

1

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

Q12857

Q01664

2

binding

up-regulates activity

0.266

We also observed moderately increased recruitment of CTCF, HDAC1, and SP1 by the full-length AP-4 onto the WT DNA beads.

SIGNOR-226586

P35222

P19022

2

binding

up-regulates activity

0.818

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

SIGNOR-265864

P62979

Q93009

0

cleavage

up-regulates quantity

0.654

Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.

SIGNOR-270824

P23396

P27361

0

phosphorylation

up-regulates

0.351

Erk phosphorylates threonine 42 residue of ribosomal protein s3.

SIGNOR-137175

O15550

P31273

1

transcriptional regulation

up-regulates quantity by expression

0.307

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260029

P19838

P25963

2

binding

down-regulates activity

0.74

Nf-kappa b is an inducible transcription factor comprised of a 50-kd (p50) and a 65-kd (p65) subunit. Induction of nf-kappa b activity, which is a critical event in many signal transduction pathways, involves release from a cytoplasmic inhibitory protein, i kappa b, followed by translocation of the active transcription factor complex into the nucleus. we demonstrate by in vitro and in vivo methods that the recently cloned i kappa b/mad-3 interacts with both the p50 and p65 subunits of nf-kappa b

SIGNOR-17688

P17252

P52566

1

phosphorylation

down-regulates

0.2

These results reveal a mechanism of downregulation of rhogdi2 activity through pkc-mediated phosphorylation of ser31.

SIGNOR-196765

Q6NUN9

Q9BXM7

0

phosphorylation

up-regulates activity

0.37

PINK1 directly phosphorylates PARIS at S322 and S613, priming it for ubiquitination by Parkin, which interacts with the C-terminus zinc finger of PARIS and tags it for destruction [ xref \u2013 xref , xref ].|Thus, by tagging PARIS for destruction, PINK1/Parkin drive the generation of new mitochondria by increasing PGC-1\u03b1 levels (Fig. 1d).

SIGNOR-278268

P18031

Q16620

1

dephosphorylation

down-regulates activity

0.38

Collectively, these data establish a direct enzyme-substrate interaction between PTP1B and phosphorylated Y705/706 (p-Y705/706) TRKB, the critical autophosphorylation sites that mediate BDNF-induced signaling.| Therefore, the data are consistent with a role of PTP1B as an inhibitor of BDNF/TRKB signaling

SIGNOR-264554

P37173

Q13347

2

binding

up-regulates

0.324

Another receptor-associated protein is trip-1, which interacts with and is phosphorylated by tbrii and contains five wd-40 repeats. The association of wd-40 repeat proteins may then allow them to play a role in signaling by the serine/threonine kinase receptors.

SIGNOR-60700

Q04759

P41594

1

phosphorylation

up-regulates activity

0.291

Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.

SIGNOR-249290

Q04206

P11309

0

phosphorylation

up-regulates

0.2

In this study we show that phosphorylation of rela/p65 at ser276 prevents its degradation by ubiquitin-mediated proteolysis. importantly, we identify pim-1 as a further kinase responsible for the phosphorylation of rela/p65 at ser276.

SIGNOR-189125

P63092

Q13258

2

binding

up-regulates activity

0.593

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

SIGNOR-256755

P67809

Q7Z6M2

2

binding

down-regulates quantity by destabilization

0.381

Here we identify FBX33 as a component of an SCF E3-ubiquitin ligase that targets the multifunctional regulator Y-box binding protein 1 (YB-1)/dbpB/p50 for polyubiquitination and destruction by the proteasome. By targeting YB-1 for proteasomal degradation, FBX33 negatively interferes with YB-1 mediated functions. FBX33 recruits Skp-1/Cul1 to YB-1

SIGNOR-271604

Q9GZQ8

Q8TD19

0

phosphorylation

down-regulates activity

0.2

LC3B is phosphorylated at Thr-50 within the LDS by serine/threonine kinase (STK) 3 and STK4. Here, we identified LIR motifs in STK3 and atypical protein kinase Cζ (PKCζ) and never in mitosis A (NIMA)-related kinase 9 (NEK9). All three kinases phosphorylated LC3B Thr-50 in vitro A phospho-mimicking substitution of Thr-50 impaired binding of several LIR-containing proteins, such as ATG4B, FYVE, and coiled-coil domain-containing 1 (FYCO1), and autophagy cargo receptors p62/sequestosome 1 (SQSTM1) and neighbor of BRCA1 gene (NBR1).

SIGNOR-273904

P23467

P12931

1

dephosphorylation

down-regulates activity

0.445

Collectively, these results suggest that PTPRB inhibits Src activation and down -- regulation of PTPRB activates Src signalling pathway required for cell invasion in A549 cells.|Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2.

SIGNOR-277132

P36894

A6ND36

1

phosphorylation

up-regulates activity

0.374

These results indicate that ALK3 phosphorylates PAWS1 predominantly at Ser610 but can also phosphorylate at Ser614 and Ser616 in vitro. |Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway.

SIGNOR-264766

Q5SQI0

Q9NY65

1

acetylation

up-regulates quantity by stabilization

0.244

Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules

SIGNOR-272250

O96017

P40337

1

phosphorylation

up-regulates

0.455

We demonstrated that checkpoint kinase-2 (chk2) binds to the beta-domain of pvhl and phosphorylates ser 111 on dna damage. Notably, this modification enhances pvhl-mediated transactivation of p53 by recruiting p300 and tip60 to the chromatin of p53 target gene

SIGNOR-177091

O00429

Q00535

0

phosphorylation

up-regulates activity

0.464

CDK5 activates DRP1 in BTICs.|To determine if CDK5 could directly phosphorylate DRP1, we performed an in vitro kinase assay with CDK5, its regulatory partner p25 and GST-DRP1 (wild type or S616A mutant) and found that CDK5 directly phosphorylates DRP1 on the S616 site (Fig. 7d).

SIGNOR-278275

P10721

Q13239

2

phosphorylation

down-regulates activity

0.2

Oncogenic c-Kit-D816V phosphorylates SLAP on residues Y120, Y258 and Y273. Mutation of the SLAP tyrosine phosphorylation sites rescues its activity

SIGNOR-263141