GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P49841	P17676	1	phosphorylation	up-regulates activity	0.457	We found that expression of srebf1a depended on GSK3β activity and that GSK3β activity was necessary for C/EBPβ phosphorylation at Thr188	SIGNOR-251644
Q96FA3	Q9NWZ3	0	phosphorylation	up-regulates activity	0.658	The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites.	SIGNOR-276128
Q9HAU4	Q13873	1	ubiquitination	down-regulates	0.503	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps.	SIGNOR-193119
P28482	Q9UPT5	1	phosphorylation	up-regulates	0.331	Erk1/2 phosphorylation enhances the binding of exo70 to other exocyst components and promotes the assembly of the exocyst complex in response to epidermal growth factor (egf) signaling.	SIGNOR-197543
Q15669	P63000	1	relocalization	down-regulates activity	0.41	Therefore, RhoH functions as a Rac1 antagonist by inhibiting Rac1 translocation to the cell plasma membrane in the regulation of cell migration and F-actin assembly of HPCs	SIGNOR-259085
P07947	P25490	1	phosphorylation	down-regulates activity	0.2	YY1 phosphorylation is mediated by Src family kinases.	SIGNOR-276941
Q70Z35	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.609	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-260571
Q96A00	Q02156	0	phosphorylation	up-regulates activity	0.261	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.	SIGNOR-249258
P23528	Q9HCK4	0	post transcriptional regulation	up-regulates quantity by expression	0.257	Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation.	SIGNOR-268378
Q9ULL1	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.323	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-260563
Q9Y261	O15111	0	phosphorylation	down-regulates	0.2	Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression	SIGNOR-195316
P51955	Q9BV73	1	phosphorylation	down-regulates	0.774	C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro.	SIGNOR-204837
Q9Y572	Q13263	1	phosphorylation	down-regulates activity	0.2	These results indicate that TRIM28 phosphorylation at S473 is RIPK3-dependent and suggest that RIPK1/RIPK3 activation induces TRIM28 phosphorylation at S473, which may play an important role in the regulation of transcriptional activity.	SIGNOR-279107
Q02156	O60716	1	phosphorylation	down-regulates	0.2	We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation	SIGNOR-201600
P12318	P51451	0	phosphorylation	up-regulates activity	0.436	To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point\|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.	SIGNOR-249312
P60484	Q96KB5	0	phosphorylation	down-regulates activity	0.504	PTEN is phosphorylated by TOPK and is required for mitotic entry. In addition, reduced PTEN phosphorylation levels upon TOPK knockdown correlated with decreased Akt activation (Fig. 4e) suggesting that TOPK mediated phosphorylation may lead to PTEN inactivation. By using various PTEN mutants in a kinase assay we concluded that TOPK phosphorylates PTEN at S380 residue in vitro (Fig. 4c).	SIGNOR-271472
Q9P227	P63000	1	gtpase-activating protein	down-regulates activity	0.43	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-260480
P42574	Q13635	1	cleavage	down-regulates	0.321	Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain.	SIGNOR-199111
Q8WU17	Q12772	1	ubiquitination	down-regulates quantity	0.477	Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner	SIGNOR-271958
P68400	Q92538	1	phosphorylation	down-regulates quantity by destabilization	0.2	We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation.	SIGNOR-277398
P45985	Q02779	0	phosphorylation	up-regulates activity	0.445	MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase.	SIGNOR-278954
Q96L34	Q13470	1	phosphorylation	down-regulates activity	0.2	We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity.Phosphorylation of TNK1 at S502 within the proline rich domain is required for TNK1 binding to 14-3-3.MARKs mediate phosphorylation at S502 and 14-3-3 binding to TNK1, which restrains the movement of TNK1 into heavy membrane-associated clusters.	SIGNOR-273865
P17302	P05771	0	phosphorylation	down-regulates activity	0.388	Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.\|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.	SIGNOR-249049
P68400	Q93009	1	phosphorylation	up-regulates quantity by stabilization	0.372	We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53.	SIGNOR-276530
Q9BYB0	O95886	0	relocalization	up-regulates activity	0.2	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264594
P30307	P24941	0	phosphorylation	up-regulates	0.754	The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry.	SIGNOR-165872
P61586	P07737	1	null	up-regulates activity	0.569	We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.\|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.	SIGNOR-253109
Q9HCE7	O15198	1	ubiquitination	down-regulates	0.669	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-195669
Q9BV68	Q16595	1	ubiquitination	down-regulates quantity by destabilization	0.385	Depletion of RNF126 by specific small interfering RNA delays the degradation of frataxin precursor and increases its stability.\|Here we report on the identification of really interesting new gene finger protein 126 (RNF126) as the E3 ligase that ubiquitinates frataxin.	SIGNOR-278663
P12931	P35916	1	phosphorylation	up-regulates	0.513	Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk.	SIGNOR-165035
P11362	P24752	1	phosphorylation	up-regulates activity	0.2	Treatment with the FGFR1 inhibitor TKI258 in FGFR1-expressing H1299 cells led to decreased Y407 phosphorylation of ACAT1 in the mitochondrial fraction, where both ACAT1 and a fraction of FGFR1 were detected\|Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity,	SIGNOR-264423
P17612	O43164	1	phosphorylation	up-regulates activity	0.2	In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h).	SIGNOR-276316
Q5UIP0	Q96T88	0	polyubiquitination	down-regulates activity	0.2	UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation.	SIGNOR-277193
O95251	P06493	0	phosphorylation	up-regulates	0.355	Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.	SIGNOR-160747
Q14934	Q9Y625	1	transcriptional regulation	up-regulates quantity by expression	0.2	NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.	SIGNOR-264023
Q969V5	P31749	1	ubiquitination	down-regulates quantity by destabilization	0.475	The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability.	SIGNOR-252437
P06241	O43561	1	phosphorylation	up-regulates	0.749	Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk.	SIGNOR-149174
P20393	Q9UBK2	0	transcriptional regulation	up-regulates quantity by expression	0.522	Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Chromatin immunoprecipitation (ChIP) assays in HepG2 cells indicate that PGC-1α is present near RORE on the proximal Bmal1 promoter.These results indicate that PGC-1α activates Bmal1 transcription by altering the local chromatin environment from a repressive to an active state.	SIGNOR-268030
P11802	P84022	1	phosphorylation	down-regulates activity	0.757	We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity	SIGNOR-232142
P51812	P25963	1	phosphorylation	down-regulates quantity by destabilization	0.368	Here, we show that RSK2 is activated by treatment with tumor necrosis factor-alpha (TNF-alpha) and directly phosphorylates IkappaBalpha at Ser 32, leading to IkappaBalpha degradation.	SIGNOR-279108
P29353	P43405	0	phosphorylation	up-regulates	0.762	The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2).	SIGNOR-59635
O94782	Q9BXW9	1	deubiquitination	down-regulates activity	0.761	The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2\|The level of monoubiquitinated FANCD2 protein increases in response to various types of DNA damage in mammalian cells	SIGNOR-263273
Q14807	P06493	0	phosphorylation	up-regulates activity	0.344	Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes	SIGNOR-100964
P17252	P52565	1	phosphorylation	down-regulates activity	0.449	PKCalpha phosphorylates RhoGDIalpha at Ser34 to reduce its affinity for RhoA (but not for Rac1 or Cdc42) .	SIGNOR-279097
Q9UPT9	P06493	0	phosphorylation	up-regulates activity	0.47	On the other hand, CDK1 enhances USP22 activity to stabilize CCNB1 during the G2/M phase.\|Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1.	SIGNOR-278241
Q9H2K2	Q9H2G9	1	ADP-ribosylation	down-regulates quantity by destabilization	0.2	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.	SIGNOR-263384
Q5FBB7	P06493	0	phosphorylation	up-regulates activity	0.2	The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl.	SIGNOR-265263
P17612	P50549	1	phosphorylation	up-regulates activity	0.292	The camp-dependent protein kinase a (pka) phosphorylates er81 on ser(191)/ser(216)ser(191) and ser(216), were identified, whose mutation to alanine reduces er81 activity upon erk-mapk stimulation.	SIGNOR-92447
P24941	P18858	1	phosphorylation	up-regulates activity	0.457	We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner.	SIGNOR-103254
Q9Y666	Q9BYP7	0	phosphorylation	down-regulates activity	0.451	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities\|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264630
P04083	P05129	0	phosphorylation	up-regulates	0.2	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.	SIGNOR-202788
Q96GX5	P06493	0	phosphorylation	up-regulates activity	0.513	We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop	SIGNOR-249653
Q9NXA8	P34897	1	post translational modification	down-regulates activity	0.235	Mitochondrial serine hydroxymethyl transferase (SHMT2) is a rate-limiting enzyme that catalyzes the catabolism of serine and drives the proliferation of osteosarcoma cells and colon cancer cells. SIRT5 directly mediates the desuccinylation of Lysine 280 on SHMT2. Therefore, SIRT5 is a candidate target to inhibit serine catabolism	SIGNOR-267644
P49841	P13807	1	phosphorylation	down-regulates activity	0.686	Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-.	SIGNOR-253007
Q15208	Q9BX46	1	phosphorylation	up-regulates activity	0.355	Phosphorylation of Rbm24 by Stk38 is crucial for the maintenance of cardiac sarcomeric gene expression in cardiac cells.\|These results indicated that Stk38 increases Rbm24 protein stability probably by interfering with the ubiquitin-proteasome protein degradation pathway.	SIGNOR-278291
O14595	P84022	1	dephosphorylation	up-regulates activity	0.424	Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3\|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-248293
Q8N2Q7	P35398	0	transcriptional regulation	up-regulates quantity by expression	0.2	Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005).	SIGNOR-265136
P01215	Q9UBR4	0	transcriptional regulation	up-regulates quantity by expression	0.387	Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim binds to CBP in TRH-dependent manner on this site and that these proteins synergistically activate the human α-GSU promoter during TRH stimulation.	SIGNOR-267207
Q9NZC7	P12931	0	phosphorylation	up-regulates	0.48	The tyrosine kinase, src, phosphorylates wwox at tyrosine 33 in the first ww domain and enhances its binding to p73.	SIGNOR-123819
P11388	P05129	0	phosphorylation	up-regulates activity	0.359	Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. \| Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides.	SIGNOR-249196
O43597	P46934	0	polyubiquitination	down-regulates quantity by destabilization	0.39	Endogenous and overexpressed Nedd4 polyubiquitinate Spry2 via Lys(48) on ubiquitin and decrease its stability.	SIGNOR-271425
Q00536	P10644	1	phosphorylation	up-regulates activity	0.272	PCTK1 regulates spindle orientation in a kinase-dependent manner. Phosphoproteomic analysis together with an RNA interference screen revealed that PCTK1 regulates spindle orientation through phosphorylation of Ser83 on KAP0, a regulatory subunit of protein kinase A (PKA)	SIGNOR-273018
P27361	P36956	1	phosphorylation	up-regulates activity	0.443	Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo.	SIGNOR-80096
P17252	Q14315	1	phosphorylation	up-regulates quantity by stabilization	0.338	We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. In vitro kinase assays combined with LC-MS confirmed hFLNc-S2233 as a substrate of Akt, whereas PKCα preferentially targeted S2236.	SIGNOR-262617
P01106	Q02127	1	transcriptional regulation	up-regulates quantity by expression	0.346	PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria.	SIGNOR-267382
P49593	O95835	1	dephosphorylation	down-regulates activity	0.2	POPX2 is capable of dephosphorylating LATS1 at Thr1079 (Figure xref ), which is a residue critical for LATS1 activity.\|POPX2 might negatively regulate the activities of MST1 and LATS1 through dephosphorylation.\|We found that POPX2 could dephosphorylate LATS1 on Threonine-1079, leading to inactivation of LATS1 kinase.	SIGNOR-276989
P54646	Q8N122	1	phosphorylation	down-regulates activity	0.693	These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.\|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK	SIGNOR-163463
Q92734	Q6AZZ1	0	ubiquitination	down-regulates quantity by destabilization	0.451	Our results suggest that TRIM68 degrades TFG at a point of pathway convergence in which downstream events lead to the activation of both NF-kappaB and IRF3.\|TRIM68 polyubiquitinates TFG leading to its degradation via its RING domain which also plays an important role in TRIM68 negative inhibition on IFN-beta production.	SIGNOR-278737
P68400	P49418	1	phosphorylation	down-regulates	0.2	Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin.	SIGNOR-149314
Q92667	O43255	0	polyubiquitination	down-regulates quantity by destabilization	0.507	Seven In-Absentia Homolog 2 (Siah2), an E3-ubiquitin ligase whose expression is induced in hypoxic conditions, formed a complex and degraded AKAP121.	SIGNOR-272641
O60674	O43583	0	transcriptional regulation	up-regulates quantity by expression	0.2	DENR directly regulates JAK2 expression.	SIGNOR-269675
P06241	Q05397	1	phosphorylation	up-regulates activity	0.602	Because Fyn deletion prevented FAK phosphorylation at tyrosine residues 397 and 576 (XREF_FIG), we generated a phosphorylation mimicking mutant of FAK to test whether restoring FAK phosphorylation in the fyn -/- mouse lung could restore lung vascular permeability responses to PAR1 agonist to the level seen in WT mice.\|Our findings that interaction of activated FAK with p120-catenins subsequent to Fyn activation of FAK facilitates reannealing of AJ leading to reestablishment of the basal endothelial barrier suggest that the Fyn-FAK pathway plays a critical role in restoring endothelial barrier function.	SIGNOR-278441
Q6P589	O43318	0	phosphorylation	down-regulates quantity by destabilization	0.2	TAK1 phosphorylated the Ser3 in the noncanonical degron motif of TIPE2 to trigger its interaction with β-TrCP for subsequent ubiquitination and degradation.	SIGNOR-273668
Q9H1K0	Q16539	0	phosphorylation	up-regulates	0.2	We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes	SIGNOR-140143
O15550	Q05516	1	transcriptional regulation	up-regulates quantity by expression	0.311	UTX catalytic activity has been reported to upregulate expression of the master transcription factor PLZF and to modulate superenhancer accessibility in invariant natural killer T cells.	SIGNOR-260038
P36956	P28482	0	phosphorylation	up-regulates	0.406	Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo.	SIGNOR-80092
P35568	Q13526	0	isomerization	up-regulates activity	0.2	In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells\|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation\|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events	SIGNOR-265757
P00533	P35637	1	phosphorylation	up-regulates activity	0.259	Thus, EGFR appears to mediate FUS nuclear translocation by phosphorylating Y6 and Y296 in FUS.	SIGNOR-279168
P24941	O14757	1	phosphorylation	up-regulates	0.554	Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency	SIGNOR-175083
Q53EZ4	P06493	0	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
P23443	O60825	1	phosphorylation	up-regulates activity	0.247	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-49371
O95631	P60709	1	post transcriptional regulation	up-regulates quantity	0.28	Netrin-1 induces β-actin translation driven by its 3’UTR.	SIGNOR-268161
P06493	Q14807	1	phosphorylation	up-regulates activity	0.344	Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes	SIGNOR-100964
P12931	P40763	1	phosphorylation	up-regulates activity	0.789	In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants.	SIGNOR-247341
P15311	P41743	0	phosphorylation	up-regulates	0.342	Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation.	SIGNOR-160855
O43189	P31269	1	transcriptional regulation	down-regulates quantity by repression	0.286	These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.	SIGNOR-260069
P61586	Q13017	0	gtpase-activating protein	down-regulates activity	0.828	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-260461
Q12774	P12931	0	phosphorylation	up-regulates activity	0.465	Arhgef5 was tyrosine-phosphorylated by Src and bound to Src to positively regulate its activity.\|Using an inducible system for Src activation, we found that Src induced podosome formation depends upon the Src SH3 domain, and identified Arhgef5 as a Src SH3 binding protein.	SIGNOR-279571
P23511	P24941	0	phosphorylation	up-regulates activity	0.439	Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa)	SIGNOR-250742
Q15139	O43597	1	phosphorylation	down-regulates quantity by destabilization	0.324	PKD negatively affects the stability of Spry2 WT but not of mutant Spry2 S112A.\|Using in vitro and in vivo assays, we show that protein kinase D (PKD) phosphorylates Spry2 at serine 112 and interacts in vivo with the C-terminal half of this protein.	SIGNOR-280091
P04637	Q13362	0	dephosphorylation	up-regulates quantity by stabilization	0.611	Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56gamma protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56gamma3-mediated inhibition of cell proliferation and cell transformation.	SIGNOR-268154
Q8IWA4	Q9NX47	0	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.\|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate.	SIGNOR-274133
P15172	Q96EB6	0	null	down-regulates activity	0.621	Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation	SIGNOR-241963
Q9NP71	P25445	1	transcriptional regulation	up-regulates quantity by expression	0.2	The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS)	SIGNOR-267947
Q14980	Q9UHD2	0	phosphorylation	up-regulates activity	0.2	Our studies now reveal TBK1 as another kinase that phosphorylates NuMA and that is required for its association with dynein and for localization of NuMA to the centrosomes in mitotic cells.	SIGNOR-278432
P62136	P55211	1	dephosphorylation	up-regulates	0.2	Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis.	SIGNOR-195992
P68400	Q15185	1	phosphorylation	up-regulates	0.354	Several lines of evidence suggest that a cpges-activating protein kinase is ck-ii (casein kinase ii). Recombinant cpges was phosphorylated directly by and associated with ck-ii in vitro, resulting in marked reduction of the k m for the substrate pgh2.	SIGNOR-123594
Q9UQM7	Q9UBS5	1	phosphorylation	down-regulates	0.237	Nmda-dependent internalization of gabab receptors requires activation of ca2+/calmodulin-dependent protein kinase ii (camkii), which associates with gabab receptors in vivo and phosphorylates serine 867 (s867) in the intracellular c terminus of the gabab1 subunit.	SIGNOR-166846
P31749	Q8N9L9	1	phosphorylation	up-regulates quantity by stabilization	0.2	HSPA1A was found to associate with ACOT4. Furthermore, we found that phosphorylation of ACOT4 at S392 by AKT decreased the binding of ACOT4 to HSPA1A, resulting in ACOT4 accumulation. \|AKT phosphorylates ACOT4 at S392 and promotes ACOT4 stability	SIGNOR-271820
P12931	O14976	1	phosphorylation	up-regulates activity	0.274	GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149.	SIGNOR-263197

P49841

P17676

1

phosphorylation

up-regulates activity

0.457

We found that expression of srebf1a depended on GSK3β activity and that GSK3β activity was necessary for C/EBPβ phosphorylation at Thr188

SIGNOR-251644

Q96FA3

Q9NWZ3

0

phosphorylation

up-regulates activity

0.658

The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). Here, we show that Pellino is phosphorylated at multiple sites by IRAK1 and IRAK4 and that activation can be achieved by phosphorylating any one of several sites or a combination of other sites.

SIGNOR-276128

Q9HAU4

Q13873

1

ubiquitination

down-regulates

0.503

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps.

SIGNOR-193119

P28482

Q9UPT5

1

phosphorylation

up-regulates

0.331

Erk1/2 phosphorylation enhances the binding of exo70 to other exocyst components and promotes the assembly of the exocyst complex in response to epidermal growth factor (egf) signaling.

SIGNOR-197543

Q15669

P63000

1

relocalization

down-regulates activity

0.41

Therefore, RhoH functions as a Rac1 antagonist by inhibiting Rac1 translocation to the cell plasma membrane in the regulation of cell migration and F-actin assembly of HPCs

SIGNOR-259085

P07947

P25490

1

phosphorylation

down-regulates activity

0.2

YY1 phosphorylation is mediated by Src family kinases.

SIGNOR-276941

Q70Z35

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.609

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-260571

Q96A00

Q02156

0

phosphorylation

up-regulates activity

0.261

A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.

SIGNOR-249258

P23528

Q9HCK4

0

post transcriptional regulation

up-regulates quantity by expression

0.257

Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation.

SIGNOR-268378

Q9ULL1

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.323

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-260563

Q9Y261

O15111

0

phosphorylation

down-regulates

0.2

Here, we show that ikk_, an important downstream kinase of tnf_, interacts with and phosphorylates foxa2 at s107/s111, thereby suppressing foxa2 transactivation activity and leading to decreased numb expression

SIGNOR-195316

P51955

Q9BV73

1

phosphorylation

down-regulates

0.774

C-nap1 hyperphosphorylation triggers the loss of both oligomerization and, crucially, interaction with the core centriole proximal-end protein, cep135. All three of these sites were identified in our in vivo analysis but only two (s2234 and s2394) were identified as nek2 phosphorylation sites in vitro.

SIGNOR-204837

Q9Y572

Q13263

1

phosphorylation

down-regulates activity

0.2

These results indicate that TRIM28 phosphorylation at S473 is RIPK3-dependent and suggest that RIPK1/RIPK3 activation induces TRIM28 phosphorylation at S473, which may play an important role in the regulation of transcriptional activity.

SIGNOR-279107

Q02156

O60716

1

phosphorylation

down-regulates

0.2

We find that ctnnd1/p120ctn phosphorylation at serine 268 (p-s268) occurs in a strictly pkc_-dependent manner,serine/threonine phosphorylation of p120-ctn has been reported to affect the integrity of ajs [12], [24] and [25]. Xia et al. (2003) reported that several residues (ser122, ser252, ser268, ser288, thr310, ser312, ser873, and thr910) in p120ctn can be either phosphorylated or dephosphorylated upon pkc activation

SIGNOR-201600

P12318

P51451

0

phosphorylation

up-regulates activity

0.436

To identify the FcgammaRII-phosphorylating protein tyrosine kinase (PTK), we used the combination of an in vitro and an in vivo approach. In an in vitro assay using recombinant cytoplasmic tails of the different FcgammaRII isoforms as well as tyrosine exchange mutants, we show that each of the BCR-associated PTKs (Lyn, Blk, Fyn, and Syk) shows different phosphorylation patterns with regard to the different FcgammaR isoforms and point|Fyn and Blk definitely phosphorylate Y-282 in the ITAM of Fc_RIIa/c, whereas the non-ITAM tyrosine residue (Y-275) becomes phosphorylated by Syk, as the phosphorylation of double point mutants shows. In addi-tion to these tyrosine residues, Fyn, Blk, and Syk might phosphorylate the most C-terminal tyrosine residue (Y-298) because altering this tyrosine residue together with one of the tyrosine residues clearly shown to be phosphorylated by the respective PTK results in the abrogation of phosphorylation.

SIGNOR-249312

P60484

Q96KB5

0

phosphorylation

down-regulates activity

0.504

PTEN is phosphorylated by TOPK and is required for mitotic entry. In addition, reduced PTEN phosphorylation levels upon TOPK knockdown correlated with decreased Akt activation (Fig. 4e) suggesting that TOPK mediated phosphorylation may lead to PTEN inactivation. By using various PTEN mutants in a kinase assay we concluded that TOPK phosphorylates PTEN at S380 residue in vitro (Fig. 4c).

SIGNOR-271472

Q9P227

P63000

1

gtpase-activating protein

down-regulates activity

0.43

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-260480

P42574

Q13635

1

cleavage

down-regulates

0.321

Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain.

SIGNOR-199111

Q8WU17

Q12772

1

ubiquitination

down-regulates quantity

0.477

Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner

SIGNOR-271958

P68400

Q92538

1

phosphorylation

down-regulates quantity by destabilization

0.2

We show that, in mitosis, GBF1 is phosphorylated on Ser292 and Ser297 by casein kinase-2 allowing recognition by the F-box protein βTrCP. GBF1 interaction with βTrCP recruits GBF1 to the SCFβTrCP ubiquitin ligase complex, triggering its degradation.

SIGNOR-277398

P45985

Q02779

0

phosphorylation

up-regulates activity

0.445

MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase.

SIGNOR-278954

Q96L34

Q13470

1

phosphorylation

down-regulates activity

0.2

We also discover a MARK-mediated phosphorylation on TNK1 at S502 that promotes an interaction between TNK1 and 14-3-3, which sequesters TNK1 and inhibits its kinase activity.Phosphorylation of TNK1 at S502 within the proline rich domain is required for TNK1 binding to 14-3-3.MARKs mediate phosphorylation at S502 and 14-3-3 binding to TNK1, which restrains the movement of TNK1 into heavy membrane-associated clusters.

SIGNOR-273865

P17302

P05771

0

phosphorylation

down-regulates activity

0.388

Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.

SIGNOR-249049

P68400

Q93009

1

phosphorylation

up-regulates quantity by stabilization

0.372

We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. Phosphorylation stabilizes USP7S and thus contributes to Mdm2 stabilization and downregulation of p53.

SIGNOR-276530

Q9BYB0

O95886

0

relocalization

up-regulates activity

0.2

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

SIGNOR-264594

P30307

P24941

0

phosphorylation

up-regulates

0.754

The cyclin e/cdk2 complex phosphorylates cdc25c on ser(214), leading to its premature activation, which coincides with higher cyclin b/cdk1 and polo-like kinase 1 (plk1) activities in an s-phase-enriched population that result in faster mitotic entry.

SIGNOR-165872

P61586

P07737

1

null

up-regulates activity

0.569

We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.

SIGNOR-253109

Q9HCE7

O15198

1

ubiquitination

down-regulates

0.669

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps

SIGNOR-195669

Q9BV68

Q16595

1

ubiquitination

down-regulates quantity by destabilization

0.385

Depletion of RNF126 by specific small interfering RNA delays the degradation of frataxin precursor and increases its stability.|Here we report on the identification of really interesting new gene finger protein 126 (RNF126) as the E3 ligase that ubiquitinates frataxin.

SIGNOR-278663

P12931

P35916

1

phosphorylation

up-regulates

0.513

Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk.

SIGNOR-165035

P11362

P24752

1

phosphorylation

up-regulates activity

0.2

Treatment with the FGFR1 inhibitor TKI258 in FGFR1-expressing H1299 cells led to decreased Y407 phosphorylation of ACAT1 in the mitochondrial fraction, where both ACAT1 and a fraction of FGFR1 were detected|Inhibition of tetrameric ACAT1 by abolishing Y407 phosphorylation or AH treatment results in decreased ACAT1 activity,

SIGNOR-264423

P17612

O43164

1

phosphorylation

up-regulates activity

0.2

In vitro kinase assays demonstrated that purified PKAc directly phosphorylates wild-type Flag–praja2, but not the Flag–praja2S342A,T389A mutant, confirming these residues as the main PKA phosphorylation sites (Fig. 5h).

SIGNOR-276316

Q5UIP0

Q96T88

0

polyubiquitination

down-regulates activity

0.2

UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation.

SIGNOR-277193

O95251

P06493

0

phosphorylation

up-regulates

0.355

Here, we show that the interaction between plk1 and hbo1 is mitosis-specific and that plk1 phosphorylates hbo1 on ser-57 in vitro and in vivo. During mitosis, cdk1 phosphorylates hbo1 on thr-85/88, creating a docking site for plk1 to be recruited. Significantly, the overexpression of hbo1 mutated at the plk1 phosphorylation site (s57a) leads to cell-cycle arrest in the g1/s phase, inhibition of chromatin loading of the minichromosome maintenance (mcm) complex, and a reduced dna replication rate.

SIGNOR-160747

Q14934

Q9Y625

1

transcriptional regulation

up-regulates quantity by expression

0.2

NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.

SIGNOR-264023

Q969V5

P31749

1

ubiquitination

down-regulates quantity by destabilization

0.475

The results of the functional studies suggest that the degradation of Akt by MULAN suppresses cell proliferation and viability.

SIGNOR-252437

P06241

O43561

1

phosphorylation

up-regulates

0.749

Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk.

SIGNOR-149174

P20393

Q9UBK2

0

transcriptional regulation

up-regulates quantity by expression

0.522

Transcriptional coactivator PGC-1α integrates the mammalian clock and energy metabolism. Here we show that PGC-1alpha (Ppargc1a), a transcriptional coactivator that regulates energy metabolism, is rhythmically expressed in the liver and skeletal muscle of mice. PGC-1alpha stimulates the expression of clock genes, notably Bmal1 (Arntl) and Rev-erbalpha (Nr1d1), through coactivation of the ROR family of orphan nuclear receptors. Chromatin immunoprecipitation (ChIP) assays in HepG2 cells indicate that PGC-1α is present near RORE on the proximal Bmal1 promoter.These results indicate that PGC-1α activates Bmal1 transcription by altering the local chromatin environment from a repressive to an active state.

SIGNOR-268030

P11802

P84022

1

phosphorylation

down-regulates activity

0.757

We have mapped CDK4 and CDK2 phosphorylation sites to Thr 8, Thr 178 and Ser 212 in Smad3. Mutation of the CDK phosphorylation sites increases Smad3 transcriptional activity

SIGNOR-232142

P51812

P25963

1

phosphorylation

down-regulates quantity by destabilization

0.368

Here, we show that RSK2 is activated by treatment with tumor necrosis factor-alpha (TNF-alpha) and directly phosphorylates IkappaBalpha at Ser 32, leading to IkappaBalpha degradation.

SIGNOR-279108

P29353

P43405

0

phosphorylation

up-regulates

0.762

The syk-family kinases (syk and zap-70) were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site on sch1 (iso2).

SIGNOR-59635

O94782

Q9BXW9

1

deubiquitination

down-regulates activity

0.761

The deubiquitinating enzyme USP1 controls the cellular levels of the DNA damage response protein Ub-FANCD2|The level of monoubiquitinated FANCD2 protein increases in response to various types of DNA damage in mammalian cells

SIGNOR-263273

Q14807

P06493

0

phosphorylation

up-regulates activity

0.344

Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes

SIGNOR-100964

P17252

P52565

1

phosphorylation

down-regulates activity

0.449

PKCalpha phosphorylates RhoGDIalpha at Ser34 to reduce its affinity for RhoA (but not for Rac1 or Cdc42) .

SIGNOR-279097

Q9UPT9

P06493

0

phosphorylation

up-regulates activity

0.47

On the other hand, CDK1 enhances USP22 activity to stabilize CCNB1 during the G2/M phase.|Phosphorylation of USP22 by CDK1 enhances its activity in deubiquitinating CCNB1.

SIGNOR-278241

Q9H2K2

Q9H2G9

1

ADP-ribosylation

down-regulates quantity by destabilization

0.2

Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.

SIGNOR-263384

Q5FBB7

P06493

0

phosphorylation

up-regulates activity

0.2

The complex between shugoshin and protein phosphatase 2A (Sgo1-PP2A) localizes to centromeres in mitosis, binds to cohesin in a reaction requiring Cdk-dependent phosphorylation of Sgo1, dephosphorylates cohesin-bound sororin, and protects a centromeric pool of cohesin from mitotic kinases and the cohesin inhibitor Wapl.

SIGNOR-265263

P17612

P50549

1

phosphorylation

up-regulates activity

0.292

The camp-dependent protein kinase a (pka) phosphorylates er81 on ser(191)/ser(216)ser(191) and ser(216), were identified, whose mutation to alanine reduces er81 activity upon erk-mapk stimulation.

SIGNOR-92447

P24941

P18858

1

phosphorylation

up-regulates activity

0.457

We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner.

SIGNOR-103254

Q9Y666

Q9BYP7

0

phosphorylation

down-regulates activity

0.451

We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs

SIGNOR-264630

P04083

P05129

0

phosphorylation

up-regulates

0.2

The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].The phosphorylation of serine 27 is essential for annexin a1 membrane localization.

SIGNOR-202788

Q96GX5

P06493

0

phosphorylation

up-regulates activity

0.513

We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop

SIGNOR-249653

Q9NXA8

P34897

1

post translational modification

down-regulates activity

0.235

Mitochondrial serine hydroxymethyl transferase (SHMT2) is a rate-limiting enzyme that catalyzes the catabolism of serine and drives the proliferation of osteosarcoma cells and colon cancer cells. SIRT5 directly mediates the desuccinylation of Lysine 280 on SHMT2. Therefore, SIRT5 is a candidate target to inhibit serine catabolism

SIGNOR-267644

P49841

P13807

1

phosphorylation

down-regulates activity

0.686

Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-.

SIGNOR-253007

Q15208

Q9BX46

1

phosphorylation

up-regulates activity

0.355

Phosphorylation of Rbm24 by Stk38 is crucial for the maintenance of cardiac sarcomeric gene expression in cardiac cells.|These results indicated that Stk38 increases Rbm24 protein stability probably by interfering with the ubiquitin-proteasome protein degradation pathway.

SIGNOR-278291

O14595

P84022

1

dephosphorylation

up-regulates activity

0.424

Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|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-248293

Q8N2Q7

P35398

0

transcriptional regulation

up-regulates quantity by expression

0.2

Some genes which are directly regulated by RORA such as NLGN1 and NTRK2 have been shown to be associated with increased susceptibility to ASD (Correia et al. 2010; Ylisaukko-oja et al. 2005).

SIGNOR-265136

P01215

Q9UBR4

0

transcriptional regulation

up-regulates quantity by expression

0.387

Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). P-Lim binds to CBP in TRH-dependent manner on this site and that these proteins synergistically activate the human α-GSU promoter during TRH stimulation.

SIGNOR-267207

Q9NZC7

P12931

0

phosphorylation

up-regulates

0.48

The tyrosine kinase, src, phosphorylates wwox at tyrosine 33 in the first ww domain and enhances its binding to p73.

SIGNOR-123819

P11388

P05129

0

phosphorylation

up-regulates activity

0.359

Here, we have shown that the enzymatic activity of topoisomerase II alpha protein purified from HeLa cell nuclei was strongly enhanced following phosphorylation by protein kinase C. | Site-directed mutagenesis studies indicated that phosphorylation of serine 29 generated both of these phosphopeptides.

SIGNOR-249196

O43597

P46934

0

polyubiquitination

down-regulates quantity by destabilization

0.39

Endogenous and overexpressed Nedd4 polyubiquitinate Spry2 via Lys(48) on ubiquitin and decrease its stability.

SIGNOR-271425

Q00536

P10644

1

phosphorylation

up-regulates activity

0.272

PCTK1 regulates spindle orientation in a kinase-dependent manner. Phosphoproteomic analysis together with an RNA interference screen revealed that PCTK1 regulates spindle orientation through phosphorylation of Ser83 on KAP0, a regulatory subunit of protein kinase A (PKA)

SIGNOR-273018

P27361

P36956

1

phosphorylation

up-regulates activity

0.443

Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo.

SIGNOR-80096

P17252

Q14315

1

phosphorylation

up-regulates quantity by stabilization

0.338

We identified the extended basophilic phosphosite motif RxRxxp[S/T]xxp[S/T] in various proteins including filamin-C (FLNc). Importantly, this extended motif, located in a unique insert in Ig-like domain 20 of FLNc, is doubly phosphorylated. The protein kinases responsible for this dual-site phosphorylation are Akt and PKCα. Proximity proteomics and interaction analysis identified filamin A-interacting protein 1 (FILIP1) as direct FLNc binding partner. FILIP1 binding induces filamin degradation, thereby negatively regulating its function. Here, dual-site phosphorylation of FLNc not only reduces FILIP1 binding, providing a mechanism to shield FLNc from FILIP1-mediated degradation, but also enables fast dynamics of FLNc necessary for its function as signaling adaptor in cross-striated muscle cells. In vitro kinase assays combined with LC-MS confirmed hFLNc-S2233 as a substrate of Akt, whereas PKCα preferentially targeted S2236.

SIGNOR-262617

P01106

Q02127

1

transcriptional regulation

up-regulates quantity by expression

0.346

PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria.

SIGNOR-267382

P49593

O95835

1

dephosphorylation

down-regulates activity

0.2

POPX2 is capable of dephosphorylating LATS1 at Thr1079 (Figure xref ), which is a residue critical for LATS1 activity.|POPX2 might negatively regulate the activities of MST1 and LATS1 through dephosphorylation.|We found that POPX2 could dephosphorylate LATS1 on Threonine-1079, leading to inactivation of LATS1 kinase.

SIGNOR-276989

P54646

Q8N122

1

phosphorylation

down-regulates activity

0.693

These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK

SIGNOR-163463

Q92734

Q6AZZ1

0

ubiquitination

down-regulates quantity by destabilization

0.451

Our results suggest that TRIM68 degrades TFG at a point of pathway convergence in which downstream events lead to the activation of both NF-kappaB and IRF3.|TRIM68 polyubiquitinates TFG leading to its degradation via its RING domain which also plays an important role in TRIM68 negative inhibition on IFN-beta production.

SIGNOR-278737

P68400

P49418

1

phosphorylation

down-regulates

0.2

Amphiphysins interact directly with clathrin and have a function in clathrin-mediated synaptic vesicle recycling and clathrin-mediated endocytosis. The n-terminal domain of clathrin bound to unphosphorylated amphiphysin-1, but not to the phosphorylated protein. The assumption that casein kinase 2 phosphorylates amphiphysin-1 at t350 and t387 was corroborated by experiments showing that: casein kinase 2 phosphorylated these residues directly in vitro,. upon activation by nerve growth factor, casein kinase 2 phosphorylates amphiphysin-1 and thereby regulates the endocytosis of clathrin-coated vesicles via the interaction between clathrin and amphiphysin.

SIGNOR-149314

Q92667

O43255

0

polyubiquitination

down-regulates quantity by destabilization

0.507

Seven In-Absentia Homolog 2 (Siah2), an E3-ubiquitin ligase whose expression is induced in hypoxic conditions, formed a complex and degraded AKAP121.

SIGNOR-272641

O60674

O43583

0

transcriptional regulation

up-regulates quantity by expression

0.2

DENR directly regulates JAK2 expression.

SIGNOR-269675

P06241

Q05397

1

phosphorylation

up-regulates activity

0.602

Because Fyn deletion prevented FAK phosphorylation at tyrosine residues 397 and 576 (XREF_FIG), we generated a phosphorylation mimicking mutant of FAK to test whether restoring FAK phosphorylation in the fyn -/- mouse lung could restore lung vascular permeability responses to PAR1 agonist to the level seen in WT mice.|Our findings that interaction of activated FAK with p120-catenins subsequent to Fyn activation of FAK facilitates reannealing of AJ leading to reestablishment of the basal endothelial barrier suggest that the Fyn-FAK pathway plays a critical role in restoring endothelial barrier function.

SIGNOR-278441

Q6P589

O43318

0

phosphorylation

down-regulates quantity by destabilization

0.2

TAK1 phosphorylated the Ser3 in the noncanonical degron motif of TIPE2 to trigger its interaction with β-TrCP for subsequent ubiquitination and degradation.

SIGNOR-273668

Q9H1K0

Q16539

0

phosphorylation

up-regulates

0.2

We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes

SIGNOR-140143

O15550

Q05516

1

transcriptional regulation

up-regulates quantity by expression

0.311

UTX catalytic activity has been reported to upregulate expression of the master transcription factor PLZF and to modulate superenhancer accessibility in invariant natural killer T cells.

SIGNOR-260038

P36956

P28482

0

phosphorylation

up-regulates

0.406

Map kinases erk1/2 phosphorylate sterol regulatory element-binding protein (srebp)-1a at serine 117 in vitro. mutation of serine 117 to alanine abolished erk2-mediated phosphorylation in vitro and the map kinase-related transcriptional activation of srebp-1a by insulin and platelet-derived growth factor in vivo.

SIGNOR-80092

P35568

Q13526

0

isomerization

up-regulates activity

0.2

In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells|Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation|Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events

SIGNOR-265757

P00533

P35637

1

phosphorylation

up-regulates activity

0.259

Thus, EGFR appears to mediate FUS nuclear translocation by phosphorylating Y6 and Y296 in FUS.

SIGNOR-279168

P24941

O14757

1

phosphorylation

up-regulates

0.554

Chk1 itself is also subject to cdk-mediated phosphorylation at serines 286 and 301 (s286 and 301). We show that chk1 s301 phosphorylation increases as cells progress through s and g2 and that both cdk1 and cdk2 are likely to contribute to this modification in vivo. We also find that substitution of s286 and s301 with non-phosphorylatable alanine residues strongly attenuates dna damage-induced chk1 activation and g2 checkpoint proficiency

SIGNOR-175083

Q53EZ4

P06493

0

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

P23443

O60825

1

phosphorylation

up-regulates activity

0.247

Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.

SIGNOR-49371

O95631

P60709

1

post transcriptional regulation

up-regulates quantity

0.28

Netrin-1 induces β-actin translation driven by its 3’UTR.

SIGNOR-268161

P06493

Q14807

1

phosphorylation

up-regulates activity

0.344

Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes

SIGNOR-100964

P12931

P40763

1

phosphorylation

up-regulates activity

0.789

In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants.

SIGNOR-247341

P15311

P41743

0

phosphorylation

up-regulates

0.342

Pkciota phosphorylated ezrin on t567 in vitro, and in sf9 cells that do not activate human ezrin. we conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by pkciota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation.

SIGNOR-160855

O43189

P31269

1

transcriptional regulation

down-regulates quantity by repression

0.286

These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.

SIGNOR-260069

P61586

Q13017

0

gtpase-activating protein

down-regulates activity

0.828

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-260461

Q12774

P12931

0

phosphorylation

up-regulates activity

0.465

Arhgef5 was tyrosine-phosphorylated by Src and bound to Src to positively regulate its activity.|Using an inducible system for Src activation, we found that Src induced podosome formation depends upon the Src SH3 domain, and identified Arhgef5 as a Src SH3 binding protein.

SIGNOR-279571

P23511

P24941

0

phosphorylation

up-regulates activity

0.439

Cdk2 phosphorylates two serine residues near the DNA-binding domain of the YA subunit of NF-Y. Cyclin A-cdk2 appears to associate with NF-Y both in vitro and in vivo. Furthermore, YA protein is phosphorylated in parallel with a cell cycle-dependent activation of cdk2 kinase and cyclin A expression. YA phosphorylation is unnecessary for heterotrimer formation with the YB-YC dimer. However, NF-Y containing a phosphorylation-deficient mutant form of YA, YA-aa, has its DNA binding activity impaired. \ To examine whether cdk2 phosphorylates the two serine residues at positions 320 and 326 in YA, we replaced either or both with alanine by site-directed mutagenesis. In a kinase assay using purified GST fusion proteins in vitro, cdk2 phosphorylated the wild type and both of the single-mutant proteins (YA-as and -sa), but not the double-mutant protein (YA-aa)

SIGNOR-250742

Q15139

O43597

1

phosphorylation

down-regulates quantity by destabilization

0.324

PKD negatively affects the stability of Spry2 WT but not of mutant Spry2 S112A.|Using in vitro and in vivo assays, we show that protein kinase D (PKD) phosphorylates Spry2 at serine 112 and interacts in vivo with the C-terminal half of this protein.

SIGNOR-280091

P04637

Q13362

0

dephosphorylation

up-regulates quantity by stabilization

0.611

Ablation of the B56gamma protein by RNAi, which abolishes the Thr55 dephosphorylation in response to DNA damage, reduces p53 stabilization, Bax expression and cell apoptosis. To investigate the molecular mechanisms, we have shown that the endogenous B56gamma protein level and association with p53 increase after DNA damage. Finally, we demonstrate that Thr55 dephosphorylation is required for B56gamma3-mediated inhibition of cell proliferation and cell transformation.

SIGNOR-268154

Q8IWA4

Q9NX47

0

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH5, a mitochondrial E3 ubiquitin ligase, has been identified as a molecule that binds mitochondrial fission 1 protein (hFis1), dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), key proteins in the control of mitochondrial fission and fusion.|Notably, a significant increase in Mfn1 level, but not Mfn2, Drp1 or hFis1 levels, was observed in MARCH5-depleted cells, indicating that Mfn1 is a major ubiquitylation substrate.

SIGNOR-274133

P15172

Q96EB6

0

null

down-regulates activity

0.621

Sir2 forms a complex with the acetyltransferase PCAF and MyoD and, when overexpressed, retards muscle differentiation

SIGNOR-241963

Q9NP71

P25445

1

transcriptional regulation

up-regulates quantity by expression

0.2

The present study provides evidence for a direct and dominant role of ChREBP in the glucose regulation of two key liver lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS)

SIGNOR-267947

Q14980

Q9UHD2

0

phosphorylation

up-regulates activity

0.2

Our studies now reveal TBK1 as another kinase that phosphorylates NuMA and that is required for its association with dynein and for localization of NuMA to the centrosomes in mitotic cells.

SIGNOR-278432

P62136

P55211

1

dephosphorylation

up-regulates

0.2

Pp1 dephosphorylated thr125 site of caspase-9 and activated caspase-9 to mediate il-2 deprivation-induced apoptosis.

SIGNOR-195992

P68400

Q15185

1

phosphorylation

up-regulates

0.354

Several lines of evidence suggest that a cpges-activating protein kinase is ck-ii (casein kinase ii). Recombinant cpges was phosphorylated directly by and associated with ck-ii in vitro, resulting in marked reduction of the k m for the substrate pgh2.

SIGNOR-123594

Q9UQM7

Q9UBS5

1

phosphorylation

down-regulates

0.237

Nmda-dependent internalization of gabab receptors requires activation of ca2+/calmodulin-dependent protein kinase ii (camkii), which associates with gabab receptors in vivo and phosphorylates serine 867 (s867) in the intracellular c terminus of the gabab1 subunit.

SIGNOR-166846

P31749

Q8N9L9

1

phosphorylation

up-regulates quantity by stabilization

0.2

HSPA1A was found to associate with ACOT4. Furthermore, we found that phosphorylation of ACOT4 at S392 by AKT decreased the binding of ACOT4 to HSPA1A, resulting in ACOT4 accumulation. |AKT phosphorylates ACOT4 at S392 and promotes ACOT4 stability

SIGNOR-271820

P12931

O14976

1

phosphorylation

up-regulates activity

0.274

GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149.

SIGNOR-263197