GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P48730	P43629	1	phosphorylation	up-regulates	0.2	In this study, we have mapped constitutive phosphorylation sites for casein kinases, protein kinase c, and an unidentified kinase on the kir cytoplasmic domain. Three of these phosphorylation sites are highly conserved in human inhibitory kir. Functional studies of the wild-type receptor and serine/threonine mutants indicated that phosphorylation of ser(394) by protein kinase c slightly suppresses kir3dl1 inhibitory function, and reduces receptor internalization and turnover.	SIGNOR-158125
Q96RD7	P12931	0	phosphorylation	up-regulates activity	0.379	We recently identified amino acids 198-200 (YLK) on the PANX1 intracellular loop that are critical for α1-AR-mediated vasoconstriction and PANX1 channel function. We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198	SIGNOR-277817
P23443	Q92519	1	phosphorylation	down-regulates quantity by destabilization	0.356	Furthermore, Smurf1-mediated ubiquitination required phosphorylation of TRIB2 by p70 S6 kinase (p70S6K) via another domain (amino acids 69-85) that is also essential for correct TRIB2 subcellular localization. Mutation of Ser-83 diminished p70S6K-induced phosphorylation of TRIB2.	SIGNOR-275433
O00444	Q9HC77	1	phosphorylation	up-regulates	0.799	Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap	SIGNOR-166007
P38936	P15172	0	transcriptional regulation	up-regulates	0.4	P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells	SIGNOR-251574
P51449	Q16552	1	transcriptional regulation	up-regulates	0.54	We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells	SIGNOR-255029
P50750	P24928	1	phosphorylation	up-regulates	0.777	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203528
Q00534	P19484	1	phosphorylation	up-regulates activity	0.2	CDK4 and CDK6 phosphorylate TFEB and TFE3.	SIGNOR-279454
P02452	Q8NBJ5	0	glycosylation	up-regulates activity	0.41	Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261152
Q9H9Z2	P27361	0	phosphorylation	down-regulates activity	0.277	Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser-200.	SIGNOR-277337
P35247	P53567	0	transcriptional regulation	up-regulates quantity by expression	0.2	Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells\| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.	SIGNOR-254058
O75807	P19484	0	transcriptional regulation	up-regulates quantity by expression	0.2	We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2α.	SIGNOR-276789
P50750	P01106	1	phosphorylation	down-regulates activity	0.54	CDK9 promotes phosphorylation of MYC on Ser 62 .	SIGNOR-279024
Q9Y6K1	P42229	0	transcriptional regulation	up-regulates quantity	0.326	… these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells	SIGNOR-255631
P05026	Q96D59	0	polyubiquitination	down-regulates quantity by destabilization	0.2	RNF183 promotes the degradation of Na, K-ATPas. We confirmed that RNF183 interacted with both α1 and β1 subunits; however, we found that RNF183 ubiquitinated only the β1 subunit, not the α1 subunit.	SIGNOR-272218
P20749	O14920	0	phosphorylation	up-regulates activity	0.365	Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.	SIGNOR-277364
Q05209	P00519	1	dephosphorylation	down-regulates activity	0.439	Several experiments suggest that the pest-type ptps negatively regulate c-abl activity: c-abl was hyperphosphorylated in ptp-pest-deficient cells dephosphorylation of c-abl by pest-type ptp represents a novel mechanism by which c-abl activity is regulated.	SIGNOR-235568
Q14012	P29475	1	phosphorylation	down-regulates activity	0.331	It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.	SIGNOR-250614
Q86U44	Q9UHD2	0	phosphorylation	up-regulates activity	0.2	TBK1 also promotes METTL3 activation and m 6 A modification to stabilize IRF3 mRNA .\|We here find TBK1, a key kinase of antiviral pathways, phosphorylates the core m 6 A methyltransferase METTL3 at serine 67.	SIGNOR-279299
Q9GZV5	P62136	0	dephosphorylation	up-regulates activity	0.542	PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase.	SIGNOR-277116
P00519	Q96PH1	1	phosphorylation	up-regulates activity	0.303	As shown in Fig. xref and c, c-Abl-phosphorylated NOX5 was mostly inhibited when c-Abl plasmid co-transfected with NOX5 Y476/Y478F mutant, then the NOX5 Y487F mutant, but not with NOX5 Y519F mutant.\|Collectively, these results indicate that Pyk2 may act as a scaffolding protein for c-Abl stimulation of NOX5 activity in Pyk2 and NOX5 complex, and c-Abl-enhanced NOX5 activity is mainly dependent on phosphorylation of NOX5 Tyr 476/478 sites.	SIGNOR-280170
P29474	Q9Y478	0	phosphorylation	up-regulates	0.2	Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.	SIGNOR-112367
Q9NYY3	P06748	1	phosphorylation	up-regulates	0.536	Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.	SIGNOR-125720
Q96PU5	P35499	1	ubiquitination	down-regulates quantity by destabilization	0.279	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253460
P63096	P00533	0	phosphorylation	up-regulates activity	0.464	RTKs directly phosphorylate Gαi on Y154, 155, and Y320.	SIGNOR-277227
P04637	Q8NEZ5	0	ubiquitination	down-regulates quantity by destabilization	0.338	We demonstrate here that SCFFbxo22-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCFFbxo22 ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. \|SCFFbxo22 forms a ternary complex with p53 and KDM4A that targets methylated p53 for degradation.	SIGNOR-273448
Q86TI0	Q13131	0	phosphorylation	down-regulates	0.425	In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar	SIGNOR-159048
P03372	Q96FW1	0	deubiquitination	down-regulates activity	0.546	OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.\|We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells.	SIGNOR-276529
O75382	Q5VSY0	1	polyubiquitination	down-regulates quantity by destabilization	0.248	Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites.	SIGNOR-271959
Q9UNH5	P06493	0	phosphorylation	up-regulates activity	0.54	We found that Cdc14A is phosphorylated on Ser411, Ser453 and Ser549 by Cdk1 early in mitosis and becomes dephosphorylated during late mitotic stages.	SIGNOR-278264
Q96HS1	Q99683	1	dephosphorylation	up-regulates activity	0.437	PGAM5 Is a Protein Ser/Thr Phosphatase That Activates ASK1. PGAM5 Dephosphorylates ASK1. This dephosphorylation unleashes phosphorylation ofThr-838 in the kinase domain, with activation of ASK1.	SIGNOR-277984
Q6UB99	P17677	1	transcriptional regulation	up-regulates quantity by expression	0.2	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.	SIGNOR-266736
P06213	P0DP23	1	phosphorylation	down-regulates	0.403	The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-24782
P55036	O60260	0	polyubiquitination	down-regulates quantity by destabilization	0.2	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s.	SIGNOR-272749
Q7RTT9	P19544	0	transcriptional regulation	up-regulates quantity by expression	0.274	ENT4 is transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses.	SIGNOR-268985
O00308	P49281	1	ubiquitination	down-regulates quantity	0.299	Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2\|This promotes DMT1 ubiquitination and degradation by WWP2.	SIGNOR-268852
O95747	P55011	1	phosphorylation	up-regulates	0.524	The secretory na-k-cl cotransporter nkcc1 is activated by secretagogues through a phosphorylation-dependent mechanism. three phosphoacceptor sites were identified in the n-terminal domain of the protein (at thr184, thr189, and thr202) none of these residues occurs in the context of strong consensus sites for known ser/thr kinases.	SIGNOR-90927
P11413	Q99558	0	phosphorylation	up-regulates activity	0.2	Mass spectrometry identified four serine residues of G6PD phosphorylated by NIK (Extended Data Fig. 8f). All of these serines, except S278, are conserved between human and mouse G6PD proteins. In transfected cells, NIK stimulated G6PD activity, which was not affected by S8A or S486A mutation but abolished by S40A mutation (Extended Data Fig. 8g).	SIGNOR-277545
P25098	P30411	1	phosphorylation	down-regulates activity	0.2	Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251445
O95644	P05231	1	transcriptional regulation	up-regulates quantity by expression	0.415	The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. \|Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.	SIGNOR-251730
P24666	P31751	1	dephosphorylation	down-regulates activity	0.2	Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.\|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3	SIGNOR-248456
P42345	P00519	0	phosphorylation	down-regulates	0.453	Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k).	SIGNOR-76562
P35247	P49715	0	transcriptional regulation	up-regulates quantity by expression	0.259	Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells\| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.	SIGNOR-254042
O00327	P51449	0	transcriptional regulation	up-regulates quantity by expression	0.502	As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression.	SIGNOR-268004
Q96FI4	Q7Z6Z7	0	ubiquitination	down-regulates quantity by destabilization	0.2	Mule and TRIM26 ubiquitylate NEIL1 in vitro within C-terminal lysine residues.	SIGNOR-278695
O00141	P14672	1	phosphorylation	up-regulates activity	0.312	We evaluated the putative role of sgk1 in the modulation of glut4. Coexpression of the kinase along with glut4 in xenopus oocytes stimulated glucose transport. The enhanced glut4 activity was paralleled by increased transporter abundance in the plasma membrane. Disruption of the sgk1 phosphorylation site on glut4 ((s274a)glut4) abrogated the stimulating effect of sgk1. In summary, sgk1 promotes glucose transporter membrane abundance via glut4 phosphorylation at ser274.	SIGNOR-236653
P14598	O60381	0	transcriptional regulation	down-regulates quantity by repression	0.265	Together, these results indicate that HBP1 may contribute to the regulation of NADPH oxidase-dependent superoxide production through transcriptional repression of the p47phox gene.	SIGNOR-261614
P28069	P01222	1	transcriptional regulation	up-regulates quantity by expression	0.438	CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-β promoter. The human TSH-β promoter contains three well defined Pit-1 DNA-binding sites.	SIGNOR-267205
Q9NQC7	O14920	0	phosphorylation	down-regulates activity	0.548	Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204716
Q99558	P50281	1	phosphorylation	up-regulates activity	0.2	A post-transcriptional process is indicated because we observed that NIK increases MT1-MMP phosphorylation and activity, but does not affect MT1-MMP mRNA expression (XREF_FIG and XREF_FIG).\|NIK increases MT1-MMP pseudopodial localization and enzymatic activity.	SIGNOR-279631
P06241	Q15700	1	phosphorylation	up-regulates activity	0.367	Recombinant PSD-93 was phosphorylated by Fyn in vitro, and Tyr-384 was identified as a major phosphorylation site. In COS7 cells, exogenously expressed PSD-93 was phosphorylated, dependent on its membrane localization. In addition, tyrosine-phosphorylated PSD-93 was able to bind to Csk, a negative regulator of Src family kinases, in vitro as well as in a brain lysate.	SIGNOR-262874
Q02750	Q9Y2U5	0	phosphorylation	up-regulates	0.414	Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation	SIGNOR-107692
P46734	Q5S007	0	phosphorylation	up-regulates activity	0.393	LRRK2 phosphorylates MKK3 and MKK7 in vitro but has a relatively minor effect on MKK6 phosphorylation.	SIGNOR-279057
P27361	Q07889	1	phosphorylation	down-regulates	0.636	For example, inactivation of sos through phosphorylation by the downstream mapk	SIGNOR-26338
O43511	Q99942	0	ubiquitination	down-regulates quantity by destabilization	0.2	E3 ubiquitin ligase Rma1 is involved in Pendrin degradation	SIGNOR-271497
O14757	Q86UE8	1	phosphorylation	down-regulates activity	0.269	Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b).	SIGNOR-262740
Q9Y618	Q9UQM7	0	phosphorylation	down-regulates	0.2	We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation.	SIGNOR-191773
P45983	Q13043	1	phosphorylation	up-regulates	0.268	C-jun n-terminal kinase enhances mst1-mediated pro-apoptotic signaling through phosphorylation at serine 82.	SIGNOR-162327
P61586	Q8N103	0	gtpase-activating protein	down-regulates activity	0.447	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-260523
Q9UQM7	Q96PM5	1	phosphorylation	down-regulates	0.296	Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53	SIGNOR-156064
P35222	Q00535	0	phosphorylation	up-regulates activity	0.371	By combining multiple network relations with PTM proteoform specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity.\|CDK5 phosphorylates beta-catenin on Ser 191 and Ser 246 (PR :000037229)	SIGNOR-279516
Q9NS23	O14965	0	phosphorylation	down-regulates	0.448	Aurora-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest.	SIGNOR-155815
Q13064	P11940	1	ubiquitination	down-regulates activity	0.2	MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA\|Altogether, it is thus clear that the ubiquitination of PABPC1 or PABPC4 by MKRN3 negatively regulates the formation of translation initiation complex (TIC), attenuates their binding to poly (A)-tail contained mRNAs, and leads to the shortened poly (A) tail-length of GNRH1 mRNA.	SIGNOR-278764
P52333	Q96LC7	1	phosphorylation	up-regulates	0.2	These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling	SIGNOR-112479
O14746	Q92630	0	phosphorylation	down-regulates activity	0.444	Dyrk2 phosphorylates TERT protein, a catalytic subunit of telomerase.\|In this study, we found that dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (Dyrk2) negatively regulates telomerase activity.	SIGNOR-279611
Q9BXW9	O14757	0	phosphorylation	up-regulates activity	0.585	In vitro and in vivo experiments show that phosphorylation of s331 is mediated by chk1, the s-phase checkpoint kinase implicated in the fanconi anemia dna repair pathway. phosphorylation at this site is dependent on chk1, signifying the importance of the s-phase checkpoint in the activation of fanconi anemia pathway.	SIGNOR-107042
P15311	P07332	1	relocalization	up-regulates	0.395	The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin.	SIGNOR-159496
Q15555	Q96GD4	0	phosphorylation	up-regulates activity	0.537	Together, these data indicate that Aurora B and CDK1 phosphorylate EB2 at distinct sites and maintain the hyperphosphorylation of EB2 and its binding affinity to MTs while SAC activity is sustained.	SIGNOR-279591
P25098	Q13371	1	phosphorylation	down-regulates activity	0.2	The phosphorylation of purified phosducin and PhLP by recombinant GRK2 proceeds rapidly and stoichiometrically (0.82 +/- 0.1 and 0.83 +/- 0.09 mol of P (i)/mol of protein, respectively).	SIGNOR-279178
P42345	P35568	1	phosphorylation	down-regulates activity	0.766	Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten	SIGNOR-106590
O15550	P41970	1	transcriptional regulation	down-regulates quantity by repression	0.2	Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase	SIGNOR-260037
P53350	O15392	1	phosphorylation	up-regulates	0.583	Thus, we conclude that plk1-mediated phosphorylation of sur at ser20 is critical for accurate chromosome segregation\|SUR (survivin)	SIGNOR-170460
P10071	Q9Y297	0	ubiquitination	down-regulates quantity by destabilization	0.671	Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage.	SIGNOR-145116
P52564	O43318	0	phosphorylation	up-regulates activity	0.764	The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination	SIGNOR-109497
P16144	P17612	0	phosphorylation	down-regulates	0.2	Additionally, we show that s1360 and s1364 of beta4 are the only residues phosphorylated by pkc and pka in cells, respectivelywe have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (s1356, s1360, and s1364), previously implicated in hd regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated	SIGNOR-156873
P37231	P46934	0	ubiquitination	up-regulates activity	0.386	First, NEDD4 interacts with and ubiquitinates PPARgamma.\|NEDD4 increases PPARgamma stability through the inhibition of its proteasomal degradation.	SIGNOR-278540
P48382	P01903	1	transcriptional regulation	up-regulates quantity by expression	0.503	In this report, we correlate the loss of IFN-γ induction of MHC class II genes with the identification of a molecular defect in an essential regulator, namely RFX5. \| We have further confirmed this finding by showing that new RFX5 leucine mutants created in vitro are incapable of transactivating a class II promoter, suggesting the identification of residues essential for RFX activity.	SIGNOR-266228
P51955	O14777	1	phosphorylation	up-regulates	0.592	Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo.	SIGNOR-94322
Q9NR50	P05198	1	guanine nucleotide exchange factor	up-regulates activity	0.833	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269126
P31749	P10586	0	dephosphorylation	down-regulates	0.342	Knock-down of lar by the l3 sirna probe markedly inhibited the insulin-stimulated increase in the phosphorylation of protein kinase b (pkb, also called akt) on serine 473 by >90%	SIGNOR-137246
P33981	Q02224	1	phosphorylation	up-regulates activity	0.43	Strikingly, phosphorylation of Cenp-E C tail by wild-type (WT) MPS1 or CDK1-cyclin B completely reverses its inhibitory effect toward Cenp-E motor ATPase in solution.	SIGNOR-278999
P01137	P62736	1	transcriptional regulation	up-regulates quantity by expression	0.419	A TGF-β1 response element that has a sequence different to that known for Smad binding has been identified in the α- SM actin promoter and seems to be essential for expression of α-SM actin in both SM cells 72 and myofibroblasts73 . How TGF-β1 activates expression of α-SM actin through this TGF-β1 control element is, as yet, unknown	SIGNOR-277681
Q96GD4	Q9NQG5	1	phosphorylation	up-regulates activity	0.2	Mechanistically, we revealed that CREPT/RPRD1B interacted with Aurora B to regulate the expression of Cyclin B1 in gastric cancer cells. Interestingly, Aurora B phosphorylates S145 in a well-conserved motif of CREPT/RPRD1B. We proposed that phosphorylation of CREPT/RPRD1B by Aurora B is required for promoting the transcription of Cyclin B1	SIGNOR-265499
Q96PX9	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.285	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-260565
P04626	Q96N67	1	phosphorylation	up-regulates	0.531	We show that the nrg1 receptor erbb2 directly binds and activates dock7 by phosphorylating tyr-1118. thus, dock7 functions as an intracellular substrate for erbb2 to promote schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of rho gtpase-gefs of the dock180 family.	SIGNOR-178348
P21860	Q96JA1	0	ubiquitination	down-regulates	0.434	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-139951
Q8ND76	Q13131	0	phosphorylation	up-regulates activity	0.2	Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. \|Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16	SIGNOR-273011
P06493	P18858	1	phosphorylation	up-regulates activity	0.364	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-103242
Q96GD4	Q15555	1	phosphorylation	up-regulates activity	0.537	Together, these data indicate that Aurora B and CDK1 phosphorylate EB2 at distinct sites and maintain the hyperphosphorylation of EB2 and its binding affinity to MTs while SAC activity is sustained.	SIGNOR-279591
P78347	O60674	0	phosphorylation	up-regulates activity	0.328	Jak2 activates tfii-i and regulates its interaction with extracellular signal-regulated kinase the interaction between tfii-i and erk, which is essential for its activity, can be regulated by jak2 through phosphorylation of tfii-i at tyrosine 248	SIGNOR-235313
P61224	O95398	0	guanine nucleotide exchange factor	up-regulates activity	0.718	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263957
P17661	Q96GD4	0	phosphorylation	down-regulates	0.546	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro.	SIGNOR-100107
Q96GD4	P10412	1	phosphorylation	up-regulates quantity by stabilization	0.2	we showed previously that phosphorylation of S27 in human histone H1.4 (H1.4S27-P), prevents binding of heterochromatin protein 1 (HP1) family members (officially known as chromobox protein homologs) to the neighboring dimethylated K26. Here, we present the first functional characterization of H1.4S27-P in vivo and in vitro. We show that H1.4S27 phosphorylation is cell-cycle-regulated and its levels peak on metaphase chromosomes. We identify further Aurora B as the kinase phosphorylating H1.4S27.	SIGNOR-262658
P49840	P12036	1	phosphorylation	down-regulates activity	0.254	Our results demonstrate that whereas GSK-3 alpha, GSK-3 beta, and cdk-5 will all phosphorylate NF-H, they generate different antibody reactivity profiles.	SIGNOR-279783
Q16827	P04626	1	dephosphorylation	down-regulates quantity by destabilization	0.403	In this study, our co-immunoprecipitation experiment along with the results derived from in vivo , cultured cells and clinical specimen confirm that PTPRO dephosphorylates ERBB2 at Y1248.\|PTPRO overexpression remarkably accelerated degradation of ERBB2 (XREF_FIG).	SIGNOR-276979
P07949	P27361	1	phosphorylation	up-regulates	0.433	We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).	SIGNOR-140298
Q05481	O75015	1	transcriptional regulation	down-regulates quantity by repression	0.2	Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription.	SIGNOR-266215
P31431	P17252	0	phosphorylation	up-regulates activity	0.732	The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant.	SIGNOR-249149
Q05D32	Q8N165	1	dephosphorylation	up-regulates quantity by stabilization	0.356	We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D).	SIGNOR-273773
Q08209	Q9NZJ5	0	phosphorylation	down-regulates activity	0.2	CN becomes phosphorylated by PERK, decreasing its activity.\|Finally, evidence is presented that PERK phosphorylates CN-A at low resting levels of Ca 2+.	SIGNOR-278933

P48730

P43629

1

phosphorylation

up-regulates

0.2

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

SIGNOR-158125

Q96RD7

P12931

0

phosphorylation

up-regulates activity

0.379

We recently identified amino acids 198-200 (YLK) on the PANX1 intracellular loop that are critical for α1-AR-mediated vasoconstriction and PANX1 channel function. We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198

SIGNOR-277817

P23443

Q92519

1

phosphorylation

down-regulates quantity by destabilization

0.356

Furthermore, Smurf1-mediated ubiquitination required phosphorylation of TRIB2 by p70 S6 kinase (p70S6K) via another domain (amino acids 69-85) that is also essential for correct TRIB2 subcellular localization. Mutation of Ser-83 diminished p70S6K-induced phosphorylation of TRIB2.

SIGNOR-275433

O00444

Q9HC77

1

phosphorylation

up-regulates

0.799

Plk2 phosphorylates the s589 and s595 residues of cpap in vitro and in vivo. This phosphorylation is critical for procentriole formation during the centrosome cycle. Plk4 also phosphorylates s595 of cpap

SIGNOR-166007

P38936

P15172

0

transcriptional regulation

up-regulates

0.4

P21 is regulated by MyoD and myogenin in normal muscle cells and the inactivation of these factors in RMS cells contributes to the silencing of p21 in RMS cells

SIGNOR-251574

P51449

Q16552

1

transcriptional regulation

up-regulates

0.54

We found that RORgt is required for the constitutive expression of IL-17 in intestinal lamina propria T cells and for the in vitro differentiation of Th17 cells from naive CD4+ T cells

SIGNOR-255029

P50750

P24928

1

phosphorylation

up-regulates

0.777

Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself

SIGNOR-203528

Q00534

P19484

1

phosphorylation

up-regulates activity

0.2

CDK4 and CDK6 phosphorylate TFEB and TFE3.

SIGNOR-279454

P02452

Q8NBJ5

0

glycosylation

up-regulates activity

0.41

Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.

SIGNOR-261152

Q9H9Z2

P27361

0

phosphorylation

down-regulates activity

0.277

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

SIGNOR-277337

P35247

P53567

0

transcriptional regulation

up-regulates quantity by expression

0.2

Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.

SIGNOR-254058

O75807

P19484

0

transcriptional regulation

up-regulates quantity by expression

0.2

We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2α.

SIGNOR-276789

P50750

P01106

1

phosphorylation

down-regulates activity

0.54

CDK9 promotes phosphorylation of MYC on Ser 62 .

SIGNOR-279024

Q9Y6K1

P42229

0

transcriptional regulation

up-regulates quantity

0.326

… these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells

SIGNOR-255631

P05026

Q96D59

0

polyubiquitination

down-regulates quantity by destabilization

0.2

RNF183 promotes the degradation of Na, K-ATPas. We confirmed that RNF183 interacted with both α1 and β1 subunits; however, we found that RNF183 ubiquitinated only the β1 subunit, not the α1 subunit.

SIGNOR-272218

P20749

O14920

0

phosphorylation

up-regulates activity

0.365

Here we show that Akt, Erk2, and IKK1/2 phosphorylate Bcl3. Phosphorylation of Ser33 by Akt induces switching of K48 ubiquitination to K63 ubiquitination and thus promotes nuclear localization and stabilization of Bcl3. Phosphorylation by Erk2 and IKK1/2 of Ser114 and Ser446 converts Bcl3 into a transcriptional coregulator by facilitating its recruitment to DNA.

SIGNOR-277364

Q05209

P00519

1

dephosphorylation

down-regulates activity

0.439

Several experiments suggest that the pest-type ptps negatively regulate c-abl activity: c-abl was hyperphosphorylated in ptp-pest-deficient cells dephosphorylation of c-abl by pest-type ptp represents a novel mechanism by which c-abl activity is regulated.

SIGNOR-235568

Q14012

P29475

1

phosphorylation

down-regulates activity

0.331

It was found that purified recombinant nNOS was phosphorylated by CaM-K Ialpha, CaM-K IIalpha, and CaM-K IV at Ser847 in vitro. Replacement of Ser847 with Ala (S847A) prevented phosphorylation by CaM kinases. Phosphorylated recombinant wild-type nNOS at Ser847 (approximately 0.5 mol of phosphate incorporation into nNOS) exhibited a 30% decrease of Vmax with little change of both the Km for L-arginine and Kact for CaM relative to unphosphorylated enzyme. The activity of mutant S847D was decreased to a level 50-60% as much as the wild-type enzyme. The decreased NOS enzyme activity of phosphorylated nNOS at Ser847 and mutant S847D was partially due to suppression of CaM binding, but not to impairment of dimer formation which is thought to be essential for enzyme activation.

SIGNOR-250614

Q86U44

Q9UHD2

0

phosphorylation

up-regulates activity

0.2

TBK1 also promotes METTL3 activation and m 6 A modification to stabilize IRF3 mRNA .|We here find TBK1, a key kinase of antiviral pathways, phosphorylates the core m 6 A methyltransferase METTL3 at serine 67.

SIGNOR-279299

Q9GZV5

P62136

0

dephosphorylation

up-regulates activity

0.542

PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase.

SIGNOR-277116

P00519

Q96PH1

1

phosphorylation

up-regulates activity

0.303

As shown in Fig. xref and c, c-Abl-phosphorylated NOX5 was mostly inhibited when c-Abl plasmid co-transfected with NOX5 Y476/Y478F mutant, then the NOX5 Y487F mutant, but not with NOX5 Y519F mutant.|Collectively, these results indicate that Pyk2 may act as a scaffolding protein for c-Abl stimulation of NOX5 activity in Pyk2 and NOX5 complex, and c-Abl-enhanced NOX5 activity is mainly dependent on phosphorylation of NOX5 Tyr 476/478 sites.

SIGNOR-280170

P29474

Q9Y478

0

phosphorylation

up-regulates

0.2

Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.

SIGNOR-112367

Q9NYY3

P06748

1

phosphorylation

up-regulates

0.536

Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.

SIGNOR-125720

Q96PU5

P35499

1

ubiquitination

down-regulates quantity by destabilization

0.279

The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).

SIGNOR-253460

P63096

P00533

0

phosphorylation

up-regulates activity

0.464

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

SIGNOR-277227

P04637

Q8NEZ5

0

ubiquitination

down-regulates quantity by destabilization

0.338

We demonstrate here that SCFFbxo22-KDM4A is a senescence-associated E3 ligase targeting methylated p53 for degradation. We find that Fbxo22 is highly expressed in senescent cells in a p53-dependent manner, and that SCFFbxo22 ubiquitylated p53 and formed a complex with a lysine demethylase, KDM4A. |SCFFbxo22 forms a ternary complex with p53 and KDM4A that targets methylated p53 for degradation.

SIGNOR-273448

Q86TI0

Q13131

0

phosphorylation

down-regulates

0.425

In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar

SIGNOR-159048

P03372

Q96FW1

0

deubiquitination

down-regulates activity

0.546

OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity.|We show that OTUB1 negatively regulates transcription mediated by ERalpha in transient reporter gene assays and transcription mediated by endogenous ERalpha in Ishikawa endometrial cancer cells.

SIGNOR-276529

O75382

Q5VSY0

1

polyubiquitination

down-regulates quantity by destabilization

0.248

Here we identify the RING finger-containing protein TRIM3 as a specific E3 ubiquitin ligase for the PSD scaffold GKAP/SAPAP1. Present in PSD fractions from rat brain, TRIM3 stimulates ubiquitination and proteasome-dependent degradation of GKAP, and induces the loss of GKAP and associated scaffold Shank1 from postsynaptic sites.

SIGNOR-271959

Q9UNH5

P06493

0

phosphorylation

up-regulates activity

0.54

We found that Cdc14A is phosphorylated on Ser411, Ser453 and Ser549 by Cdk1 early in mitosis and becomes dephosphorylated during late mitotic stages.

SIGNOR-278264

Q96HS1

Q99683

1

dephosphorylation

up-regulates activity

0.437

PGAM5 Is a Protein Ser/Thr Phosphatase That Activates ASK1. PGAM5 Dephosphorylates ASK1. This dephosphorylation unleashes phosphorylation ofThr-838 in the kinase domain, with activation of ASK1.

SIGNOR-277984

Q6UB99

P17677

1

transcriptional regulation

up-regulates quantity by expression

0.2

Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.

SIGNOR-266736

P06213

P0DP23

1

phosphorylation

down-regulates

0.403

The in vitro phosphorylation of calmodulin by the insulin receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.

SIGNOR-24782

P55036

O60260

0

polyubiquitination

down-regulates quantity by destabilization

0.2

S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s.

SIGNOR-272749

Q7RTT9

P19544

0

transcriptional regulation

up-regulates quantity by expression

0.274

ENT4 is transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses.

SIGNOR-268985

O00308

P49281

1

ubiquitination

down-regulates quantity

0.299

Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2|This promotes DMT1 ubiquitination and degradation by WWP2.

SIGNOR-268852

O95747

P55011

1

phosphorylation

up-regulates

0.524

The secretory na-k-cl cotransporter nkcc1 is activated by secretagogues through a phosphorylation-dependent mechanism. three phosphoacceptor sites were identified in the n-terminal domain of the protein (at thr184, thr189, and thr202) none of these residues occurs in the context of strong consensus sites for known ser/thr kinases.

SIGNOR-90927

P11413

Q99558

0

phosphorylation

up-regulates activity

0.2

Mass spectrometry identified four serine residues of G6PD phosphorylated by NIK (Extended Data Fig. 8f). All of these serines, except S278, are conserved between human and mouse G6PD proteins. In transfected cells, NIK stimulated G6PD activity, which was not affected by S8A or S486A mutation but abolished by S40A mutation (Extended Data Fig. 8g).

SIGNOR-277545

P25098

P30411

1

phosphorylation

down-regulates activity

0.2

Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.

SIGNOR-251445

O95644

P05231

1

transcriptional regulation

up-regulates quantity by expression

0.415

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.

SIGNOR-251730

P24666

P31751

1

dephosphorylation

down-regulates activity

0.2

Reduction in the levels of both LMW-PTP isoforms in vitro and in vivo increased tyrosine phosphorylation of IR and AktSer473 and increased IRS-1- and IRS-2-associated PI3-K activities in both liver and fat.|Activated PI3-K stimulates Akt (or protein kinase B) that in turn phosphorylates and inactivates glycogen synthase kinase-3

SIGNOR-248456

P42345

P00519

0

phosphorylation

down-regulates

0.453

Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k).

SIGNOR-76562

P35247

P49715

0

transcriptional regulation

up-regulates quantity by expression

0.259

Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.

SIGNOR-254042

O00327

P51449

0

transcriptional regulation

up-regulates quantity by expression

0.502

As RORs function as transcriptional activators and their expression correlates with histone acetylation and chromatin accessibility, RORs are thought to function as positive regulators of Bmal1 expression at its peak levels, whereas REV-ERBs block ROR and negatively regulate Bmal1 at the trough of its expression.

SIGNOR-268004

Q96FI4

Q7Z6Z7

0

ubiquitination

down-regulates quantity by destabilization

0.2

Mule and TRIM26 ubiquitylate NEIL1 in vitro within C-terminal lysine residues.

SIGNOR-278695

O00141

P14672

1

phosphorylation

up-regulates activity

0.312

We evaluated the putative role of sgk1 in the modulation of glut4. Coexpression of the kinase along with glut4 in xenopus oocytes stimulated glucose transport. The enhanced glut4 activity was paralleled by increased transporter abundance in the plasma membrane. Disruption of the sgk1 phosphorylation site on glut4 ((s274a)glut4) abrogated the stimulating effect of sgk1. In summary, sgk1 promotes glucose transporter membrane abundance via glut4 phosphorylation at ser274.

SIGNOR-236653

P14598

O60381

0

transcriptional regulation

down-regulates quantity by repression

0.265

Together, these results indicate that HBP1 may contribute to the regulation of NADPH oxidase-dependent superoxide production through transcriptional repression of the p47phox gene.

SIGNOR-261614

P28069

P01222

1

transcriptional regulation

up-regulates quantity by expression

0.438

CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-β promoter. The human TSH-β promoter contains three well defined Pit-1 DNA-binding sites.

SIGNOR-267205

Q9NQC7

O14920

0

phosphorylation

down-regulates activity

0.548

Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.

SIGNOR-204716

Q99558

P50281

1

phosphorylation

up-regulates activity

0.2

A post-transcriptional process is indicated because we observed that NIK increases MT1-MMP phosphorylation and activity, but does not affect MT1-MMP mRNA expression (XREF_FIG and XREF_FIG).|NIK increases MT1-MMP pseudopodial localization and enzymatic activity.

SIGNOR-279631

P06241

Q15700

1

phosphorylation

up-regulates activity

0.367

Recombinant PSD-93 was phosphorylated by Fyn in vitro, and Tyr-384 was identified as a major phosphorylation site. In COS7 cells, exogenously expressed PSD-93 was phosphorylated, dependent on its membrane localization. In addition, tyrosine-phosphorylated PSD-93 was able to bind to Csk, a negative regulator of Src family kinases, in vitro as well as in a brain lysate.

SIGNOR-262874

Q02750

Q9Y2U5

0

phosphorylation

up-regulates

0.414

Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation

SIGNOR-107692

P46734

Q5S007

0

phosphorylation

up-regulates activity

0.393

LRRK2 phosphorylates MKK3 and MKK7 in vitro but has a relatively minor effect on MKK6 phosphorylation.

SIGNOR-279057

P27361

Q07889

1

phosphorylation

down-regulates

0.636

For example, inactivation of sos through phosphorylation by the downstream mapk

SIGNOR-26338

O43511

Q99942

0

ubiquitination

down-regulates quantity by destabilization

0.2

E3 ubiquitin ligase Rma1 is involved in Pendrin degradation

SIGNOR-271497

O14757

Q86UE8

1

phosphorylation

down-regulates activity

0.269

Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b).

SIGNOR-262740

Q9Y618

Q9UQM7

0

phosphorylation

down-regulates

0.2

We demonstrated that camkii directly bound and phosphorylated smrt at ser-1407, thereby facilitating smrt translocation from the nucleus to the cytoplasm and proteasome-dependent degradation.

SIGNOR-191773

P45983

Q13043

1

phosphorylation

up-regulates

0.268

C-jun n-terminal kinase enhances mst1-mediated pro-apoptotic signaling through phosphorylation at serine 82.

SIGNOR-162327

P61586

Q8N103

0

gtpase-activating protein

down-regulates activity

0.447

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-260523

Q9UQM7

Q96PM5

1

phosphorylation

down-regulates

0.296

Phosphorylation of pirh2 by calmodulin-dependent kinase ii impairs its ability to ubiquitinate p53

SIGNOR-156064

P35222

Q00535

0

phosphorylation

up-regulates activity

0.371

By combining multiple network relations with PTM proteoform specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity.|CDK5 phosphorylates beta-catenin on Ser 191 and Ser 246 (PR :000037229)

SIGNOR-279516

Q9NS23

O14965

0

phosphorylation

down-regulates

0.448

Aurora-a appears to phosphorylate rassf1a at threonine202 and/or serine203 that reside within the known microtubule-binding domain of rassf1a. Substitutions of these residues with glutamic acid at both positions, mimicking constitutive phosphorylation of rassf1a, disrupt rassf1a interactions with microtubules and abolish its ability to induce m-phase cell cycle arrest.

SIGNOR-155815

Q13064

P11940

1

ubiquitination

down-regulates activity

0.2

MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA|Altogether, it is thus clear that the ubiquitination of PABPC1 or PABPC4 by MKRN3 negatively regulates the formation of translation initiation complex (TIC), attenuates their binding to poly (A)-tail contained mRNAs, and leads to the shortened poly (A) tail-length of GNRH1 mRNA.

SIGNOR-278764

P52333

Q96LC7

1

phosphorylation

up-regulates

0.2

These results suggest that the tyrosines at positions 597 and 667, contained within itim-like motifs, are likely targets of phosphorylation by several classes of signaling molecules, including lck, jak3, and emt. The tyrosine located at position y691 was also contributing to the phosphorylation of the wild-type siglec tail by lck and jak3 kinases. Y597 and y667 are likely involved in intracellular signaling

SIGNOR-112479

O14746

Q92630

0

phosphorylation

down-regulates activity

0.444

Dyrk2 phosphorylates TERT protein, a catalytic subunit of telomerase.|In this study, we found that dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 2 (Dyrk2) negatively regulates telomerase activity.

SIGNOR-279611

Q9BXW9

O14757

0

phosphorylation

up-regulates activity

0.585

In vitro and in vivo experiments show that phosphorylation of s331 is mediated by chk1, the s-phase checkpoint kinase implicated in the fanconi anemia dna repair pathway. phosphorylation at this site is dependent on chk1, signifying the importance of the s-phase checkpoint in the activation of fanconi anemia pathway.

SIGNOR-107042

P15311

P07332

1

relocalization

up-regulates

0.395

The recruitment and the activation of fes to the cell-cell contacts in confluent cells depend on its interaction with ezrin.

SIGNOR-159496

Q15555

Q96GD4

0

phosphorylation

up-regulates activity

0.537

Together, these data indicate that Aurora B and CDK1 phosphorylate EB2 at distinct sites and maintain the hyperphosphorylation of EB2 and its binding affinity to MTs while SAC activity is sustained.

SIGNOR-279591

P25098

Q13371

1

phosphorylation

down-regulates activity

0.2

The phosphorylation of purified phosducin and PhLP by recombinant GRK2 proceeds rapidly and stoichiometrically (0.82 +/- 0.1 and 0.83 +/- 0.09 mol of P (i)/mol of protein, respectively).

SIGNOR-279178

P42345

P35568

1

phosphorylation

down-regulates activity

0.766

Mtor induced the serine phosphorylation of irs-1 (ser-636/639), and such phosphorylation was inhibited by rapamycin. These results suggest that tnf impairs insulin signaling through irs-1 by activation of a pi 3-kinase/akt/mtor pathway, which is antagonized by pten

SIGNOR-106590

O15550

P41970

1

transcriptional regulation

down-regulates quantity by repression

0.2

Our findings reveal a dual role for UTX in suppressing acute myeloid leukaemia via repression of oncogenic ETS and upregulation of tumor suppressive GATA programs. several ETS transcription factors, including Elf4, Etv6, Erg, Fli1, Ets2, Spi1 and Elk3 were upregulated immediately after Utx loss in the preleukaemic phase

SIGNOR-260037

P53350

O15392

1

phosphorylation

up-regulates

0.583

Thus, we conclude that plk1-mediated phosphorylation of sur at ser20 is critical for accurate chromosome segregation|SUR (survivin)

SIGNOR-170460

P10071

Q9Y297

0

ubiquitination

down-regulates quantity by destabilization

0.671

Third, we and others have recently shown that only phosphorylated Ci/Gli3 are able to directly bind Slimb/BetaTrCP, that Gli3 is polyubiquitinated in the cell, and that mutations of 4 lysine residues, the putative ubiquitination sites in the Gli3 C-terminal region, inhibit Gli3 processing These observations further support the notion that Ci/Gli3 processing is carried out by the proteasome because the deletion of the cleavage site is expected to often disrupt the protease-mediated site-specific cleavage.

SIGNOR-145116

P52564

O43318

0

phosphorylation

up-regulates activity

0.764

The activity of tak1 to phosphorylate mkk6, which activates the jnk-p38 kinase pathway, is directly regulated by k63-linked polyubiquitination

SIGNOR-109497

P16144

P17612

0

phosphorylation

down-regulates

0.2

Additionally, we show that s1360 and s1364 of beta4 are the only residues phosphorylated by pkc and pka in cells, respectivelywe have defined three regions on beta4 that together harbor all the serine and threonine phosphorylation sites and show that three serines (s1356, s1360, and s1364), previously implicated in hd regulation, prevent the interaction of beta4 with the plectin actin-binding domain when phosphorylated

SIGNOR-156873

P37231

P46934

0

ubiquitination

up-regulates activity

0.386

First, NEDD4 interacts with and ubiquitinates PPARgamma.|NEDD4 increases PPARgamma stability through the inhibition of its proteasomal degradation.

SIGNOR-278540

P48382

P01903

1

transcriptional regulation

up-regulates quantity by expression

0.503

In this report, we correlate the loss of IFN-γ induction of MHC class II genes with the identification of a molecular defect in an essential regulator, namely RFX5. | We have further confirmed this finding by showing that new RFX5 leucine mutants created in vitro are incapable of transactivating a class II promoter, suggesting the identification of residues essential for RFX activity.

SIGNOR-266228

P51955

O14777

1

phosphorylation

up-regulates

0.592

Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo.

SIGNOR-94322

Q9NR50

P05198

1

guanine nucleotide exchange factor

up-regulates activity

0.833

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269126

P31749

P10586

0

dephosphorylation

down-regulates

0.342

Knock-down of lar by the l3 sirna probe markedly inhibited the insulin-stimulated increase in the phosphorylation of protein kinase b (pkb, also called akt) on serine 473 by >90%

SIGNOR-137246

P33981

Q02224

1

phosphorylation

up-regulates activity

0.43

Strikingly, phosphorylation of Cenp-E C tail by wild-type (WT) MPS1 or CDK1-cyclin B completely reverses its inhibitory effect toward Cenp-E motor ATPase in solution.

SIGNOR-278999

P01137

P62736

1

transcriptional regulation

up-regulates quantity by expression

0.419

A TGF-β1 response element that has a sequence different to that known for Smad binding has been identified in the α- SM actin promoter and seems to be essential for expression of α-SM actin in both SM cells 72 and myofibroblasts73 . How TGF-β1 activates expression of α-SM actin through this TGF-β1 control element is, as yet, unknown

SIGNOR-277681

Q96GD4

Q9NQG5

1

phosphorylation

up-regulates activity

0.2

Mechanistically, we revealed that CREPT/RPRD1B interacted with Aurora B to regulate the expression of Cyclin B1 in gastric cancer cells. Interestingly, Aurora B phosphorylates S145 in a well-conserved motif of CREPT/RPRD1B. We proposed that phosphorylation of CREPT/RPRD1B by Aurora B is required for promoting the transcription of Cyclin B1

SIGNOR-265499

Q96PX9

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.285

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-260565

P04626

Q96N67

1

phosphorylation

up-regulates

0.531

We show that the nrg1 receptor erbb2 directly binds and activates dock7 by phosphorylating tyr-1118. thus, dock7 functions as an intracellular substrate for erbb2 to promote schwann cell migration. This provides an unanticipated mechanism through which ligand-dependent tyrosine phosphorylation can trigger the activation of rho gtpase-gefs of the dock180 family.

SIGNOR-178348

P21860

Q96JA1

0

ubiquitination

down-regulates

0.434

We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.

SIGNOR-139951

Q8ND76

Q13131

0

phosphorylation

up-regulates activity

0.2

Our in vitro and cellular analyses supported the mass spectrometry data that implicated serine 326 (S326) as the phospho-acceptor site on CCNY by AMPK. |Mechanistically the S326 phosphorylation by AMPK promotes the interaction of CCNY with CDK16, which in turn autophosphorylates S336, which serves as a marker for active CCNY-CDK16

SIGNOR-273011

P06493

P18858

1

phosphorylation

up-regulates activity

0.364

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-103242

Q96GD4

Q15555

1

phosphorylation

up-regulates activity

0.537

Together, these data indicate that Aurora B and CDK1 phosphorylate EB2 at distinct sites and maintain the hyperphosphorylation of EB2 and its binding affinity to MTs while SAC activity is sustained.

SIGNOR-279591

P78347

O60674

0

phosphorylation

up-regulates activity

0.328

Jak2 activates tfii-i and regulates its interaction with extracellular signal-regulated kinase the interaction between tfii-i and erk, which is essential for its activity, can be regulated by jak2 through phosphorylation of tfii-i at tyrosine 248

SIGNOR-235313

P61224

O95398

0

guanine nucleotide exchange factor

up-regulates activity

0.718

Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.

SIGNOR-263957

P17661

Q96GD4

0

phosphorylation

down-regulates

0.546

We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. In the present study, we found aurora-b phosphorylates desmin at ser-11, thr-16, and ser-59, in vitro.

SIGNOR-100107

Q96GD4

P10412

1

phosphorylation

up-regulates quantity by stabilization

0.2

we showed previously that phosphorylation of S27 in human histone H1.4 (H1.4S27-P), prevents binding of heterochromatin protein 1 (HP1) family members (officially known as chromobox protein homologs) to the neighboring dimethylated K26. Here, we present the first functional characterization of H1.4S27-P in vivo and in vitro. We show that H1.4S27 phosphorylation is cell-cycle-regulated and its levels peak on metaphase chromosomes. We identify further Aurora B as the kinase phosphorylating H1.4S27.

SIGNOR-262658

P49840

P12036

1

phosphorylation

down-regulates activity

0.254

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

SIGNOR-279783

Q16827

P04626

1

dephosphorylation

down-regulates quantity by destabilization

0.403

In this study, our co-immunoprecipitation experiment along with the results derived from in vivo , cultured cells and clinical specimen confirm that PTPRO dephosphorylates ERBB2 at Y1248.|PTPRO overexpression remarkably accelerated degradation of ERBB2 (XREF_FIG).

SIGNOR-276979

P07949

P27361

1

phosphorylation

up-regulates

0.433

We hypothesized that ret could directly phosphorylate fak and erk. erk 2 could be phosphorylated at y187 (y204 in erk1).

SIGNOR-140298

Q05481

O75015

1

transcriptional regulation

down-regulates quantity by repression

0.2

Thus, these results indicate that these cloned ZNF140 and ZNF91 proteins function as repressors for the human Fc gamma RIIB transcription.

SIGNOR-266215

P31431

P17252

0

phosphorylation

up-regulates activity

0.732

The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant.

SIGNOR-249149

Q05D32

Q8N165

1

dephosphorylation

up-regulates quantity by stabilization

0.356

We found that peptides corresponding to phosphoserines 194 and 216 of PDIK1L (S385 and S413 of STK35) were efficiently dephosphorylated by SCP4, whereas no activity was detected for the other two phosphopeptides (Figure 6D).

SIGNOR-273773

Q08209

Q9NZJ5

0

phosphorylation

down-regulates activity

0.2

CN becomes phosphorylated by PERK, decreasing its activity.|Finally, evidence is presented that PERK phosphorylates CN-A at low resting levels of Ca 2+.

SIGNOR-278933