GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q9Y566	P12814	1	relocalization	up-regulates activity	0.273	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-264583
P06493	P60891	1	phosphorylation	up-regulates activity	0.254	CDK1 contributes to upregulation of PRPS1 activity by phosphorylating PRPS1 at S103\|In conclusion, compared with upregulation of PRPS1 expression levels, increased PRPS1 activity, which is marked by S103 phosphorylation	SIGNOR-265728
P49736	P24941	0	phosphorylation	up-regulates	0.735	In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2	SIGNOR-144000
P05129	P04083	1	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
P45985	P41279	0	phosphorylation	up-regulates	0.559	Furthermore, we found that immunoprecipitated tpl-2 could directly phosphorylate and activate both mek-1 and mkk4 (also known as sek-1)	SIGNOR-196744
P17612	P04035	1	phosphorylation	down-regulates activity	0.333	The intact, 100 kd microsomal enzyme and the 53 kd catalytic fragment of rat HMG-CoA reductase are both phosphorylated and inactivated by the AMP-activated protein kinase. this site is highly phosphorylated in intact liver under these conditions (Ser872 in the human enzyme).	SIGNOR-249992
O43303	P41002	0	ubiquitination	down-regulates quantity by destabilization	0.539	Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation.	SIGNOR-266364
Q16539	P38936	1	phosphorylation	up-regulates quantity by stabilization	0.445	The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.\|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro.	SIGNOR-89436
O60716	P27361	0	phosphorylation	down-regulates activity	0.293	Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation.	SIGNOR-277506
P54760	P29474	1	phosphorylation	up-regulates activity	0.311	These results suggest that activation of Eph-B4 with Ephrin-B2/Fc stimulates eNOS phosphorylation in vitro (XREF_FIG), eg, eNOS may be a downstream mediator of Eph-B4 signaling in endothelial cells.	SIGNOR-279172
P13497	Q02388	1	cleavage	up-regulates quantity	0.604	We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the C-terminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA/DTAG within the NC-2 domain. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen.	SIGNOR-256338
Q70Z35	P67775	0	dephosphorylation	up-regulates activity	0.2	PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ.	SIGNOR-277184
P06493	Q96PY5	1	phosphorylation	up-regulates activity	0.2	In this study we have identified the formin FMNL2 as a novel substrate for CDK1 that plays a role in maintaining adhesion complexes and facilitates cell cycle–dependent changes in adhesion complexes. Knockdown of FMNL2 or expression of a nonphosphorylatable S1016A mutant resulted in the loss of adhesion complexes and stress fibers within the cell body, with peripheral structures being maintained.	SIGNOR-273555
Q9BXM7	Q9UJA2	1	phosphorylation	down-regulates quantity	0.429	In vitro kinase assays using recombinant proteins under various control conditions indicated that PINK1 directly phosphorylates CLS1 (XREF_FIG).\|Similar to Fbxo15, knockdown of PINK1 kinase using shRNA increased CLS1 levels, whereas overexpression of PINK1 plasmid decreased CLS1 levels .	SIGNOR-280065
Q06830	P06239	0	phosphorylation	down-regulates activity	0.2	Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.	SIGNOR-276277
P40763	P19525	0	phosphorylation	up-regulates activity	0.612	Silencing PKR gene expression in HepG2 cells with siRNA reduced STAT3 phosphorylation at Tyr705 and Ser727 (XREF_FIG).\|The results also revealed that PKR activates STAT3, a transcription factor associated with primary liver tumors, which is suggested to promote tumor cell proliferation.	SIGNOR-279613
P53350	Q14790	1	phosphorylation	down-regulates quantity by destabilization	0.371	By phosphorylating S387 in procaspase-8 Cdk1/cyclin B1 generates a phospho-epitope for the binding of the PBD of Plk1. Subsequently, S305 in procaspase-8 is phosphorylated by Plk1 during mitosis. Using an RNAi-based strategy we could demonstrate that the extrinsic cell death is increased upon Fas-stimulation when endogenous caspase-8 is replaced by a mutant (S305A) mimicking the non-phosphorylated form. Together, our data show that sequential phosphorylation by Cdk1/cyclin B1 and Plk1 decreases the sensitivity of cells toward stimuli of the extrinsic pathway during mitosis.	SIGNOR-272989
P17612	P14136	1	phosphorylation	down-regulates activity	0.283	GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments.	SIGNOR-249713
P05129	P06127	1	phosphorylation	up-regulates	0.341	Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation.	SIGNOR-85183
O15297	Q9NR19	0	transcriptional regulation	up-regulates quantity by expression	0.2	As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;	SIGNOR-276560
P45984	P16615	1	phosphorylation	up-regulates activity	0.2	JNK2 Enhances SERCA2 Function in a CaMKII-Independent Manner..\|We found that JNK2 and SERCA2 proteins are physically associated with each other, and that JNK2 directly elevates the maximal rate of the SERCA2 activity by phosphorylating SERCA2.	SIGNOR-279540
P41970	O15550	0	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
Q9HC98	P0DMV8	1	phosphorylation	up-regulates activity	0.425	Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation.	SIGNOR-273885
P27361	P56270	1	phosphorylation	up-regulates	0.299	Together, these results show that activation of saf-1 in response to il-1 and -6 is mediated via map kinase-regulated phosphorylation.	SIGNOR-114475
Q13526	P45984	0	phosphorylation	up-regulates quantity by stabilization	0.2	Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation.	SIGNOR-277563
O60341	O15297	0	dephosphorylation	down-regulates activity	0.465	We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.	SIGNOR-276905
P27361	Q9NZQ3	1	phosphorylation	up-regulates	0.422	Spin90 was phosphorylated by erk1, which was, itself, activated by cell adhesion and platelet-derived growth factor. Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck	SIGNOR-118747
P50406	Q00535	0	phosphorylation	down-regulates activity	0.374	Cdk5 phosphorylates the 5-HT6R on serine 350 (Ser350)\|This suggests that the 5-HT6R is unable to interact with GPRIN1 when it is phosphorylated by Cdk5.	SIGNOR-264407
P35712	Q14669	0	ubiquitination	down-regulates quantity by destabilization	0.397	In this article, we focused on Trip 12, an E3 ubiquitin ligase, which polyubiquitinates Sox6.\|Therefore, Sox6 is a specific substrate to Trip12, by which it is polyubiquitinated and degraded.	SIGNOR-278579
P35236	Q02156	0	phosphorylation	up-regulates activity	0.2	HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. (Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient.	SIGNOR-276050
P48730	P35968	1	phosphorylation	down-regulates activity	0.328	CKIdelta phosphorylates VEGFR2 at both DSG and DDTD phosphodegrons to promote its interaction with beta-TRCP1.\|In a reciprocal set of experiments, we found that overexpression of CKIdelta markedly decreased the half-life of VEGFR2 (XREF_FIG).	SIGNOR-280235
P27037	P36896	1	phosphorylation	up-regulates	0.687	In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase	SIGNOR-99995
P08237	O75385	0	phosphorylation	down-regulates activity	0.2	Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).	SIGNOR-274035
Q8N752	P10070	1	phosphorylation	up-regulates	0.333	Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed	SIGNOR-179972
P01008	P00734	1	cleavage	down-regulates activity	0.948	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264136
Q9UQM7	Q14524	1	phosphorylation	up-regulates activity	0.398	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).\|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. \| Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275772
P15311	P17252	0	phosphorylation	up-regulates	0.547	Phosphorylation of ezrin is required for both conformational activation and for signaling to downstream events. The activating c-terminal threonine phosphorylation on t567 was first described to be downstream of the rho pathway (matsui et al., 1998). Additional studies have implicated protein kinase c (pkc) in the phosphorylation of ezrin t567.	SIGNOR-133223
P36507	P04049	0	phosphorylation	up-regulates	0.733	To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1.	SIGNOR-36553
Q13526	O14965	0	phosphorylation	down-regulates activity	0.254	Here, we found that aurora a can interact with and phosphorylate pin1 at ser16, which suppresses the g2/m function of pin1 by disrupting its binding ability and mitotic entry.	SIGNOR-202487
Q15365	P31751	0	phosphorylation	down-regulates activity	0.429	We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs.	SIGNOR-262625
Q12778	P46527	1	transcriptional regulation	up-regulates quantity by expression	0.627	To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter.	SIGNOR-277739
P04275	P29122	0	cleavage	up-regulates activity	0.293	Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine	SIGNOR-260367
P12931	Q86UR1	1	phosphorylation	up-regulates	0.408	Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation.	SIGNOR-168545
Q53HL2	Q96GD4	0	phosphorylation	up-regulates activity	0.82	AURKB directly phosphorylated CDCA8 at Ser(154), Ser(219), Ser(275), and Thr(278) and seemed to stabilize CDCA8 protein in cancer cells.\|Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis.	SIGNOR-279506
P27361	P04150	1	phosphorylation	down-regulates	0.542	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.\|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-154409
P01116	Q07890	0	guanine nucleotide exchange factor	up-regulates	0.713	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-175265
P19838	P49841	0	phosphorylation	up-regulates quantity by stabilization	0.388	GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α.	SIGNOR-251251
P29353	Q05209	0	dephosphorylation	down-regulates	0.675	The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions.	SIGNOR-44361
Q5TCY1	P10636	1	phosphorylation	down-regulates	0.451	Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation.	SIGNOR-148970
P48729	P78362	1	phosphorylation	up-regulates activity	0.25	Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins.	SIGNOR-275460
P15941	P49841	0	phosphorylation	down-regulates activity	0.456	GSK3beta binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3beta decreases binding of MUC1 to beta-catenin in vitro and in vivo.	SIGNOR-249356
O60216	Q9Y6M0	0	cleavage	up-regulates	0.2	Rad21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand dna breaks. Interestingly, rad21 is cleaved by a caspase-like esp1/separase at the onset of anaphase to trigger sister chromatid separation.	SIGNOR-115426
P37231	P23769	0	null	down-regulates activity	0.369	GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis	SIGNOR-132949
P43405	Q02548	1	phosphorylation	down-regulates activity	0.422	PAX5 tyrosine phosphorylation by SYK co-operatively functions with its serine phosphorylation to cancel the PAX5-dependent repression of BLIMP1: A mechanism for antigen-triggered plasma cell differentiation.	SIGNOR-269084
P37231	Q13547	1	relocalization	down-regulates	0.617	These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome	SIGNOR-143961
P60953	Q7Z6J4	0	guanine nucleotide exchange factor	up-regulates activity	0.483	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-260552
P29353	Q02156	0	phosphorylation	up-regulates activity	0.2	Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.	SIGNOR-263048
P07948	P40259	1	phosphorylation	up-regulates activity	0.678	Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b	SIGNOR-251398
P05129	Q92686	1	phosphorylation	up-regulates activity	0.429	Phosphorylation of RC3 by PKC alpha, beta, or gamma was stimulated by Ca2+, phospholipid, and diacylglycerol. A single site, Ser36, which is adjacent to the predicted calmodulin (CaM)-binding domain, was phosphorylated by these enzymes. Phosphorylation of RC3 by PKC or PKM, a protease-degraded PKC, was inhibited by CaM. The effect of CaM apparently targets at RC3, as phosphorylation of protamine sulfate by PKM was not inhibited by CaM.	SIGNOR-248915
P53350	O14920	1	phosphorylation	down-regulates	0.343	Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma	SIGNOR-181802
P35226	P31751	0	phosphorylation	up-regulates activity	0.292	the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate	SIGNOR-249582
P53350	P04049	1	phosphorylation	up-regulates activity	0.289	An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (XREF_FIG).\|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation.	SIGNOR-278190
P06493	Q86WB0	1	phosphorylation	down-regulates	0.253	Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1	SIGNOR-154047
P08311	P25116	1	cleavage	down-regulates activity	0.583	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.	SIGNOR-263564
Q12857	P15173	1	transcriptional regulation	up-regulates quantity by expression	0.2	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma\|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263983
Q9Y297	O15534	1	ubiquitination	down-regulates	0.57	We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1	SIGNOR-137755
P23743	P12931	0	phosphorylation	up-regulates	0.459	Diacylglycerol kinase-alpha phosphorylation by src on y335 is required for activation, membrane recruitment and hgf-induced cell motility.	SIGNOR-157365
Q6YBV0	Q6IQ22	0	relocalization	down-regulates quantity by destabilization	0.445	We also found that Rab12 promotes constitutive degradation of PAT4 (proton‐coupled amino‐acid transporter 4\|Rab12 regulates lysosomal localization or degradation of amino‐acid transporters.	SIGNOR-264763
P01106	P27361	0	phosphorylation	up-regulates activity	0.707	ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation	SIGNOR-236250
P05783	P06493	0	phosphorylation	up-regulates	0.338	We identified k18 ser33 as an interphase phosphorylation site, which increases its phosphorylation during mitosis in cultured cells and regenerating liver, and as an in vitro cdc2 kinase phosphorylation site. K18 ser33 phosphorylation dictates binding to 14_3_3 proteins	SIGNOR-55994
Q6PGQ7	P49841	0	phosphorylation	up-regulates	0.258	It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation	SIGNOR-201519
P27707	Q13535	0	phosphorylation	up-regulates activity	0.2	Since activation of dCK by IR was not prevented by KU-60019 at longer times, but could be suppressed if the ATR inhibitor was combined with the ATM inhibitor, we propose that dCK is activated by ATR when ATM is inhibited.\|Taken together, these data indicate that ATR, like ATM [15], can directly phosphorylate dCK at Ser 74 in vitro and thereby increase its activity.Most dCK activators share the feature of inducing DNA damage followed by DNA damage response, a complex signaling network aimed to preserve genome integrity.	SIGNOR-279494
Q15382	Q14318	1	gtpase-activating protein	down-regulates activity	0.535	Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1.	SIGNOR-233568
Q93077	Q86Y13	0	monoubiquitination	up-regulates activity	0.2	2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271759
Q16512	P00533	1	phosphorylation	down-regulates activity	0.2	This identified thr654 in egfr as the pkn1 phosphorylation siteit has been shown that the phosphorylation of egfr at thr654 by pkc reduces the tyrosine kinase activity of the receptor	SIGNOR-174755
O95835	P60891	1	phosphorylation	down-regulates quantity by destabilization	0.2	Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness.	SIGNOR-276505
Q12778	Q16512	0	phosphorylation	down-regulates	0.2	Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1.	SIGNOR-97882
P09619	P23470	0	dephosphorylation	down-regulates activity	0.338	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254715
P32519	P67775	0	dephosphorylation	down-regulates activity	0.2	Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response	SIGNOR-248634
P04049	O60674	0	phosphorylation	up-regulates activity	0.617	JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process.	SIGNOR-251361
O96017	P30307	1	phosphorylation	down-regulates activity	0.856	Activated chk2 in turn phosphorylates cdc25c at serine-216 contributing to the g2/m checkpoints. Cds1 phosphorylates and inactivates cdc25 in vitro\|CDC25C is phosphorylated on Ser 216 throughout interphase, but not in mitosis. This creates a binding site for 14‐3‐3 proteins \| It has been suggested that 14‐3‐3 protein binding is responsible for retaining Cdc25C in the cytoplasm during interphase, thereby contributing to the prevention of premature initiation of mitotic events	SIGNOR-102779
P25098	P00533	0	phosphorylation	up-regulates activity	0.2	Previous studies showed that EGFR activation results in association of GRK2 with the EGFR and subsequent phosphorylation of GRK2 at three tyrosine residues (Tyr 13, -86, and -92), resulting in activation of GRK2.\|We propose that GRK2 activation by EGFR leads to GRK2 phosphorylation of Mst2 at these sites, which, in turn, regulates the Mst2-Nek2A-PP1\u03b3 complex ( xref ).	SIGNOR-279368
P28482	P49407	1	phosphorylation	down-regulates	0.727	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-67630
Q07666	P28482	0	phosphorylation	up-regulates	0.666	In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites	SIGNOR-96414
P24385	Q13627	0	phosphorylation	down-regulates	0.395	Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells.	SIGNOR-202838
Q86YJ5	Q9UHN6	1	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271533
P12931	Q13905	1	phosphorylation	up-regulates	0.671	C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases.	SIGNOR-128273
Q12931	Q9BXM7	0	phosphorylation	up-regulates activity	0.612	This would mean that PINK1 knockdown should reduce TRAP1 activity, thereby potentiating BAY induced cell death.\|PINK1 can phosphorylate TRAP1 to prevent apoptosis induced by oxidative stress.	SIGNOR-278186
P49281	O00308	0	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
O60318	P24941	0	phosphorylation	up-regulates activity	0.2	To study the inducible regulation of GANP DNA-primase during cell activation, we examined phosphorylation induced by various kinds of kinases.We observed that the cell cycle-associated kinase Cdks induced phosphorylation of GANP in vitro. Examination of immunoprecipitates of Cdk2 from B cells revealed phosphorylation of GANP-PD at a consensus sequence of Cdk phosphorylation at Ser502 (S/T-P-X-K/R) (Fig. (Fig.1C1C Left; ref. 22).	SIGNOR-262734
P24928	Q9NP77	0	dephosphorylation	up-regulates activity	0.855	Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.\| Depletion of Ssu72 impairs transcription in vitro	SIGNOR-248815
P53350	Q96FF9	1	phosphorylation	down-regulates activity	0.705	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.	SIGNOR-276122
P06241	Q15417	1	phosphorylation	down-regulates activity	0.333	We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin	SIGNOR-251159
O00623	P50542	1	ubiquitination	up-regulates activity	0.653	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.	SIGNOR-253020
P48436	O76039	0	phosphorylation	down-regulates activity	0.2	Based on these studies, we hypothesized that Cdkl5 dependent phosphorylation at Ser 199 suppresses Sox9 function during AKI.\|We also found that Cdkl5 phosphorylates Sox9 at Ser 199 residue during kidney injury in vivo.	SIGNOR-279457
P49841	Q92993	1	phosphorylation	up-regulates	0.367	We demonstrate that gsk-3 phosphorylates serine 86 of the p53-acetyltransferase tip60. A tip60(s86a) mutant was less active to induce p53 k120 acetylation, histone 4 acetylation, and expression of puma	SIGNOR-174049
Q9UM73	P10636	1	phosphorylation	up-regulates quantity	0.2	All these results point to the critical role played by ALK in the phosphorylation and accumulation of tau and in the associated memory impairment seen in 3xTg-AD mice.	SIGNOR-279318
P42345	O60260	1	phosphorylation	down-regulates activity	0.2	MTOR phosphorylates PARK2 at Ser127 Through biochemical, mutational, and genetic studies, we identified PARK2 as a mTORC1 substrate. mTORC1 phosphorylates PARK2 at Ser127, which blocks its cellular ubiquitination activity, thereby hindering its tumor suppressor effect on eIF4B's stability.	SIGNOR-277586
Q8NEZ5	O14867	1	ubiquitination	down-regulates quantity	0.282	Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22.	SIGNOR-259331
Q00613	Q02750	0	phosphorylation	up-regulates activity	0.287	This study indicates that mTORC1, MEK1, p38 and DYRK2 induce HSF1 activity to a similar level but phosphorylate HSF1 primarily at S326 as well as S363, a known inhibitory site [71,72], S221, also thought to be an inhibitory site [70], or at S241 and S344, which are two novel phosphorylation sites with unknown function.\|While AKT1, mTORC1, MEK1, p38 and DYRK2 can all activate HSF1, the current study indicates that activity of only AKT1 and mTORC1 maintains a strong association with HSF1 activity in tumours (Fig. 4).	SIGNOR-279208

Q9Y566

P12814

1

relocalization

up-regulates activity

0.273

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-264583

P06493

P60891

1

phosphorylation

up-regulates activity

0.254

CDK1 contributes to upregulation of PRPS1 activity by phosphorylating PRPS1 at S103|In conclusion, compared with upregulation of PRPS1 expression levels, increased PRPS1 activity, which is marked by S103 phosphorylation

SIGNOR-265728

P49736

P24941

0

phosphorylation

up-regulates

0.735

In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2

SIGNOR-144000

P05129

P04083

1

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

P45985

P41279

0

phosphorylation

up-regulates

0.559

Furthermore, we found that immunoprecipitated tpl-2 could directly phosphorylate and activate both mek-1 and mkk4 (also known as sek-1)

SIGNOR-196744

P17612

P04035

1

phosphorylation

down-regulates activity

0.333

The intact, 100 kd microsomal enzyme and the 53 kd catalytic fragment of rat HMG-CoA reductase are both phosphorylated and inactivated by the AMP-activated protein kinase. this site is highly phosphorylated in intact liver under these conditions (Ser872 in the human enzyme).

SIGNOR-249992

O43303

P41002

0

ubiquitination

down-regulates quantity by destabilization

0.539

Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation.

SIGNOR-266364

Q16539

P38936

1

phosphorylation

up-regulates quantity by stabilization

0.445

The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro.

SIGNOR-89436

O60716

P27361

0

phosphorylation

down-regulates activity

0.293

Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. TGFβ promotes monoubiquitination of p120-catenin through Smurf1 to induce junction dissociation.

SIGNOR-277506

P54760

P29474

1

phosphorylation

up-regulates activity

0.311

These results suggest that activation of Eph-B4 with Ephrin-B2/Fc stimulates eNOS phosphorylation in vitro (XREF_FIG), eg, eNOS may be a downstream mediator of Eph-B4 signaling in endothelial cells.

SIGNOR-279172

P13497

Q02388

1

cleavage

up-regulates quantity

0.604

We show that bone morphogenetic protein-1 (BMP-1), which exhibits procollagen C-proteinase activity, cleaves the C-terminal propeptide from human procollagen VII. The cleavage occurs at the BMP-1 consensus cleavage site SYAA/DTAG within the NC-2 domain. Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen.

SIGNOR-256338

Q70Z35

P67775

0

dephosphorylation

up-regulates activity

0.2

PREX2 is dephosphorylated by PP1α and PP2A.PAK-mediated phosphorylation of PREX2 reduced GEF activity toward Rac1 by inhibiting PREX2 binding to PIP3 and Gβγ.

SIGNOR-277184

P06493

Q96PY5

1

phosphorylation

up-regulates activity

0.2

In this study we have identified the formin FMNL2 as a novel substrate for CDK1 that plays a role in maintaining adhesion complexes and facilitates cell cycle–dependent changes in adhesion complexes. Knockdown of FMNL2 or expression of a nonphosphorylatable S1016A mutant resulted in the loss of adhesion complexes and stress fibers within the cell body, with peripheral structures being maintained.

SIGNOR-273555

Q9BXM7

Q9UJA2

1

phosphorylation

down-regulates quantity

0.429

In vitro kinase assays using recombinant proteins under various control conditions indicated that PINK1 directly phosphorylates CLS1 (XREF_FIG).|Similar to Fbxo15, knockdown of PINK1 kinase using shRNA increased CLS1 levels, whereas overexpression of PINK1 plasmid decreased CLS1 levels .

SIGNOR-280065

Q06830

P06239

0

phosphorylation

down-regulates activity

0.2

Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. To determine whether Prxs are phosphorylated, we subjected recombinant human PrxI and II to an in vitro kinase assay with two nonreceptor PTKs, Lck and Abl, in the presence of [γ-32P]ATP. Both PTKs phosphorylated PrxI and PrxII. Phosphorylation of the wild-type protein was detected, whereas that of the Y194F mutant was not (Figure 1B), indicating that Tyr194 is the only site of tyrosine phosphorylation.

SIGNOR-276277

P40763

P19525

0

phosphorylation

up-regulates activity

0.612

Silencing PKR gene expression in HepG2 cells with siRNA reduced STAT3 phosphorylation at Tyr705 and Ser727 (XREF_FIG).|The results also revealed that PKR activates STAT3, a transcription factor associated with primary liver tumors, which is suggested to promote tumor cell proliferation.

SIGNOR-279613

P53350

Q14790

1

phosphorylation

down-regulates quantity by destabilization

0.371

By phosphorylating S387 in procaspase-8 Cdk1/cyclin B1 generates a phospho-epitope for the binding of the PBD of Plk1. Subsequently, S305 in procaspase-8 is phosphorylated by Plk1 during mitosis. Using an RNAi-based strategy we could demonstrate that the extrinsic cell death is increased upon Fas-stimulation when endogenous caspase-8 is replaced by a mutant (S305A) mimicking the non-phosphorylated form. Together, our data show that sequential phosphorylation by Cdk1/cyclin B1 and Plk1 decreases the sensitivity of cells toward stimuli of the extrinsic pathway during mitosis.

SIGNOR-272989

P17612

P14136

1

phosphorylation

down-regulates activity

0.283

GFAP can serve as a substrate for phosphorylation by CAMP-dependent protein kinase. CAMP-dependent protein kinase or protein kinase C phosphorylated Ser-8, Ser-13, and Ser-34.each phosphorylation was shown to induce disassembly of the glial filaments.

SIGNOR-249713

P05129

P06127

1

phosphorylation

up-regulates

0.341

Cd5 is a good pkc substrate. Phosphorylation of cd5 is necessary for cd5-mediated lipid second messenger generation.

SIGNOR-85183

O15297

Q9NR19

0

transcriptional regulation

up-regulates quantity by expression

0.2

As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;

SIGNOR-276560

P45984

P16615

1

phosphorylation

up-regulates activity

0.2

JNK2 Enhances SERCA2 Function in a CaMKII-Independent Manner..|We found that JNK2 and SERCA2 proteins are physically associated with each other, and that JNK2 directly elevates the maximal rate of the SERCA2 activity by phosphorylating SERCA2.

SIGNOR-279540

P41970

O15550

0

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

Q9HC98

P0DMV8

1

phosphorylation

up-regulates activity

0.425

Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation.

SIGNOR-273885

P27361

P56270

1

phosphorylation

up-regulates

0.299

Together, these results show that activation of saf-1 in response to il-1 and -6 is mediated via map kinase-regulated phosphorylation.

SIGNOR-114475

Q13526

P45984

0

phosphorylation

up-regulates quantity by stabilization

0.2

Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation.

SIGNOR-277563

O60341

O15297

0

dephosphorylation

down-regulates activity

0.465

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

SIGNOR-276905

P27361

Q9NZQ3

1

phosphorylation

up-regulates

0.422

Spin90 was phosphorylated by erk1, which was, itself, activated by cell adhesion and platelet-derived growth factor. Such phosphorylation of spin90 likely promotes the interaction of the spin90.betapix.wasp complex and nck

SIGNOR-118747

P50406

Q00535

0

phosphorylation

down-regulates activity

0.374

Cdk5 phosphorylates the 5-HT6R on serine 350 (Ser350)|This suggests that the 5-HT6R is unable to interact with GPRIN1 when it is phosphorylated by Cdk5.

SIGNOR-264407

P35712

Q14669

0

ubiquitination

down-regulates quantity by destabilization

0.397

In this article, we focused on Trip 12, an E3 ubiquitin ligase, which polyubiquitinates Sox6.|Therefore, Sox6 is a specific substrate to Trip12, by which it is polyubiquitinated and degraded.

SIGNOR-278579

P35236

Q02156

0

phosphorylation

up-regulates activity

0.2

HePTP is phosphorylated by PKC isozymes at Ser-225 in vitro. While all isozymes phosphorylated Ser-225 predominantly and Ser-113 to a lesser extent (Fig. (Fig.5),5), they differed strikingly in how much 32P they incorporated into HePTP during the 30-min assay. PKC θ was the most efficient, while PKC ζ and PKC μ were clearly less potent; PKC δ, ɛ, and η were quite inefficient.

SIGNOR-276050

P48730

P35968

1

phosphorylation

down-regulates activity

0.328

CKIdelta phosphorylates VEGFR2 at both DSG and DDTD phosphodegrons to promote its interaction with beta-TRCP1.|In a reciprocal set of experiments, we found that overexpression of CKIdelta markedly decreased the half-life of VEGFR2 (XREF_FIG).

SIGNOR-280235

P27037

P36896

1

phosphorylation

up-regulates

0.687

In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase

SIGNOR-99995

P08237

O75385

0

phosphorylation

down-regulates activity

0.2

Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1).Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels.Similar results were also obtained using ULK2 as the kinase (data not shown).

SIGNOR-274035

Q8N752

P10070

1

phosphorylation

up-regulates

0.333

Gli2 is phosphorylated by gsk3 and ck1 for the fbxw11 (betatrcp2)-mediated degradation ci is phosphorylated by pka at multiple sites priming phosphorylation by both gsk3 and cki, leading to partial proteolysis. The pka, gsk3, and cki sites are conserved in gli2 and gli3, vertebrate homologs of ci that are similarly processed

SIGNOR-179972

P01008

P00734

1

cleavage

down-regulates activity

0.948

Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1

SIGNOR-264136

Q9UQM7

Q14524

1

phosphorylation

up-regulates activity

0.398

Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. | Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5

SIGNOR-275772

P15311

P17252

0

phosphorylation

up-regulates

0.547

Phosphorylation of ezrin is required for both conformational activation and for signaling to downstream events. The activating c-terminal threonine phosphorylation on t567 was first described to be downstream of the rho pathway (matsui et al., 1998). Additional studies have implicated protein kinase c (pkc) in the phosphorylation of ezrin t567.

SIGNOR-133223

P36507

P04049

0

phosphorylation

up-regulates

0.733

To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1.

SIGNOR-36553

Q13526

O14965

0

phosphorylation

down-regulates activity

0.254

Here, we found that aurora a can interact with and phosphorylate pin1 at ser16, which suppresses the g2/m function of pin1 by disrupting its binding ability and mitotic entry.

SIGNOR-202487

Q15365

P31751

0

phosphorylation

down-regulates activity

0.429

We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation.TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs.

SIGNOR-262625

Q12778

P46527

1

transcriptional regulation

up-regulates quantity by expression

0.627

To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter.

SIGNOR-277739

P04275

P29122

0

cleavage

up-regulates activity

0.293

Like PACE,PACE4 was able to process pro-vWF to its mature form, and efficient cleavage required both the P4 arginine and the P2 lysine

SIGNOR-260367

P12931

Q86UR1

1

phosphorylation

up-regulates

0.408

Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation.

SIGNOR-168545

Q53HL2

Q96GD4

0

phosphorylation

up-regulates activity

0.82

AURKB directly phosphorylated CDCA8 at Ser(154), Ser(219), Ser(275), and Thr(278) and seemed to stabilize CDCA8 protein in cancer cells.|Phosphorylation and activation of cell division cycle associated 8 by aurora kinase B plays a significant role in human lung carcinogenesis.

SIGNOR-279506

P27361

P04150

1

phosphorylation

down-regulates

0.542

Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.

SIGNOR-154409

P01116

Q07890

0

guanine nucleotide exchange factor

up-regulates

0.713

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.

SIGNOR-175265

P19838

P49841

0

phosphorylation

up-regulates quantity by stabilization

0.388

GSK-3 beta forms an in vivo complex with and specifically phosphorylates NF-kappa B1/p105 at Ser-903 and Ser-907 in vitro. GSK-3 beta has a dual effect on p105: it stabilizes p105 under resting conditions and primes p105 for degradation upon tumor necrosis factor (TNF)-alpha treatment. Indeed, constitutive processing of p105 to p50 occurs at a higher rate in cells lacking GSK-3 beta with respect to wild-type cells and can be reduced upon reintroduction of GSK-3 beta by transfection. S903A and S907A point mutations impair p105 proteolysis in response to TNF-α.

SIGNOR-251251

P29353

Q05209

0

dephosphorylation

down-regulates

0.675

The shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (y239/240) that mediate protein-protein interactions.

SIGNOR-44361

Q5TCY1

P10636

1

phosphorylation

down-regulates

0.451

Direct tau phosphorylation by ttbk1 at ser198, ser199, ser202 and ser422, which are also phosphorylated in phfs. Ttbk1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that ttbk1 is a neuron-specific dual kinase involved in tau phosphorylation at ad-related sites and is also associated with tau aggregation.

SIGNOR-148970

P48729

P78362

1

phosphorylation

up-regulates activity

0.25

Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins.

SIGNOR-275460

P15941

P49841

0

phosphorylation

down-regulates activity

0.456

GSK3beta binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3beta decreases binding of MUC1 to beta-catenin in vitro and in vivo.

SIGNOR-249356

O60216

Q9Y6M0

0

cleavage

up-regulates

0.2

Rad21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand dna breaks. Interestingly, rad21 is cleaved by a caspase-like esp1/separase at the onset of anaphase to trigger sister chromatid separation.

SIGNOR-115426

P37231

P23769

0

null

down-regulates activity

0.369

GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis

SIGNOR-132949

P43405

Q02548

1

phosphorylation

down-regulates activity

0.422

PAX5 tyrosine phosphorylation by SYK co-operatively functions with its serine phosphorylation to cancel the PAX5-dependent repression of BLIMP1: A mechanism for antigen-triggered plasma cell differentiation.

SIGNOR-269084

P37231

Q13547

1

relocalization

down-regulates

0.617

These data suggest that c/ebp beta activates a single unified pathway of adipogenesis involving its stimulation of ppargamma expression, which then activates c/ebp alpha expression by dislodging hdac1 from the promoter for degradation in the proteasome

SIGNOR-143961

P60953

Q7Z6J4

0

guanine nucleotide exchange factor

up-regulates activity

0.483

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-260552

P29353

Q02156

0

phosphorylation

up-regulates activity

0.2

Among them, Ser(29) in p52(Shc) (equivalent to Ser(138) in p66(Shc)) was phosphorylated only after TPA stimulation. Phosphorylation of this site together with the intact phosphotyrosine-binding domain was essential for ShcA binding to the protein-tyrosine phosphatase PTP-PEST. TPA-induced ShcA phosphorylation at this site (and hence, its association with PTP-PEST) was inhibited by a protein kinase C-specific inhibitor and was induced by overexpression of constitutively active mutants of protein kinase Calpha, -epsilon, and -delta isoforms.

SIGNOR-263048

P07948

P40259

1

phosphorylation

up-regulates activity

0.678

Y182 of CD79a appears to be the initial and preferred site of Ag receptor phosphorylation by Src family kinases. In vitro, Src family Lyn and Fyn predominantly phosphorylate this residue in CD79a, and Y195 does so in CD79b

SIGNOR-251398

P05129

Q92686

1

phosphorylation

up-regulates activity

0.429

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

SIGNOR-248915

P53350

O14920

1

phosphorylation

down-regulates

0.343

Plk1 phosphorylates serines 733, 740, and 750 in the gammabd of ikkbeta in vitro. Phosphorylating gammabd with plk1 decreased its affinity for ikkgamma

SIGNOR-181802

P35226

P31751

0

phosphorylation

up-regulates activity

0.292

the polycomb group silencing protein Bmi1 can be phosphorylated by AKT, which enhances its oncogenic potential in PCa. Overexpression of Bmi1 can act in combination with PTEN haploinsufficiency to induce invasive carcinogenic formation in the prostate

SIGNOR-249582

P53350

P04049

1

phosphorylation

up-regulates activity

0.289

An in vitro kinase assay demonstrated that PLK1 directly phosphorylated CRAF at S338 and S339, but not at S621 (XREF_FIG).|These results demonstrate that PLK1 increases the stability of CRAF protein by preventing proteasome degradation.

SIGNOR-278190

P06493

Q86WB0

1

phosphorylation

down-regulates

0.253

Moreover, we found cyclin b1/cdk1 to phosphorylate nipa at ser-395 in mitosis. Mutation of both ser-359 and ser-395 impaired effective inactivation of the scfnipa complex, resulting in reduced levels of mitotic cyclin b1

SIGNOR-154047

P08311

P25116

1

cleavage

down-regulates activity

0.583

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3 cleaved at multiple sites and would be expected to disable PAR1 by cleaving COOH-terminal to the activation site.

SIGNOR-263564

Q12857

P15173

1

transcriptional regulation

up-regulates quantity by expression

0.2

NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,

SIGNOR-263983

Q9Y297

O15534

1

ubiquitination

down-regulates

0.57

We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1

SIGNOR-137755

P23743

P12931

0

phosphorylation

up-regulates

0.459

Diacylglycerol kinase-alpha phosphorylation by src on y335 is required for activation, membrane recruitment and hgf-induced cell motility.

SIGNOR-157365

Q6YBV0

Q6IQ22

0

relocalization

down-regulates quantity by destabilization

0.445

We also found that Rab12 promotes constitutive degradation of PAT4 (proton‐coupled amino‐acid transporter 4|Rab12 regulates lysosomal localization or degradation of amino‐acid transporters.

SIGNOR-264763

P01106

P27361

0

phosphorylation

up-regulates activity

0.707

ERK1 phosphorylates MYC Ser62 resulting in MYC stabilization and activation

SIGNOR-236250

P05783

P06493

0

phosphorylation

up-regulates

0.338

We identified k18 ser33 as an interphase phosphorylation site, which increases its phosphorylation during mitosis in cultured cells and regenerating liver, and as an in vitro cdc2 kinase phosphorylation site. K18 ser33 phosphorylation dictates binding to 14_3_3 proteins

SIGNOR-55994

Q6PGQ7

P49841

0

phosphorylation

up-regulates

0.258

It suggests that gsk3_ activity is required for hbora-mediated mitotic entry through ser274 and ser278 phosphorylation

SIGNOR-201519

P27707

Q13535

0

phosphorylation

up-regulates activity

0.2

Since activation of dCK by IR was not prevented by KU-60019 at longer times, but could be suppressed if the ATR inhibitor was combined with the ATM inhibitor, we propose that dCK is activated by ATR when ATM is inhibited.|Taken together, these data indicate that ATR, like ATM [15], can directly phosphorylate dCK at Ser 74 in vitro and thereby increase its activity.Most dCK activators share the feature of inducing DNA damage followed by DNA damage response, a complex signaling network aimed to preserve genome integrity.

SIGNOR-279494

Q15382

Q14318

1

gtpase-activating protein

down-regulates activity

0.535

Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1.

SIGNOR-233568

Q93077

Q86Y13

0

monoubiquitination

up-regulates activity

0.2

2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.

SIGNOR-271759

Q16512

P00533

1

phosphorylation

down-regulates activity

0.2

This identified thr654 in egfr as the pkn1 phosphorylation siteit has been shown that the phosphorylation of egfr at thr654 by pkc reduces the tyrosine kinase activity of the receptor

SIGNOR-174755

O95835

P60891

1

phosphorylation

down-regulates quantity by destabilization

0.2

Recruitment of TRAF2 to PRPS1/2 requires phosphorylation of PRPS1 S285 or PRPS2 T285, which is mediated by low stiffness-activated large tumor suppressor (LATS)1/2 kinases.LATS1/2-dependent S/T285 phosphorylation is required for PRPS1/2 ubiquitination and degradation at low stiffness.

SIGNOR-276505

Q12778

Q16512

0

phosphorylation

down-regulates

0.2

Furthermore, estrogen induced phosphorylation and perinuclear localization of the cell survival forkhead transcription factor fkhr in the cytoplasm in a pak1-dependent manner. In addition, pak1 directly interacted with fkhr and phosphorylated it. The noticed phosphorylation-dependent exclusion of fkhr from the nucleus impaired the ability of fkhr to activate its target fas ligand promoter containing the fkhr binding motif (fre) in cells treated with estrogen or expressing catalytically active pak1.

SIGNOR-97882

P09619

P23470

0

dephosphorylation

down-regulates activity

0.338

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

SIGNOR-254715

P32519

P67775

0

dephosphorylation

down-regulates activity

0.2

Elf-1 enhances the expression of CD3zeta, whereas it suppresses the expression of FcRgamma gene and lupus T cells have decreased amounts of DNA-binding 98 kDa form of Elf-1. We show that the aberrantly increased PP2A in lupus T cells dephosphorylates Elf-1 at Thr-231. Dephosphorylation results in limited expression and binding of the 98 kDa Elf-1 form to the CD3zeta and FcRgamma promoters. Suppression of the expression of the PP2A leads to increased expression of CD3zeta and decreased expression of FcRgamma genes and correction of the early signaling response

SIGNOR-248634

P04049

O60674

0

phosphorylation

up-regulates activity

0.617

JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process.

SIGNOR-251361

O96017

P30307

1

phosphorylation

down-regulates activity

0.856

Activated chk2 in turn phosphorylates cdc25c at serine-216 contributing to the g2/m checkpoints. Cds1 phosphorylates and inactivates cdc25 in vitro|CDC25C is phosphorylated on Ser 216 throughout interphase, but not in mitosis. This creates a binding site for 14‐3‐3 proteins | It has been suggested that 14‐3‐3 protein binding is responsible for retaining Cdc25C in the cytoplasm during interphase, thereby contributing to the prevention of premature initiation of mitotic events

SIGNOR-102779

P25098

P00533

0

phosphorylation

up-regulates activity

0.2

Previous studies showed that EGFR activation results in association of GRK2 with the EGFR and subsequent phosphorylation of GRK2 at three tyrosine residues (Tyr 13, -86, and -92), resulting in activation of GRK2.|We propose that GRK2 activation by EGFR leads to GRK2 phosphorylation of Mst2 at these sites, which, in turn, regulates the Mst2-Nek2A-PP1\u03b3 complex ( xref ).

SIGNOR-279368

P28482

P49407

1

phosphorylation

down-regulates

0.727

Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation

SIGNOR-67630

Q07666

P28482

0

phosphorylation

up-regulates

0.666

In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites

SIGNOR-96414

P24385

Q13627

0

phosphorylation

down-regulates

0.395

Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells.

SIGNOR-202838

Q86YJ5

Q9UHN6

1

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.

SIGNOR-271533

P12931

Q13905

1

phosphorylation

up-regulates

0.671

C3g is activated upon phosphorylation at tyrosine 504 c3g is phosphorylated in vivo on y504 upon coexpression with src or hck, two members of the src family tyrosine kinases.

SIGNOR-128273

Q12931

Q9BXM7

0

phosphorylation

up-regulates activity

0.612

This would mean that PINK1 knockdown should reduce TRAP1 activity, thereby potentiating BAY induced cell death.|PINK1 can phosphorylate TRAP1 to prevent apoptosis induced by oxidative stress.

SIGNOR-278186

P49281

O00308

0

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

O60318

P24941

0

phosphorylation

up-regulates activity

0.2

To study the inducible regulation of GANP DNA-primase during cell activation, we examined phosphorylation induced by various kinds of kinases.We observed that the cell cycle-associated kinase Cdks induced phosphorylation of GANP in vitro. Examination of immunoprecipitates of Cdk2 from B cells revealed phosphorylation of GANP-PD at a consensus sequence of Cdk phosphorylation at Ser502 (S/T-P-X-K/R) (Fig. (Fig.1C1C Left; ref. 22).

SIGNOR-262734

P24928

Q9NP77

0

dephosphorylation

up-regulates activity

0.855

Phosphorylation of serine-2 (S2) and serine-5 (S5) of the C-terminal domain (CTD) of RNA polymerase II (RNAP II) is a dynamic process that regulates the transcription cycle and coordinates recruitment of RNA processing factors. The Fcp1 CTD phosphatase catalyzes dephosphorylation of S2-P.| Depletion of Ssu72 impairs transcription in vitro

SIGNOR-248815

P53350

Q96FF9

1

phosphorylation

down-regulates activity

0.705

Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.

SIGNOR-276122

P06241

Q15417

1

phosphorylation

down-regulates activity

0.333

We identify, for the first time, tyrosine-phosphorylated calponin h3 within COS 7 cells, before and after their transfection with the pSV vector containing cDNA encoding the cytoplasmic, Src-related, tyrosine kinase, Fyn. we have localized the tyrosines phosphorylated without actin to Tyr261 in calponin h3 and to Tyr261 and Tyr182 in calponin h1. Tyrosine phosphorylation of calponins inhibits their binding to F-actin

SIGNOR-251159

O00623

P50542

1

ubiquitination

up-regulates activity

0.653

Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.

SIGNOR-253020

P48436

O76039

0

phosphorylation

down-regulates activity

0.2

Based on these studies, we hypothesized that Cdkl5 dependent phosphorylation at Ser 199 suppresses Sox9 function during AKI.|We also found that Cdkl5 phosphorylates Sox9 at Ser 199 residue during kidney injury in vivo.

SIGNOR-279457

P49841

Q92993

1

phosphorylation

up-regulates

0.367

We demonstrate that gsk-3 phosphorylates serine 86 of the p53-acetyltransferase tip60. A tip60(s86a) mutant was less active to induce p53 k120 acetylation, histone 4 acetylation, and expression of puma

SIGNOR-174049

Q9UM73

P10636

1

phosphorylation

up-regulates quantity

0.2

All these results point to the critical role played by ALK in the phosphorylation and accumulation of tau and in the associated memory impairment seen in 3xTg-AD mice.

SIGNOR-279318

P42345

O60260

1

phosphorylation

down-regulates activity

0.2

MTOR phosphorylates PARK2 at Ser127 Through biochemical, mutational, and genetic studies, we identified PARK2 as a mTORC1 substrate. mTORC1 phosphorylates PARK2 at Ser127, which blocks its cellular ubiquitination activity, thereby hindering its tumor suppressor effect on eIF4B's stability.

SIGNOR-277586

Q8NEZ5

O14867

1

ubiquitination

down-regulates quantity

0.282

Here, we show that heme triggers the degradation of Bach1, a pro-metastatic transcription factor, by promoting its interaction with the ubiquitin ligase Fbxo22.

SIGNOR-259331

Q00613

Q02750

0

phosphorylation

up-regulates activity

0.287

This study indicates that mTORC1, MEK1, p38 and DYRK2 induce HSF1 activity to a similar level but phosphorylate HSF1 primarily at S326 as well as S363, a known inhibitory site [71,72], S221, also thought to be an inhibitory site [70], or at S241 and S344, which are two novel phosphorylation sites with unknown function.|While AKT1, mTORC1, MEK1, p38 and DYRK2 can all activate HSF1, the current study indicates that activity of only AKT1 and mTORC1 maintains a strong association with HSF1 activity in tumours (Fig. 4).

SIGNOR-279208