GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P62834	Q92565	0	guanine nucleotide exchange factor	up-regulates activity	0.648	We found here that cAMP-dependent activation of Epac1 and Rap1 but not PKA is able to activate CaMKI to mediate Ser47 (S47) phosphorylation in GCM1. Epac1 and Epac2 proteins were identified as cAMP-binding proteins with guanine nucleotide exchange factor (GEF) activities for the small GTPases, Rap1 and Rap2	SIGNOR-262682
P03952	P01042	1	cleavage	up-regulates activity	0.779	Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1).	SIGNOR-263548
Q9Y3C5	P31749	0	phosphorylation	down-regulates quantity	0.456	Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity	SIGNOR-252558
P10721	P35232	1	phosphorylation	up-regulates activity	0.2	In this study, we showed that c-Kit associates with PHB to upregulate phospho-PHB in the lipid raft of the plasma membrane.\|c-Kit phosphorylates PHB at the Tyr259 residue.	SIGNOR-278362
P38398	Q7Z6Z7	0	ubiquitination	down-regulates quantity by destabilization	0.397	Collectively, these data indicate that HUWE1 targets BRCA1, but not BARD1, for polyubiquitination and degradation.Because HUWE1 promotes BRCA1 ubiquitination and degradation, we wondered whether it might contribute to the reduced BRCA1 protein levels in sporadic breast cancer.	SIGNOR-278583
Q9UPT5	P28482	0	phosphorylation	up-regulates	0.331	Erk1/2 phosphorylation enhances the binding of exo70 to other exocyst components and promotes the assembly of the exocyst complex in response to epidermal growth factor (egf) signaling.	SIGNOR-197543
Q07889	P01111	1	guanine nucleotide exchange factor	up-regulates activity	0.78	Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras	SIGNOR-110566
O60566	P06493	0	phosphorylation	up-regulates	0.777	Here, we demonstrate that bubr1 is phosphorylated on the cdk1 site t620, which triggers the recruitment of plk1 and phosphorylation of bubr1 by plk1 both in vitro and in vivo. Phosphorylation does not appear to be required for spindle checkpoint function but instead is important for the stability of kinetochore-microtubule (kt-mt) interactions	SIGNOR-157642
Q07812	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	The E3 ligase parkin, which is known to trigger mitochondria specific autophagy, ubiquitylates BAX K128 and targets the pro apoptotic BCL-2 protein for proteasomal degradation.	SIGNOR-278529
P33176	Q9NX95	1	relocalization	up-regulates activity	0.56	Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes.	SIGNOR-264811
Q16539	P42574	1	phosphorylation	down-regulates	0.775	Consequently, p38-mapk can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response.	SIGNOR-122099
Q15653	Q15418	0	phosphorylation	down-regulates quantity by destabilization	0.369	By using recombinant wild-type and mutant IkappaBbeta proteins, both active ERK2 and RSK1 were found to directly phosphorylate IkappaBbeta, but only active RSK1 phosphorylated IkappaBbeta on Ser19 and Ser23, two sites known to mediate the subsequent ubiquitination and degradation.	SIGNOR-280114
P24071	P67775	0	dephosphorylation	up-regulates activity	0.323	Furthermore, FcalphaRI activation is induced by protein phosphatase 2A (PP2A) after it dephosphorylates a single serine residue (S263) in the FcalphaRI intracellular tail	SIGNOR-264858
Q8NBJ5	P02461	1	glycosylation	up-regulates activity	0.404	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-261154
P42224	P49336	0	phosphorylation	up-regulates activity	0.392	We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation.	SIGNOR-273179
P12931	O14578	1	phosphorylation	up-regulates activity	0.273	CitK is tyrosine phosphorylated by Src in response to EphB2 signaling.	SIGNOR-279484
P16104	Q14493	0	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265405
O15111	P31749	0	phosphorylation	up-regulates	0.668	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-187006
P23458	P29597	1	phosphorylation	up-regulates	0.527	These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1.	SIGNOR-43080
P05549	P68400	0	phosphorylation	up-regulates	0.307	Ck2 phosphorylates ap-2_ and increases its transcriptional activity	SIGNOR-175130
P98177	P24941	0	phosphorylation	down-regulates	0.518	Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity	SIGNOR-183655
Q06124	P46527	1	dephosphorylation	up-regulates activity	0.281	Moreover, SHP-2 was strongly activated on G-CSF stimulation and specifically dephosphorylated p27(Kip1) in vitro.\|Most importantly, we could illustrate that SHP-2 modulates p27 (Kip1) stability and contributes to p27 (Kip1)-mediated cell cycle progression.	SIGNOR-277168
Q16236	P15559	1	transcriptional regulation	up-regulates quantity by expression	0.487	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256275
O14965	Q02224	1	phosphorylation	down-regulates activity	0.48	Aurora A also phosphorylates and inhibits the centromere-associated kinesin CENP-E involved in efficient chromosome congression ( xref ; xref ).	SIGNOR-280187
P53778	O15297	0	dephosphorylation	down-regulates	0.297	Ppm1d selectively inhibits p38 activation by dephosphorylating thr 180.	SIGNOR-135976
O75030	P78527	0	phosphorylation	up-regulates activity	0.2	These results suggest that DNA-PK can target MITF-S325 for phosphorylation. In melanocytes and melanoma cells, MITF is rapidly phosphorylated by DNA-PK and interacts with NBS1–RAD50 but not MRE11, destabilizing the MRN complex.	SIGNOR-277899
P04792	P31749	0	phosphorylation	down-regulates	0.66	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-252526
Q9BV47	Q13158	1	dephosphorylation	down-regulates activity	0.366	This multi-functionality of fadd may depend primarily on its subcellular location. Fadd shuttles between the cytosol and the nucleus and this signal is unclear;however, fadd trafficking requires phosphorylation of the protein on ser194dusp26 suppresses cell proliferation by fadd dephosphorylation	SIGNOR-204559
Q05655	P30411	1	phosphorylation	down-regulates activity	0.301	In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation.	SIGNOR-249108
P56750	Q8TBB1	0	ubiquitination	down-regulates quantity by destabilization	0.294	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272900
P28482	P53805	1	phosphorylation	up-regulates activity	0.27	Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively \|Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin.	SIGNOR-249198
P23470	P06213	1	dephosphorylation	up-regulates activity	0.365	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-254703
P61586	P85298	0	gtpase-activating protein	down-regulates activity	0.427	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-260463
P49715	P04150	0	transcriptional regulation	up-regulates quantity by expression	0.455	We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα	SIGNOR-256116
P07585	P09237	0	cleavage	down-regulates quantity by destabilization	0.61	Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.	SIGNOR-256352
P43405	Q92918	1	phosphorylation	up-regulates activity	0.348	BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation.	SIGNOR-246567
P40763	Q02156	0	phosphorylation	up-regulates	0.399	Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation.	SIGNOR-143832
Q9UBP6	Q15418	0	phosphorylation	down-regulates	0.324	Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro.	SIGNOR-135948
Q969H0	Q5VWQ8	1	ubiquitination	down-regulates quantity by destabilization	0.327	DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1	SIGNOR-254774
Q9BZE0	P17612	0	phosphorylation	down-regulates activity	0.283	Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity	SIGNOR-145131
P42345	P03372	1	phosphorylation	up-regulates activity	0.498	Thus our results indicate that the interaction between ER\u03b1 and raptor is necessary to recruit raptor to the nucleus, where mTOR phosphorylates and activates ER\u03b1.	SIGNOR-278295
P33981	P21589	1	phosphorylation	up-regulates activity	0.2	Intermolecular NTE phosphorylation by Mps1 requires a topology in which sites proximal to the NTE interact with the active Mps1 in order to promote phosphorylation.	SIGNOR-280157
P15036	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-260035
Q13153	P18669	1	phosphorylation	down-regulates	0.2	Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity.	SIGNOR-91594
P42345	Q8N122	1	phosphorylation	up-regulates activity	0.989	The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo.	SIGNOR-184959
P63000	O43295	0	gtpase-activating protein	down-regulates activity	0.566	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-260518
P51813	Q05397	1	phosphorylation	up-regulates	0.551	Bmx phosphorylated focal adhesion kinase (fak) at tyr577 subsequent to its src-mediated phosphorylation at tyr576. Loss of bmx by rna interference or by genetic deletion in mouse embryonic fibroblasts (mefs) markedly impaired fak activity.	SIGNOR-202139
Q14774	P19419	1	transcriptional regulation	up-regulates quantity by expression	0.2	In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.	SIGNOR-261622
P49841	Q96RR4	1	phosphorylation	down-regulates	0.272	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-198134
P42262	P51608	0	transcriptional regulation	down-regulates quantity by repression	0.323	Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A.	SIGNOR-264684
P46531	O14672	0	cleavage	up-regulates activity	0.782	ADAM10-mediated Notch1 cleavage is the rate limiting-step for release of the NICD and subsequent activation of Notch1 signaling. In T cells ADAM10-mediated Notch1 shedding controls T cell development	SIGNOR-259838
Q15139	Q96P20	1	phosphorylation	up-regulates activity	0.332	PKD at the Golgi phosphorylates NLRP3 to release it from mitochondria-associated endoplasmic reticulum membranes, allowing for assembly of the mature inflammasome in the cytosol.\|These data thus suggest that PKD activity at the Golgi is sufficient to activate the NLRP3 inflammasome.	SIGNOR-279428
Q96EB6	O75376	1	null	up-regulates	0.621	In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.	SIGNOR-253505
P08123	P03956	0	cleavage	down-regulates quantity by destabilization	0.401	In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.	SIGNOR-272337
P42858	Q9UHD2	0	phosphorylation	up-regulates activity	0.289	Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity.	SIGNOR-270350
Q01094	Q13490	0	ubiquitination	up-regulates activity	0.336	The ability of cIAP1 to promote wt E2F1 transcriptional activity was retained by all E2F1 mutants, except the K161R/164R mutant for which cIAP1 was completely inactive and the K185R whose basal transactivation activity was weakly enhanced by cIAP1 (XREF_FIG).\|Here, we demonstrated that the E3-ubiquitin ligase cellular inhibitor of apoptosis 1 (cIAP1) increases E2F1 K63-poly-ubiquitination on the lysine residue 161/164 cluster, which is associated with the transcriptional factor stability and activity.	SIGNOR-278688
Q15139	Q9Y5P4	1	phosphorylation	down-regulates	0.2	In this study, we identify cert as a novel in vivo pkd substrate. Phosphorylation on serine 132 by pkd decreases the affinity of cert toward its lipid target phosphatidylinositol 4-phosphate at golgi membranes and reduces ceramide transfer activity	SIGNOR-156500
P15173	P38936	1	transcriptional regulation	down-regulates quantity by repression	0.331	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-251575
P54132	Q13535	0	phosphorylation	up-regulates activity	0.852	It is noteworthy that an active BLM seems to be unnecessary to the activation of BRCA1, either after gamma-rays or HU, even though BRCA1 and BLM helicase are activated by ATR in response to stalled replication, and despite the fact that they colocalize after replication arrest.\|These results show that BLM phosphorylation by ATR after replication fork arrest is not important for its relocalization.	SIGNOR-278978
Q9BZ95	Q14653	1	methylation	up-regulates activity	0.2	We found that lysine methyltransferase NSD3 interacts with and directly monomethylates IRF3 in the nucleus, leading to the enhanced IRF3 transcriptional activity and antiviral immune responses.	SIGNOR-259198
A6NLU0	P14635	1	ubiquitination	down-regulates quantity by destabilization	0.32	We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis.	SIGNOR-271476
P04626	Q96JA1	0	ubiquitination	down-regulates	0.403	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-139948
Q9H8S9	Q13188	0	phosphorylation	up-regulates	0.85	Mob1, which forms a complex with lats1/2, is also phosphorylated by mst1/2, resulting in an enhanced lats1/2 mob1 interaction.	SIGNOR-175809
O00755	P09238	1	transcriptional regulation	up-regulates quantity by expression	0.2	We first proved that Wnt7a activated the canonical Wnt pathway through direct regulation of the MMP10 gene.	SIGNOR-278867
O95997	P49841	0	phosphorylation	down-regulates activity	0.2	Glycogen synthase kinase-3beta (GSK3beta) negatively regulates PTTG1 and human securin protein stability, and GSK3beta inactivation correlates with securin accumulation in breast tumors.\|Here, we demonstrate that glycogen synthase kinase-3\u03b2 (GSK3\u03b2) phosphorylates securin to promote its proteolysis via SCF(\u03b2TrCP) E3 ubiquitin ligase.	SIGNOR-279188
P06493	Q9NXR1	1	phosphorylation	up-regulates activity	0.654	We found that Nudel and NudE were also phosphorylated in M phase (Fig. (Fig.22 and and3).3). First, Nudel and NudE were specifically phosphorylated in M phase. Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro.Due to conservation of the S/TP motifs, NudE may also be phosphorylated at similar sites by these kinases, though it contains an additional potential Cdk site at S282 (SPNR).	SIGNOR-274077
O75676	P16220	1	phosphorylation	up-regulates	0.605	Msk1 and msk2 directly phosphorilate and activete transcription factors such as creb1, atf1 msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation.	SIGNOR-157158
O75030	Q15661	1	transcriptional regulation	up-regulates quantity by expression	0.2	The transcription of tryptase gene in human mast cells is regulated by mi transcription factor \|Using mutant constructs of tryptase promoter, we observed that two E-box (CANNTG) motifs including between -817 to -715 and -421 to -202 are able to involve in the transactivation of tryptase gene by MITF-A.	SIGNOR-251725
Q9BXK1	P12931	0	phosphorylation	up-regulates activity	0.245	We further confirmed that the Tyr-10 residue of KLF16 is phosphorylated in uterine cells (Fig. 7c). Additional experiments using both pharmacological and dominant negative inhibitors of Src further supported a role for this tyrosine kinase in modulating the activity of KLF16 (Fig. 7, d and f).	SIGNOR-276398
P29353	Q9UM73	0	phosphorylation	up-regulates	0.456	Anaplastic lymphoma kinase (alk), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the ptb domain of shcc in three neuroblastoma cells. In vitro kinase assay revealed that shcc is a potent substrate of the activated alk kinase. The alk gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the alk kinase, which results in hyperphosphorylation of shcc.	SIGNOR-91534
P01100	P28482	0	phosphorylation	up-regulates activity	0.792	We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2.	SIGNOR-236010
Q8WWN8	P63000	1	gtpase-activating protein	down-regulates activity	0.47	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-260456
Q8TDC3	P30305	1	phosphorylation	down-regulates	0.506	Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3	SIGNOR-124839
P08559	P12931	0	phosphorylation	down-regulates activity	0.348	Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1).	SIGNOR-277204
Q13153	Q12778	1	phosphorylation	down-regulates activity	0.358	Pak1 efficiently phosphorylated GST-FKHR.	SIGNOR-279242
Q9P286	P15976	1	phosphorylation	up-regulates activity	0.2	In addition, we defined GATA1 Ser161, Ser187 were the main phosphorylation sites by PAK5.	SIGNOR-278297
P28482	P11362	1	phosphorylation	down-regulates	0.309	Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling	SIGNOR-200880
Q9P286	Q9ULA0	1	phosphorylation	down-regulates quantity by destabilization	0.2	We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. \| PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway.	SIGNOR-275651
Q99638	P00519	0	phosphorylation	up-regulates activity	0.477	The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. \| c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL \|these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress.	SIGNOR-260843
P06241	Q96J02	1	phosphorylation	down-regulates activity	0.366	Tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB. The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation	SIGNOR-245332
Q9NRC8	Q5TEC6	1	deacetylation	up-regulates activity	0.2	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37.	SIGNOR-275883
P53041	P48730	0	phosphorylation	up-regulates activity	0.333	Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90.	SIGNOR-277373
P46531	P51608	0	transcriptional regulation	down-regulates quantity by repression	0.29	As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1	SIGNOR-264675
P98171	P63000	1	gtpase-activating protein	down-regulates activity	0.479	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-260460
P46531	Q92993	0	acetylation	down-regulates	0.414	This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60.	SIGNOR-156923
P08581	P17252	0	phosphorylation	down-regulates	0.256	These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor.	SIGNOR-37718
O75676	P18846	1	phosphorylation	up-regulates	0.615	Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1.	SIGNOR-116252
P68400	P18887	1	phosphorylation	up-regulates	0.395	Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair	SIGNOR-165419
Q92786	Q9Y478	0	phosphorylation	down-regulates quantity by destabilization	0.2	Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation.	SIGNOR-277609
P26651	Q16539	0	phosphorylation	down-regulates activity	0.357	TTP appears to be a p38Î±/Î² MAPK target and pretreating skeletal muscle with a p38Î±/Î² MAPK inhibitor reduces TTP phosphorylation.	SIGNOR-253596
Q5S007	P61020	1	phosphorylation	up-regulates activity	0.599	Using recombinant proteins, we show here that LRRK2 phosphorylates Rab5b at its Thr6 residue in in vitro kinase assays with mass spectrophotometry analysis. Phosphorylation of Rab5b by LRRK2 on the threonine residue was confirmed by western analysis using cells stably expressing LRRK2 G2019S. The phosphomimetic T6D mutant exhibited stronger GTPase activity than that of the wild-type Rab5b. In addition, phosphorylation of Rab5b by LRRK2 also exhibited GTPase activity stronger than that of the unphosphorylated Rab5b protein.	SIGNOR-276873
P48436	P17612	0	phosphorylation	up-regulates	0.465	We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta.	SIGNOR-137085
P17612	Q14643	1	phosphorylation	down-regulates activity	0.556	IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site.	SIGNOR-249996
P35790	Q99541	1	phosphorylation	down-regulates quantity by destabilization	0.2	In addition, as a protein kinase, CHKalpha2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth	SIGNOR-267649
P00519	P18206	1	phosphorylation	up-regulates activity	0.38	Abl is the tyrosine kinase that phosphorylates vinculin Y822.\|Finally we show that Abl inhibition prevents vinculin actions in cadherin containing complexes, resulting in defects in cell stiffening.	SIGNOR-278464
P55283	P63000	1	null	up-regulates activity	0.273	Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.	SIGNOR-253103
Q15797	Q9HCE7	0	ubiquitination	down-regulates	0.708	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps	SIGNOR-195660
P30291	O43660	1	phosphorylation	down-regulates activity	0.2	These results indicate that WEE1 promotes PRL1 phosphorylation.\|WEE1 promotes PRL1 degradation .	SIGNOR-279579
P29597	Q14765	1	phosphorylation	up-regulates activity	0.656	IL-12 activates the Janus family tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693.	SIGNOR-279303
P50613	P03372	1	phosphorylation	up-regulates	0.413	Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7.	SIGNOR-81170

P62834

Q92565

0

guanine nucleotide exchange factor

up-regulates activity

0.648

We found here that cAMP-dependent activation of Epac1 and Rap1 but not PKA is able to activate CaMKI to mediate Ser47 (S47) phosphorylation in GCM1. Epac1 and Epac2 proteins were identified as cAMP-binding proteins with guanine nucleotide exchange factor (GEF) activities for the small GTPases, Rap1 and Rap2

SIGNOR-262682

P03952

P01042

1

cleavage

up-regulates activity

0.779

Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1).

SIGNOR-263548

Q9Y3C5

P31749

0

phosphorylation

down-regulates quantity

0.456

Upon inhibition of the AKT pathway or mutation of T135, the phosphorylation at one of these sites is virtually eliminated, suggesting that AKT may phosphorylate RNF11 at T135. Moreover, RNF11 is phosphorylated by AKT in vitro and is recognized by phospho-AKT substrate antibodies. RNF11 shows enhanced binding to 14-3-3 in WM239 cells compared with that seen in the parental WM35 cells which have low AKT activity

SIGNOR-252558

P10721

P35232

1

phosphorylation

up-regulates activity

0.2

In this study, we showed that c-Kit associates with PHB to upregulate phospho-PHB in the lipid raft of the plasma membrane.|c-Kit phosphorylates PHB at the Tyr259 residue.

SIGNOR-278362

P38398

Q7Z6Z7

0

ubiquitination

down-regulates quantity by destabilization

0.397

Collectively, these data indicate that HUWE1 targets BRCA1, but not BARD1, for polyubiquitination and degradation.Because HUWE1 promotes BRCA1 ubiquitination and degradation, we wondered whether it might contribute to the reduced BRCA1 protein levels in sporadic breast cancer.

SIGNOR-278583

Q9UPT5

P28482

0

phosphorylation

up-regulates

0.331

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

SIGNOR-197543

Q07889

P01111

1

guanine nucleotide exchange factor

up-regulates activity

0.78

Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras

SIGNOR-110566

O60566

P06493

0

phosphorylation

up-regulates

0.777

Here, we demonstrate that bubr1 is phosphorylated on the cdk1 site t620, which triggers the recruitment of plk1 and phosphorylation of bubr1 by plk1 both in vitro and in vivo. Phosphorylation does not appear to be required for spindle checkpoint function but instead is important for the stability of kinetochore-microtubule (kt-mt) interactions

SIGNOR-157642

Q07812

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

The E3 ligase parkin, which is known to trigger mitochondria specific autophagy, ubiquitylates BAX K128 and targets the pro apoptotic BCL-2 protein for proteasomal degradation.

SIGNOR-278529

P33176

Q9NX95

1

relocalization

up-regulates activity

0.56

Conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes.

SIGNOR-264811

Q16539

P42574

1

phosphorylation

down-regulates

0.775

Consequently, p38-mapk can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response.

SIGNOR-122099

Q15653

Q15418

0

phosphorylation

down-regulates quantity by destabilization

0.369

By using recombinant wild-type and mutant IkappaBbeta proteins, both active ERK2 and RSK1 were found to directly phosphorylate IkappaBbeta, but only active RSK1 phosphorylated IkappaBbeta on Ser19 and Ser23, two sites known to mediate the subsequent ubiquitination and degradation.

SIGNOR-280114

P24071

P67775

0

dephosphorylation

up-regulates activity

0.323

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

SIGNOR-264858

Q8NBJ5

P02461

1

glycosylation

up-regulates activity

0.404

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-261154

P42224

P49336

0

phosphorylation

up-regulates activity

0.392

We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation.

SIGNOR-273179

P12931

O14578

1

phosphorylation

up-regulates activity

0.273

CitK is tyrosine phosphorylated by Src in response to EphB2 signaling.

SIGNOR-279484

P16104

Q14493

0

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265405

O15111

P31749

0

phosphorylation

up-regulates

0.668

Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta

SIGNOR-187006

P23458

P29597

1

phosphorylation

up-regulates

0.527

These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055 and that this phosphorylation requires another kinase, most likely jak1.

SIGNOR-43080

P05549

P68400

0

phosphorylation

up-regulates

0.307

Ck2 phosphorylates ap-2_ and increases its transcriptional activity

SIGNOR-175130

P98177

P24941

0

phosphorylation

down-regulates

0.518

Additionally, ck1, dyrk1a, and cdk2 also phosphorylate foxos at various sites to inhibit foxos activity

SIGNOR-183655

Q06124

P46527

1

dephosphorylation

up-regulates activity

0.281

Moreover, SHP-2 was strongly activated on G-CSF stimulation and specifically dephosphorylated p27(Kip1) in vitro.|Most importantly, we could illustrate that SHP-2 modulates p27 (Kip1) stability and contributes to p27 (Kip1)-mediated cell cycle progression.

SIGNOR-277168

Q16236

P15559

1

transcriptional regulation

up-regulates quantity by expression

0.487

In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).

SIGNOR-256275

O14965

Q02224

1

phosphorylation

down-regulates activity

0.48

Aurora A also phosphorylates and inhibits the centromere-associated kinesin CENP-E involved in efficient chromosome congression ( xref ; xref ).

SIGNOR-280187

P53778

O15297

0

dephosphorylation

down-regulates

0.297

Ppm1d selectively inhibits p38 activation by dephosphorylating thr 180.

SIGNOR-135976

O75030

P78527

0

phosphorylation

up-regulates activity

0.2

These results suggest that DNA-PK can target MITF-S325 for phosphorylation. In melanocytes and melanoma cells, MITF is rapidly phosphorylated by DNA-PK and interacts with NBS1–RAD50 but not MRE11, destabilizing the MRN complex.

SIGNOR-277899

P04792

P31749

0

phosphorylation

down-regulates

0.66

First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.

SIGNOR-252526

Q9BV47

Q13158

1

dephosphorylation

down-regulates activity

0.366

This multi-functionality of fadd may depend primarily on its subcellular location. Fadd shuttles between the cytosol and the nucleus and this signal is unclear;however, fadd trafficking requires phosphorylation of the protein on ser194dusp26 suppresses cell proliferation by fadd dephosphorylation

SIGNOR-204559

Q05655

P30411

1

phosphorylation

down-regulates activity

0.301

In addition, we found a protein kinase C-dependent phosphorylation of Ser(346) that was mutually exclusive with the basal phosphorylation at Ser(348) and therefore may be implicated in differential regulation of B2 receptor activation. Functional analysis of receptor mutants revealed that a low phosphorylation stoichiometry is sufficient to initiate receptor sequestration while a clustered phosphorylation around Ser(346) is necessary for desensitization of the B2 receptor-induced phospholipase C activation.

SIGNOR-249108

P56750

Q8TBB1

0

ubiquitination

down-regulates quantity by destabilization

0.294

We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.

SIGNOR-272900

P28482

P53805

1

phosphorylation

up-regulates activity

0.27

Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin.

SIGNOR-249198

P23470

P06213

1

dephosphorylation

up-regulates activity

0.365

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-254703

P61586

P85298

0

gtpase-activating protein

down-regulates activity

0.427

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-260463

P49715

P04150

0

transcriptional regulation

up-regulates quantity by expression

0.455

We show that in addition, DEX-bound GR directly promotes the expression of adipogenic TFs, including C/EBPβ, Klf5, Klf9, and C/EBPα

SIGNOR-256116

P07585

P09237

0

cleavage

down-regulates quantity by destabilization

0.61

Degradation of decorin by matrix metalloproteinases. These data indicate proteolytic degradation of DCN by MMP-2, MMP-3 and MMP-7, and suggest the possibility that, under pathophysiological conditions, the digestion by the MMPs may induce tissue reactions mediated by TGF-beta1 released from DCN in the connective tissues.

SIGNOR-256352

P43405

Q92918

1

phosphorylation

up-regulates activity

0.348

BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation.

SIGNOR-246567

P40763

Q02156

0

phosphorylation

up-regulates

0.399

Abrogation of pkcdelta activity inhibited insulin-induced stat3 phosphorylation, pkcdelta-stat3 association and nuclear translocation.

SIGNOR-143832

Q9UBP6

Q15418

0

phosphorylation

down-regulates

0.324

Pkb and ribosomal s6 kinase (rsk) both phosphorylated mettl1 at ser27 in vitro.

SIGNOR-135948

Q969H0

Q5VWQ8

1

ubiquitination

down-regulates quantity by destabilization

0.327

DAB2IP protein levels can be negatively regulated by the activity of the E3-ubiquitin ligases Fbw7, Skp2, and Smurf1

SIGNOR-254774

Q9BZE0

P17612

0

phosphorylation

down-regulates activity

0.283

Protein kinase a (pka) and glycogen synthase kinase 3beta sequentially phosphorylate gli2 at multiple sites, identified by mutagenesis, thus resulting in a reduction of its transcriptional activity

SIGNOR-145131

P42345

P03372

1

phosphorylation

up-regulates activity

0.498

Thus our results indicate that the interaction between ER\u03b1 and raptor is necessary to recruit raptor to the nucleus, where mTOR phosphorylates and activates ER\u03b1.

SIGNOR-278295

P33981

P21589

1

phosphorylation

up-regulates activity

0.2

Intermolecular NTE phosphorylation by Mps1 requires a topology in which sites proximal to the NTE interact with the active Mps1 in order to promote phosphorylation.

SIGNOR-280157

P15036

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-260035

Q13153

P18669

1

phosphorylation

down-regulates

0.2

Activated pak1 inhibits glycolysis by association of its catalytic domain with pgam-b and subsequent phosphorylation of the enzyme on serine residues 23 and 118, thereby abolishing pgam activity.

SIGNOR-91594

P42345

Q8N122

1

phosphorylation

up-regulates activity

0.989

The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser(863), reduced mTORC1 activity both in vitro and in vivo.

SIGNOR-184959

P63000

O43295

0

gtpase-activating protein

down-regulates activity

0.566

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-260518

P51813

Q05397

1

phosphorylation

up-regulates

0.551

Bmx phosphorylated focal adhesion kinase (fak) at tyr577 subsequent to its src-mediated phosphorylation at tyr576. Loss of bmx by rna interference or by genetic deletion in mouse embryonic fibroblasts (mefs) markedly impaired fak activity.

SIGNOR-202139

Q14774

P19419

1

transcriptional regulation

up-regulates quantity by expression

0.2

In this study, we have identified cell cycle regulatory genes as downstream targets of the homeobox gene HLX in cultured trophoblast cells, namely RB1, MYC, EGR1, CDKN1C, ELK1, CCNB1, and JUN. RB1 and MYC mRNA expression was increased with HLX inactivation, whereas EGR1, CDKN1C, ELK1, CCNB1, and JUN mRNA expression was decreased compared with mock-transfected control cells.

SIGNOR-261622

P49841

Q96RR4

1

phosphorylation

down-regulates

0.272

Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.

SIGNOR-198134

P42262

P51608

0

transcriptional regulation

down-regulates quantity by repression

0.323

Bicuculline treatment also leads to an increase in the levels of the transcriptional repressor MeCP2, which binds to the GluR2 promoter along with the corepressors HDAC1 and mSin3A.

SIGNOR-264684

P46531

O14672

0

cleavage

up-regulates activity

0.782

ADAM10-mediated Notch1 cleavage is the rate limiting-step for release of the NICD and subsequent activation of Notch1 signaling. In T cells ADAM10-mediated Notch1 shedding controls T cell development

SIGNOR-259838

Q15139

Q96P20

1

phosphorylation

up-regulates activity

0.332

PKD at the Golgi phosphorylates NLRP3 to release it from mitochondria-associated endoplasmic reticulum membranes, allowing for assembly of the mature inflammasome in the cytosol.|These data thus suggest that PKD activity at the Golgi is sufficient to activate the NLRP3 inflammasome.

SIGNOR-279428

Q96EB6

O75376

1

null

up-regulates

0.621

In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.

SIGNOR-253505

P08123

P03956

0

cleavage

down-regulates quantity by destabilization

0.401

In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775–Ile776 or Gly775–Lys776 in native type I, II or III collagen molecules3,4.

SIGNOR-272337

P42858

Q9UHD2

0

phosphorylation

up-regulates activity

0.289

Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity.

SIGNOR-270350

Q01094

Q13490

0

ubiquitination

up-regulates activity

0.336

The ability of cIAP1 to promote wt E2F1 transcriptional activity was retained by all E2F1 mutants, except the K161R/164R mutant for which cIAP1 was completely inactive and the K185R whose basal transactivation activity was weakly enhanced by cIAP1 (XREF_FIG).|Here, we demonstrated that the E3-ubiquitin ligase cellular inhibitor of apoptosis 1 (cIAP1) increases E2F1 K63-poly-ubiquitination on the lysine residue 161/164 cluster, which is associated with the transcriptional factor stability and activity.

SIGNOR-278688

Q15139

Q9Y5P4

1

phosphorylation

down-regulates

0.2

In this study, we identify cert as a novel in vivo pkd substrate. Phosphorylation on serine 132 by pkd decreases the affinity of cert toward its lipid target phosphatidylinositol 4-phosphate at golgi membranes and reduces ceramide transfer activity

SIGNOR-156500

P15173

P38936

1

transcriptional regulation

down-regulates quantity by repression

0.331

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-251575

P54132

Q13535

0

phosphorylation

up-regulates activity

0.852

It is noteworthy that an active BLM seems to be unnecessary to the activation of BRCA1, either after gamma-rays or HU, even though BRCA1 and BLM helicase are activated by ATR in response to stalled replication, and despite the fact that they colocalize after replication arrest.|These results show that BLM phosphorylation by ATR after replication fork arrest is not important for its relocalization.

SIGNOR-278978

Q9BZ95

Q14653

1

methylation

up-regulates activity

0.2

We found that lysine methyltransferase NSD3 interacts with and directly monomethylates IRF3 in the nucleus, leading to the enhanced IRF3 transcriptional activity and antiviral immune responses.

SIGNOR-259198

A6NLU0

P14635

1

ubiquitination

down-regulates quantity by destabilization

0.32

We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis.

SIGNOR-271476

P04626

Q96JA1

0

ubiquitination

down-regulates

0.403

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-139948

Q9H8S9

Q13188

0

phosphorylation

up-regulates

0.85

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

SIGNOR-175809

O00755

P09238

1

transcriptional regulation

up-regulates quantity by expression

0.2

We first proved that Wnt7a activated the canonical Wnt pathway through direct regulation of the MMP10 gene.

SIGNOR-278867

O95997

P49841

0

phosphorylation

down-regulates activity

0.2

Glycogen synthase kinase-3beta (GSK3beta) negatively regulates PTTG1 and human securin protein stability, and GSK3beta inactivation correlates with securin accumulation in breast tumors.|Here, we demonstrate that glycogen synthase kinase-3\u03b2 (GSK3\u03b2) phosphorylates securin to promote its proteolysis via SCF(\u03b2TrCP) E3 ubiquitin ligase.

SIGNOR-279188

P06493

Q9NXR1

1

phosphorylation

up-regulates activity

0.654

We found that Nudel and NudE were also phosphorylated in M phase (Fig. (Fig.22 and and3).3). First, Nudel and NudE were specifically phosphorylated in M phase. Moreover, both proteins were phosphorylated by Cdc2 and Erk2 in vitro.Due to conservation of the S/TP motifs, NudE may also be phosphorylated at similar sites by these kinases, though it contains an additional potential Cdk site at S282 (SPNR).

SIGNOR-274077

O75676

P16220

1

phosphorylation

up-regulates

0.605

Msk1 and msk2 directly phosphorilate and activete transcription factors such as creb1, atf1 msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation.

SIGNOR-157158

O75030

Q15661

1

transcriptional regulation

up-regulates quantity by expression

0.2

The transcription of tryptase gene in human mast cells is regulated by mi transcription factor |Using mutant constructs of tryptase promoter, we observed that two E-box (CANNTG) motifs including between -817 to -715 and -421 to -202 are able to involve in the transactivation of tryptase gene by MITF-A.

SIGNOR-251725

Q9BXK1

P12931

0

phosphorylation

up-regulates activity

0.245

We further confirmed that the Tyr-10 residue of KLF16 is phosphorylated in uterine cells (Fig. 7c). Additional experiments using both pharmacological and dominant negative inhibitors of Src further supported a role for this tyrosine kinase in modulating the activity of KLF16 (Fig. 7, d and f).

SIGNOR-276398

P29353

Q9UM73

0

phosphorylation

up-regulates

0.456

Anaplastic lymphoma kinase (alk), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the ptb domain of shcc in three neuroblastoma cells. In vitro kinase assay revealed that shcc is a potent substrate of the activated alk kinase. The alk gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the alk kinase, which results in hyperphosphorylation of shcc.

SIGNOR-91534

P01100

P28482

0

phosphorylation

up-regulates activity

0.792

We have recently shown that erk phosphorylates multiple residues within the carboxylterminal transactivation domain (tad) of c-fos, thus resulting in its increased transcriptional activity. ERK2 phosphorylated c-Fos TADs that included Thr- 325, Thr-331, or Ser-374 as unique phospho-acceptor sites, thus indicating that these residues can serve as in vitro targets for the enzymatic activity of ERK2.

SIGNOR-236010

Q8WWN8

P63000

1

gtpase-activating protein

down-regulates activity

0.47

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-260456

Q8TDC3

P30305

1

phosphorylation

down-regulates

0.506

Hssad1 specifically phosphorylated wee1a, cdc25-c, and -b on ser-642, ser-216, and ser-361 in vitro, respectivelyphosphorylation of cdc25 triggers cell-cycle arrest by the sequestration of cdc25 by 14-3-3

SIGNOR-124839

P08559

P12931

0

phosphorylation

down-regulates activity

0.348

Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1).

SIGNOR-277204

Q13153

Q12778

1

phosphorylation

down-regulates activity

0.358

Pak1 efficiently phosphorylated GST-FKHR.

SIGNOR-279242

Q9P286

P15976

1

phosphorylation

up-regulates activity

0.2

In addition, we defined GATA1 Ser161, Ser187 were the main phosphorylation sites by PAK5.

SIGNOR-278297

P28482

P11362

1

phosphorylation

down-regulates

0.309

Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling

SIGNOR-200880

Q9P286

Q9ULA0

1

phosphorylation

down-regulates quantity by destabilization

0.2

We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. | PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway.

SIGNOR-275651

Q99638

P00519

0

phosphorylation

up-regulates activity

0.477

The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. | c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL |these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress.

SIGNOR-260843

P06241

Q96J02

1

phosphorylation

down-regulates activity

0.366

Tyrosine phosphorylation of Itch appears to reduce its interaction with its substrate JunB. The turnover of JunB is accelerated in Fyn-deficient T cells, which is further reconstituted by Itch Tyr371 mutation

SIGNOR-245332

Q9NRC8

Q5TEC6

1

deacetylation

up-regulates activity

0.2

Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37.

SIGNOR-275883

P53041

P48730

0

phosphorylation

up-regulates activity

0.333

Here, we show an "on/off switch" mechanism for PP5 regulation. The casein kinase 1δ (CK1δ) phosphorylates T362 in the catalytic domain of PP5, which activates and enhances phosphatase activity independent of Hsp90.

SIGNOR-277373

P46531

P51608

0

transcriptional regulation

down-regulates quantity by repression

0.29

As the first step to reveal how MeCP2 phosphorylation may regulate Notch signaling, we conducted chromatin immunoprecipitation (ChIP) experiment to determine whether the phosphor-mutant MeCP2 protein has altered promoter occupancy at the promoters of Dll1 and Notch1. We found increased binding of the phosphor-mutant protein at the promoters of both Dll1 and Notch1

SIGNOR-264675

P98171

P63000

1

gtpase-activating protein

down-regulates activity

0.479

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-260460

P46531

Q92993

0

acetylation

down-regulates

0.414

This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60.

SIGNOR-156923

P08581

P17252

0

phosphorylation

down-regulates

0.256

These data show that phosphorylation of ser985 is a key mechanism for the negative regulation of hgf/sf receptor.

SIGNOR-37718

O75676

P18846

1

phosphorylation

up-regulates

0.615

Msk1 and msk2 directly phosphorilate and activate transcription factors such as creb1, atf1.

SIGNOR-116252

P68400

P18887

1

phosphorylation

up-regulates

0.395

Xrcc1 phosphorylation by ck2 is required for its stability and efficient dna repair

SIGNOR-165419

Q92786

Q9Y478

0

phosphorylation

down-regulates quantity by destabilization

0.2

Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation.

SIGNOR-277609

P26651

Q16539

0

phosphorylation

down-regulates activity

0.357

TTP appears to be a p38Î±/Î² MAPK target and pretreating skeletal muscle with a p38Î±/Î² MAPK inhibitor reduces TTP phosphorylation.

SIGNOR-253596

Q5S007

P61020

1

phosphorylation

up-regulates activity

0.599

Using recombinant proteins, we show here that LRRK2 phosphorylates Rab5b at its Thr6 residue in in vitro kinase assays with mass spectrophotometry analysis. Phosphorylation of Rab5b by LRRK2 on the threonine residue was confirmed by western analysis using cells stably expressing LRRK2 G2019S. The phosphomimetic T6D mutant exhibited stronger GTPase activity than that of the wild-type Rab5b. In addition, phosphorylation of Rab5b by LRRK2 also exhibited GTPase activity stronger than that of the unphosphorylated Rab5b protein.

SIGNOR-276873

P48436

P17612

0

phosphorylation

up-regulates

0.465

We find that activation of camp-dependent protein kinase a (pka) induces phosphorylation of sox9 on its two s64 and s181 pka sites, and its nuclear localization by enhancing sox9 binding to the nucleocytoplasmic transport protein importin beta.

SIGNOR-137085

P17612

Q14643

1

phosphorylation

down-regulates activity

0.556

IP(3)R-I was phosphorylated by PKA and PKG in vitro and exclusively by PKG in vivo. Sequential phosphorylation by PKA and by PKG-Ialpha in vitro showed that PKA phosphorylated the same site as PKG (presumably S(1755)) and an additional PKA-specific site (S(1589)). Phosphorylation of IP(3)R-I in microsomes by PKG, PKA, or a combination of PKG and PKA inhibited IP(3)-induced Ca(2+) release to the same extent, implying that inhibition was mediated by phosphorylation of the PKG-specific site.

SIGNOR-249996

P35790

Q99541

1

phosphorylation

down-regulates quantity by destabilization

0.2

In addition, as a protein kinase, CHKalpha2 phosphorylates PLIN2 at Tyrosine 232 and PLIN3 at Tyrosine 251. Phosphorylated PLIN2 and PLIN3 are separated from lipid droplets and degraded by Hsc70-mediated autophagy, thereby promoting lipid droplet lipolysis, fatty acid oxidation and glioblastoma growth

SIGNOR-267649

P00519

P18206

1

phosphorylation

up-regulates activity

0.38

Abl is the tyrosine kinase that phosphorylates vinculin Y822.|Finally we show that Abl inhibition prevents vinculin actions in cadherin containing complexes, resulting in defects in cell stiffening.

SIGNOR-278464

P55283

P63000

1

null

up-regulates activity

0.273

Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.

SIGNOR-253103

Q15797

Q9HCE7

0

ubiquitination

down-regulates

0.708

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

SIGNOR-195660

P30291

O43660

1

phosphorylation

down-regulates activity

0.2

These results indicate that WEE1 promotes PRL1 phosphorylation.|WEE1 promotes PRL1 degradation .

SIGNOR-279579

P29597

Q14765

1

phosphorylation

up-regulates activity

0.656

IL-12 activates the Janus family tyrosine kinases JAK2 and Tyk2, which in turn phosphorylate STAT4 on tyrosine 693.

SIGNOR-279303

P50613

P03372

1

phosphorylation

up-regulates

0.413

Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7.

SIGNOR-81170