GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q9Y5B0	P67870	0	phosphorylation	down-regulates activity	0.327	We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.\| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. \| Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified	SIGNOR-251064
Q14680	P30305	1	phosphorylation	down-regulates activity	0.533	In the present study we show that the human pEg3 kinase is able to specifically phosphorylate CDC25B in vitro. One phosphorylation site was identified and corresponded to serine 323[Ä] Taken together these results suggest that pEg3 is a potential regulator of the G2/M progression and may act antagonistically to the CDC25B phosphatase	SIGNOR-255655
P12931	P08559	1	phosphorylation	down-regulates activity	0.348	Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1).	SIGNOR-277204
P09486	P15036	0	transcriptional regulation	up-regulates quantity by expression	0.305	Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin	SIGNOR-259874
P63279	P01100	1	sumoylation	down-regulates activity	0.365	We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.\|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity.	SIGNOR-263013
Q96GD4	Q96BD8	1	phosphorylation	up-regulates activity	0.736	Aurora B directly phosphorylated Ska1 and Ska3 in vitro, and expression of phosphomimetic mutants of Ska1 and Ska3 impaired Ska KT recruitment and formation of stable KT-MT fibers (K-fibers), disrupting mitotic progression. We propose that Aurora B phosphorylation antagonizes the interaction between the Ska complex and the KMN network, thereby controlling Ska recruitment to KTs and stabilization of KT-MT attachments.	SIGNOR-262662
Q07912	P12931	0	phosphorylation	up-regulates activity	0.385	We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity.	SIGNOR-276342
Q9UQ80	P07288	1	transcriptional regulation	down-regulates quantity by repression	0.2	Ectopic expression of ebp1, a member of the PA2G4 family, inhibits the proliferation and induces the differentiation of human breast and prostate cancer cell lines. Ebp1 inhibits transcription of E2F1 and androgen receptor regulated genes such as prostate specific antigen (PSA) through its interactions with histone deacetylases (HDACs)	SIGNOR-253662
Q8NEB9	P12931	0	phosphorylation	up-regulates activity	0.42	Given that VPS34 is activated by Src mediated tyrosine phosphorylation, we next determined if VPS34 was tyrosine phosphorylated following insulin treatment.\|These data indicate that VPS34 is an effector of insulin-mediated signal transduction and that Src phosphorylation of VPS34 is required for this function.	SIGNOR-278456
Q9HCE7	Q96AC1	1	ubiquitination	down-regulates quantity by destabilization	0.2	Smurf1 mediates Kindlin-2 proteasomal degradation.\|Smurf1 promotes polyubiquitination of Kindlin-2.	SIGNOR-278614
Q6PHR2	P53990	1	phosphorylation	down-regulates activity	0.624	ULK3 phosphorylation of IST1 is required to sustain the abscission checkpoint and inhibits IST1 function in abscission.	SIGNOR-278205
O15068	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.619	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-260559
P22455	P23760	0	transcriptional regulation	up-regulates quantity by expression	0.365	FGFR4 is a transcriptional target of PAX3 and the PAX3-FOXO1 fusion protein found in ARMS.	SIGNOR-251572
P00519	P11387	1	phosphorylation	up-regulates activity	0.399	This study demonstrates that ABL1-dependent phosphorylation up-regulates topo I activity. The ABL1 SH3 domain bound directly to the N-terminal region of topo I. The results demonstrate that ABL1 phosphorylated topo I at Tyr268 in core subdomain II.	SIGNOR-260775
Q9Y210	P06241	0	phosphorylation	up-regulates activity	0.505	Fyn phosphorylates TRPC6 and increases its diacylglycerol stimulated single channel activity.	SIGNOR-279717
P31751	Q13243	1	phosphorylation	up-regulates activity	0.362	Here we show that Akt2 kinase phosphorylated SRp40 in vivo and in vitro. Mutation of Ser86 on SRp40 blocked in vitro phosphorylation.	SIGNOR-262633
O75143	O75385	0	phosphorylation	up-regulates	0.917	Ulks directly phosphorylate atg13	SIGNOR-183957
O43638	P48023	1	transcriptional regulation	down-regulates quantity by repression	0.2	As we expected, Fkhl18 suppressed, dose-dependently,human and mouseFasLpromoter in bovine vascularsmooth muscle cells	SIGNOR-261612
P31323	O43164	0	polyubiquitination	down-regulates quantity by destabilization	0.2	Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits	SIGNOR-271858
Q9BVG3	Q9H257	1	ubiquitination	up-regulates activity	0.51	Importantly, using in vitro ubiquitination assays with purified proteins, we verified that CARD9 is directly ubiquitinated by TRIM62 at residue K125; this ubiquitination is dependent on the ligase activity of TRIM62 and does not occur in CARD9 Delta11 (XREF_FIG).	SIGNOR-278552
P23458	P08575	0	dephosphorylation	up-regulates	0.454	These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3,	SIGNOR-87154
Q92729	P35222	1	dephosphorylation	down-regulates activity	0.4	Protein tyrosine phosphatase receptor U (PTPRU) has been shown to be a tumor suppressor in colon cancer by dephosphorylating \u03b2-catenin and reducing the activation of \u03b2-catenin signaling.	SIGNOR-277095
O00187	P06681	1	cleavage	up-regulates activity	0.436	The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase	SIGNOR-263416
O94989	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.571	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-260540
Q00535	P04626	1	phosphorylation	up-regulates activity	0.274	Since Tyr-654 is the ERBB2 phosphorylation site on beta-catenin, this result is consistent with our hypothesis that CDK5 activates ERBB2 , which in turn phosphorylates beta-catenin on Tyr-654, leading to a shift of beta-catenin away from the adherens junction and into the nucleus where it can serve as a transcriptional co-activator.\|Taken together with the results of our kinase analysis, these observations suggest that CDK5 phosphorylation of both ERBB2 and ERBB3 and AR could drive a feedback loop, in which ERBB2 and ERBB3 promotes beta-catenin transcriptional activity that then contributes to higher expression of ERBB3.	SIGNOR-279155
P28482	C9JLW8	1	phosphorylation	down-regulates activity	0.2	When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.\| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation	SIGNOR-264774
Q06609	P53350	0	phosphorylation	up-regulates activity	0.508	Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin.\|Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase\u2013mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin.	SIGNOR-278187
P04637	P24941	0	phosphorylation	up-regulates activity	0.871	The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A	SIGNOR-119379
Q9NYA1	Q8TD94	0	transcriptional regulation	up-regulates quantity by expression	0.2	KLF14 Is a Transcriptional Activator of SK1 Gene Expression in Endothelial Cells	SIGNOR-266047
O95863	P68400	0	phosphorylation	up-regulates quantity by stabilization	0.348	Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively.	SIGNOR-161771
O15516	P04150	1	transcriptional regulation	down-regulates quantity by repression	0.41	We recently reported that the basic helix-loop- helix transcription factor Clock, which is a histone acetyltransferase and a central component of the self-oscillating transcription factor loop that generates circadian rhythms, represses GR transcriptional activity by acetylating lysine residues within the 'lysine cluster' located in the hinge region of the receptor. This Clock-mediated repression of GR transcriptional activity oscillates in inverse phase to the HPA axis, acting as a target tissue counter-regulatory mechanism to the diurnally fluctuating circulating glucocorticoids.	SIGNOR-253699
P10301	P12931	0	phosphorylation	down-regulates activity	0.58	The small gtpase, r-ras, affects cell adhesion by maintaining integrin activity. Activated src oncogene phosphorylates r-ras and suppresses integrin activity. the src phosphorylation site in r-ras was tyrosine 66	SIGNOR-111189
Q05655	Q6NXT1	1	phosphorylation	up-regulates activity	0.2	The mechanism by which phosphorylation of Ankrd54 by PKC\u03b4 enhances cytoplasmic accumulation of Ankrd54 and its interaction with Lyn remains to be determined.\|This revealed, in agreement with the biochemical analysis, that PKCdelta significantly promotes cytoplasmic accumulation of Ankrd54.	SIGNOR-279259
Q13485	Q9HCE7	0	ubiquitination	down-regulates activity	0.745	Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes.	SIGNOR-236096
Q8N5S9	P31749	1	phosphorylation	up-regulates activity	0.379	Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway.	SIGNOR-252609
Q5JUK2	P10721	1	transcriptional regulation	up-regulates quantity by expression	0.346	Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.	SIGNOR-266205
O75385	Q8NEB9	1	phosphorylation	up-regulates activity	0.713	In the nucleation step of autophagy, The ULK1 complex phosphorylates and activates the Beclin-1-VPS34 complex.	SIGNOR-279670
Q9BT88	O60260	0	polyubiquitination	down-regulates quantity by destabilization	0.2	Parkin binds to the C2A and C2B domains of synaptotagmin XI resulting in the polyubiquitination of synaptotagmin XI. Parkin-mediated ubiquitination also enhances the turnover of sytXI.	SIGNOR-272672
O14920	O15111	0	phosphorylation	up-regulates activity	0.67	Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays.	SIGNOR-250772
Q9NWF9	Q8IUC6	1	ubiquitination	down-regulates quantity by destabilization	0.355	Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins.	SIGNOR-271609
P41220	Q13976	0	phosphorylation	up-regulates activity	0.68	Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction.	SIGNOR-249241
P20042	Q14232	0	guanine nucleotide exchange factor	up-regulates activity	0.78	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269129
P41279	Q99558	1	phosphorylation	up-regulates activity	0.559	In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha	SIGNOR-249387
Q00535	P49768	1	phosphorylation	up-regulates	0.51	Cyclin-dependent kinase-5/p35 phosphorylates presenilin 1 to regulate carboxy-terminal fragment stabilityhere we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates ps1 on threonine(354) within c-ps1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize c-ps1.	SIGNOR-89145
Q14164	Q9UNN5	1	phosphorylation	down-regulates quantity by destabilization	0.283	Upon virus infection, the kinase IKKɛ directly phosphorylates FAF1 at Ser556 and triggers FAF1 de-aggregation. Moreover, Ser556 phosphorylation promotes FAF1 lysosomal degradation, consequently relieving FAF1-dependent suppression of MAVS.	SIGNOR-277618
Q9BVI0	P31749	0	phosphorylation	down-regulates	0.552	Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function.	SIGNOR-252529
P67775	O15344	0	ubiquitination	down-regulates quantity by destabilization	0.453	MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation	SIGNOR-271467
A1L390	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.354	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-260585
O95644	P35354	1	transcriptional regulation	up-regulates quantity by expression	0.316	NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration	SIGNOR-264026
Q99717	O00238	0	phosphorylation	up-regulates activity	0.68	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255260
P41212	Q16549	0	phosphorylation	down-regulates	0.2	In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site	SIGNOR-95622
Q9H2G9	Q9NTX7	0	ubiquitination	down-regulates quantity by destabilization	0.409	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.	SIGNOR-263340
P04637	Q13627	0	phosphorylation	up-regulates	0.417	Dyrk1a phosphorylates p53 and inhibits proliferation of embryonic neuronal cells. we found that dyrk1a phosphorylates p53 at ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor h19-7 cells. In addition, dyrk1a-induced p53 phosphorylation at ser-15 led to a robust induction of p53 target genes	SIGNOR-167407
P17252	Q14432	1	phosphorylation	up-regulates	0.2	Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding.	SIGNOR-184452
Q13114	O43318	1	ubiquitination	up-regulates activity	0.457	Biological investigations demonstrated that TRAF3 activates TAK1 protein kinase activity via a direct binding to TAK1, then the RING finger of TRAF3 ubiquitinates TAK1, leading to TAK1 phosphorylation and activation.\|TRAF3 activates TAK1 through ubiquitination.	SIGNOR-278787
Q96AX2	P17252	0	phosphorylation	down-regulates activity	0.2	We also show that Rab37 is phosphorylated by protein kinase Cα (PKCα) at threonine 172 (T172), leading to attenuation of its GTP-bound state, and impairment of the Rab37-mediated exocytosis of TIMP1, and thus reduces its suppression activity on lung cancer cell motility.	SIGNOR-273803
Q13094	Q92918	0	phosphorylation	up-regulates	0.778	The serine/threonine kinase hpk-1 phosphorylates serine 376 of slp-76 and induces the interaction with 14-3-3 proteins	SIGNOR-153613
P29401	P31749	0	phosphorylation	up-regulates activity	0.282	Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis.	SIGNOR-265101
P15884	P30874	1	transcriptional regulation	up-regulates quantity by expression	0.358	Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain.	SIGNOR-261618
Q93009	O15151	1	deubiquitination	up-regulates	0.757	Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins.	SIGNOR-139453
P31751	Q13043	1	phosphorylation	down-regulates	0.262	Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt.	SIGNOR-201125
P06493	O75170	1	phosphorylation	down-regulates activity	0.261	We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit.	SIGNOR-273587
Q12906	P05771	0	phosphorylation	up-regulates activity	0.2	Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.\|Our results support a model in which PMA stimulation activates PKCβI to phosphorylate NF90-Ser647, and this phosphorylation triggers NF90 relocation to the cytoplasm and stabilize IL-2 mRNA.	SIGNOR-168173
Q13177	Q9NYV4	0	phosphorylation	up-regulates activity	0.2	Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway	SIGNOR-273110
Q9NZQ7	Q9BZS1	0	transcriptional regulation	up-regulates quantity by expression	0.468	FOXP3 expression additionally increased programmed death ligand 1 (PD-L1) expression, which, when inhibited with CCL5, decreased the tumor burden and Treg infiltration in orthotopic murine, Pan-02 PDAC tumors	SIGNOR-277728
P49959	P68400	0	phosphorylation	up-regulates activity	0.2	Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689.	SIGNOR-265893
P33981	P53350	0	phosphorylation	up-regulates activity	0.381	Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro	SIGNOR-276199
P49840	Q07869	1	phosphorylation	up-regulates activity	0.2	GSK-3alpha phosphorylates PPARalpha at Ser280, located in the ligand binding domain.\|These results suggest that GSK-3alpha positively regulates PPARalpha activity through Ser280 phosphorylation.	SIGNOR-278515
P48730	Q16665	1	phosphorylation	down-regulates	0.324	In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha	SIGNOR-167476
P68431	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-265413
Q12968	P48729	0	phosphorylation	down-regulates activity	0.59	Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4.	SIGNOR-109781
Q13315	Q8N163	1	phosphorylation	up-regulates activity	0.587	Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.	SIGNOR-267661
O60260	Q16665	1	ubiquitination	down-regulates quantity by destabilization	0.2	These results indicate that Parkin inhibits HIF-1alpha transcriptional activity.\|Ubiquitination of HIF-1alpha at lysine 477 by Parkin.	SIGNOR-278542
Q14457	P31749	0	phosphorylation	down-regulates activity	0.564	In addition, pharmacological inhibition of AKT1 enhanced BECN1 stability in both assays, leaving about twice the amount of BECN1 at 90 min compared to control (Fig. 4i\u2013l).\|The oncogenic kinase AKT1 phosphorylates BECN1 at positions S234, S295, which leads to sequestration of this peripheral membrane binding protein xref to the cytoskeleton with the result of inhibition of autophagy xref .	SIGNOR-279666
P49841	Q13418	0	phosphorylation	down-regulates activity	0.69	ILK can also directly phosphorylates GSK-3\u03b2 at Ser 9, inactivate it, and lead to activation of some transcription factors [ ].\|ILK knockdown activates GSK-3beta.	SIGNOR-278252
O43462	Q96BA8	1	cleavage	up-regulates	0.568	Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes	SIGNOR-143820
Q12866	Q8NB16	1	phosphorylation	up-regulates quantity by stabilization	0.2	TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6).	SIGNOR-274118
Q9P1W9	Q13200	1	phosphorylation	up-regulates activity	0.2	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).	SIGNOR-273896
P42574	P49137	0	phosphorylation	up-regulates activity	0.311	MK2 Phosphorylates Caspase-3, Facilitates Nuclear Translocation of Caspase 3, and Regulates Apoptosis.\|Over-expression of MK2 led to an increase in nuclear caspase-3 activity.	SIGNOR-278960
P14859	P35580	1	transcriptional regulation	up-regulates quantity by expression	0.2	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238772
P20226	Q7Z6Z7	0	ubiquitination	down-regulates quantity	0.337	Having established that Huwe1 mediates TBP ubiquitination in vitro, we then asked which E2 conjugating enzymes work best with Huwe1 in this reaction.\|Upregulation of Huwe1 expression during myogenesis induces TBP degradation and myotube differentiation.	SIGNOR-278696
Q7Z6J0	P31749	0	phosphorylation	down-regulates	0.394	We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh.	SIGNOR-252501
O95835	Q13043	0	phosphorylation	up-regulates	0.623	We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity.	SIGNOR-133551
P27361	P51168	1	phosphorylation	down-regulates quantity by destabilization	0.278	Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.	SIGNOR-249447
P23396	O14920	0	phosphorylation	up-regulates activity	0.332	IKKbeta overexpression activated NF-kappaB measured by luciferase assays , and also induced the nuclear translocation of wild-type, but not S209A, RPS3 (XREF_FIG).\|Therefore, RPS3 S209 phosphorylation by IKK\u03b2 is apparently required for RPS3 in directing NF-\u03baB to a specific subset of target genes.	SIGNOR-278360
P49841	P26358	1	phosphorylation	down-regulates quantity	0.272	We determined that in a human lung cell line, glycogen synthase kinase 3beta (GSK3beta) phosphorylated DNMT1 to recruit beta-transducin repeat-containing protein (betaTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3beta function and thereby attenuating DNMT1 degradation.	SIGNOR-279181
P63279	O95243	1	sumoylation	up-regulates activity	0.2	MBD4 is sumoylated at three main sites: K137, K215 and K377.\|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.\|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro.	SIGNOR-275678
P17661	P06493	0	phosphorylation	down-regulates quantity by destabilization	0.2	In line with this, we found that in Drp/MC mice desmin was hyperphosphorylated in Ser-31 by a hyperactivated Cdk-1.	SIGNOR-278331
Q13490	O15519	1	ubiquitination	down-regulates quantity	0.663	Moreover, API-1 increased c-FLIP ubiquitination and decreased c-FLIP stability.\|Thus, we conclude that API-1 reduces c-FLIP levels by facilitating its degradation through the ubiquitin and proteasome dependent pathway.	SIGNOR-278687
P08631	Q13905	1	phosphorylation	up-regulates	0.498	We also showed that ctla-4 receptor signaling mediates tyrosine phosphorylation in the c3g protein, and that this is required for augmented activation of rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (lfa-1). ctla-4 signaling leads to phosphorylation of c3g tyrosine 504. the src family member hck phosphorylates c3g downstream of ctla-4.	SIGNOR-203613
P06493	O94901	1	phosphorylation	down-regulates activity	0.358	Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions.	SIGNOR-263099
Q9NRM7	Q4VCS5	1	phosphorylation	up-regulates quantity by stabilization	0.516	Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130	SIGNOR-275846
Q00535	P48730	0	phosphorylation	up-regulates activity	0.555	We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro.	SIGNOR-250798
Q9P275	Q9H6R0	1	deubiquitination	up-regulates quantity by stabilization	0.508	Loss of the deubiquitinase USP36 destabilizes the RNA helicase DHX33 and causes preimplantation lethality in mice.	SIGNOR-272289
P31749	P29375	1	phosphorylation	up-regulates activity	0.303	We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment.	SIGNOR-274062
P69905	P30519	0	null	down-regulates activity	0.254	Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme	SIGNOR-251814
P60484	P98170	0	ubiquitination	down-regulates quantity	0.691	Finally, we found that XIAP can directly ubiquitinate PTEN in vitro.\|Overexpression of XIAP induces polyubiquitination of PTEN and proteasome dependent decrease of PTEN protein levels.	SIGNOR-278751
P27361	O75581	1	phosphorylation	up-regulates	0.313	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6.	SIGNOR-169004
P11362	Q8WU20	1	phosphorylation	up-regulates activity	0.867	As shown in xref , wild type FGFR1c phosphorylated FRS2\u03b1 on tyrosine 196 whereas the V429E mutant did not.	SIGNOR-280013
P35236	Q04759	0	phosphorylation	up-regulates activity	0.2	PKC θ is required for HePTP translocation to the immune synapse. PKC θ phosphorylates HePTP at S225 in primary T cells.	SIGNOR-276045

Q9Y5B0

P67870

0

phosphorylation

down-regulates activity

0.327

We found that only phosphorylated FCP1 can physically interact with TFIIF. We set out to purify an FCP1 kinase from HeLa cells and identified casein kinase 2, which, surprisingly, displayed a negative effect on FCP1-associated activities.| Phosphorylation of FCP1 by CK2 Inhibits the Transcription Elongation Activity of FCP1. | Two in vivo phosphorylation sites within the C terminus of FCP1 at Ser-575 and Ser-740 were identified

SIGNOR-251064

Q14680

P30305

1

phosphorylation

down-regulates activity

0.533

In the present study we show that the human pEg3 kinase is able to specifically phosphorylate CDC25B in vitro. One phosphorylation site was identified and corresponded to serine 323[Ä] Taken together these results suggest that pEg3 is a potential regulator of the G2/M progression and may act antagonistically to the CDC25B phosphatase

SIGNOR-255655

P12931

P08559

1

phosphorylation

down-regulates activity

0.348

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

SIGNOR-277204

P09486

P15036

0

transcriptional regulation

up-regulates quantity by expression

0.305

Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin

SIGNOR-259874

P63279

P01100

1

sumoylation

down-regulates activity

0.365

We report here that lysine 265 of c-Fos is conjugated by the peptidic posttranslational modifiers SUMO-1, SUMO-2, and SUMO-3 and that c-Jun can be sumoylated on lysine 257 as well as on the previously described lysine 229. Sumoylation of c-Fos preferentially occurs in the context of c-Jun/c-Fos heterodimers.|Inhibition of c-Fos and c-Jun sumoylation stimulates AP-1-dependent transcription activity.

SIGNOR-263013

Q96GD4

Q96BD8

1

phosphorylation

up-regulates activity

0.736

Aurora B directly phosphorylated Ska1 and Ska3 in vitro, and expression of phosphomimetic mutants of Ska1 and Ska3 impaired Ska KT recruitment and formation of stable KT-MT fibers (K-fibers), disrupting mitotic progression. We propose that Aurora B phosphorylation antagonizes the interaction between the Ska complex and the KMN network, thereby controlling Ska recruitment to KTs and stabilization of KT-MT attachments.

SIGNOR-262662

Q07912

P12931

0

phosphorylation

up-regulates activity

0.385

We identified two Src phosphorylation sites within the MHR (Y859, Y860). Addition of Src-phosphorylated MHR to the Ack1 KD enhanced enzymatic activity.

SIGNOR-276342

Q9UQ80

P07288

1

transcriptional regulation

down-regulates quantity by repression

0.2

Ectopic expression of ebp1, a member of the PA2G4 family, inhibits the proliferation and induces the differentiation of human breast and prostate cancer cell lines. Ebp1 inhibits transcription of E2F1 and androgen receptor regulated genes such as prostate specific antigen (PSA) through its interactions with histone deacetylases (HDACs)

SIGNOR-253662

Q8NEB9

P12931

0

phosphorylation

up-regulates activity

0.42

Given that VPS34 is activated by Src mediated tyrosine phosphorylation, we next determined if VPS34 was tyrosine phosphorylated following insulin treatment.|These data indicate that VPS34 is an effector of insulin-mediated signal transduction and that Src phosphorylation of VPS34 is required for this function.

SIGNOR-278456

Q9HCE7

Q96AC1

1

ubiquitination

down-regulates quantity by destabilization

0.2

Smurf1 mediates Kindlin-2 proteasomal degradation.|Smurf1 promotes polyubiquitination of Kindlin-2.

SIGNOR-278614

Q6PHR2

P53990

1

phosphorylation

down-regulates activity

0.624

ULK3 phosphorylation of IST1 is required to sustain the abscission checkpoint and inhibits IST1 function in abscission.

SIGNOR-278205

O15068

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.619

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-260559

P22455

P23760

0

transcriptional regulation

up-regulates quantity by expression

0.365

FGFR4 is a transcriptional target of PAX3 and the PAX3-FOXO1 fusion protein found in ARMS.

SIGNOR-251572

P00519

P11387

1

phosphorylation

up-regulates activity

0.399

This study demonstrates that ABL1-dependent phosphorylation up-regulates topo I activity. The ABL1 SH3 domain bound directly to the N-terminal region of topo I. The results demonstrate that ABL1 phosphorylated topo I at Tyr268 in core subdomain II.

SIGNOR-260775

Q9Y210

P06241

0

phosphorylation

up-regulates activity

0.505

Fyn phosphorylates TRPC6 and increases its diacylglycerol stimulated single channel activity.

SIGNOR-279717

P31751

Q13243

1

phosphorylation

up-regulates activity

0.362

Here we show that Akt2 kinase phosphorylated SRp40 in vivo and in vitro. Mutation of Ser86 on SRp40 blocked in vitro phosphorylation.

SIGNOR-262633

O75143

O75385

0

phosphorylation

up-regulates

0.917

Ulks directly phosphorylate atg13

SIGNOR-183957

O43638

P48023

1

transcriptional regulation

down-regulates quantity by repression

0.2

As we expected, Fkhl18 suppressed, dose-dependently,human and mouseFasLpromoter in bovine vascularsmooth muscle cells

SIGNOR-261612

P31323

O43164

0

polyubiquitination

down-regulates quantity by destabilization

0.2

Praja2 controls the stability of PKA regulatory subunits. Praja2 ubiquitylates RIIα/β subunits. Subunits

SIGNOR-271858

Q9BVG3

Q9H257

1

ubiquitination

up-regulates activity

0.51

Importantly, using in vitro ubiquitination assays with purified proteins, we verified that CARD9 is directly ubiquitinated by TRIM62 at residue K125; this ubiquitination is dependent on the ligase activity of TRIM62 and does not occur in CARD9 Delta11 (XREF_FIG).

SIGNOR-278552

P23458

P08575

0

dephosphorylation

up-regulates

0.454

These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3,

SIGNOR-87154

Q92729

P35222

1

dephosphorylation

down-regulates activity

0.4

Protein tyrosine phosphatase receptor U (PTPRU) has been shown to be a tumor suppressor in colon cancer by dephosphorylating \u03b2-catenin and reducing the activation of \u03b2-catenin signaling.

SIGNOR-277095

O00187

P06681

1

cleavage

up-regulates activity

0.436

The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase

SIGNOR-263416

O94989

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.571

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-260540

Q00535

P04626

1

phosphorylation

up-regulates activity

0.274

Since Tyr-654 is the ERBB2 phosphorylation site on beta-catenin, this result is consistent with our hypothesis that CDK5 activates ERBB2 , which in turn phosphorylates beta-catenin on Tyr-654, leading to a shift of beta-catenin away from the adherens junction and into the nucleus where it can serve as a transcriptional co-activator.|Taken together with the results of our kinase analysis, these observations suggest that CDK5 phosphorylation of both ERBB2 and ERBB3 and AR could drive a feedback loop, in which ERBB2 and ERBB3 promotes beta-catenin transcriptional activity that then contributes to higher expression of ERBB3.

SIGNOR-279155

P28482

C9JLW8

1

phosphorylation

down-regulates activity

0.2

When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.| While substitution of S4 or S18 with Ala did not affect the phosphorylation of MCRIP1 by ERK, substitution of either S21 or T30 significantly reduced MCRIP1 phosphorylation

SIGNOR-264774

Q06609

P53350

0

phosphorylation

up-regulates activity

0.508

Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin.|Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase\u2013mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin.

SIGNOR-278187

P04637

P24941

0

phosphorylation

up-regulates activity

0.871

The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A

SIGNOR-119379

Q9NYA1

Q8TD94

0

transcriptional regulation

up-regulates quantity by expression

0.2

KLF14 Is a Transcriptional Activator of SK1 Gene Expression in Endothelial Cells

SIGNOR-266047

O95863

P68400

0

phosphorylation

up-regulates quantity by stabilization

0.348

Serines 11 and 92 participate in the control of snail1 stability and positively regulate snail1 repressive function and its interaction with msin3a corepressor. Furthermore, serines 11 and 92 are required for snail1-mediated emt and cell viability, respectively. Pka and ck2 have been characterized as the main kinases responsible for in vitro snail1 phosphorylation at serine 11 and 92, respectively.

SIGNOR-161771

O15516

P04150

1

transcriptional regulation

down-regulates quantity by repression

0.41

We recently reported that the basic helix-loop- helix transcription factor Clock, which is a histone acetyltransferase and a central component of the self-oscillating transcription factor loop that generates circadian rhythms, represses GR transcriptional activity by acetylating lysine residues within the 'lysine cluster' located in the hinge region of the receptor. This Clock-mediated repression of GR transcriptional activity oscillates in inverse phase to the HPA axis, acting as a target tissue counter-regulatory mechanism to the diurnally fluctuating circulating glucocorticoids.

SIGNOR-253699

P10301

P12931

0

phosphorylation

down-regulates activity

0.58

The small gtpase, r-ras, affects cell adhesion by maintaining integrin activity. Activated src oncogene phosphorylates r-ras and suppresses integrin activity. the src phosphorylation site in r-ras was tyrosine 66

SIGNOR-111189

Q05655

Q6NXT1

1

phosphorylation

up-regulates activity

0.2

The mechanism by which phosphorylation of Ankrd54 by PKC\u03b4 enhances cytoplasmic accumulation of Ankrd54 and its interaction with Lyn remains to be determined.|This revealed, in agreement with the biochemical analysis, that PKCdelta significantly promotes cytoplasmic accumulation of Ankrd54.

SIGNOR-279259

Q13485

Q9HCE7

0

ubiquitination

down-regulates activity

0.745

Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes.

SIGNOR-236096

Q8N5S9

P31749

1

phosphorylation

up-regulates activity

0.379

Protein kinase B (PKB) was recently reported to be activated on the phosphorylation of Thr(308) by Ca(2+)/calmodulin-dependent protein kinase kinase alpha (CaM-kinase kinase alpha), suggesting that PKB was regulated through not only the phosphoinositide 3-kinase pathway but also the Ca(2+)/calmodulin protein kinase pathway.

SIGNOR-252609

Q5JUK2

P10721

1

transcriptional regulation

up-regulates quantity by expression

0.346

Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.

SIGNOR-266205

O75385

Q8NEB9

1

phosphorylation

up-regulates activity

0.713

In the nucleation step of autophagy, The ULK1 complex phosphorylates and activates the Beclin-1-VPS34 complex.

SIGNOR-279670

Q9BT88

O60260

0

polyubiquitination

down-regulates quantity by destabilization

0.2

Parkin binds to the C2A and C2B domains of synaptotagmin XI resulting in the polyubiquitination of synaptotagmin XI. Parkin-mediated ubiquitination also enhances the turnover of sytXI.

SIGNOR-272672

O14920

O15111

0

phosphorylation

up-regulates activity

0.67

Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays.

SIGNOR-250772

Q9NWF9

Q8IUC6

1

ubiquitination

down-regulates quantity by destabilization

0.355

Triad3A promotes proteolytic degradation of adapter proteins. A, Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins.

SIGNOR-271609

P41220

Q13976

0

phosphorylation

up-regulates activity

0.68

Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction.

SIGNOR-249241

P20042

Q14232

0

guanine nucleotide exchange factor

up-regulates activity

0.78

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

SIGNOR-269129

P41279

Q99558

1

phosphorylation

up-regulates activity

0.559

In studies of NIK, we found that Thr-559 located within the activation loop of its kinase domain regulates NIK action. Alanine substitution of Thr-559 but not other serine or threonine residues within the activation loop abolishes its activity and its ability to phosphorylate and activate IKKalpha

SIGNOR-249387

Q00535

P49768

1

phosphorylation

up-regulates

0.51

Cyclin-dependent kinase-5/p35 phosphorylates presenilin 1 to regulate carboxy-terminal fragment stabilityhere we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates ps1 on threonine(354) within c-ps1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize c-ps1.

SIGNOR-89145

Q14164

Q9UNN5

1

phosphorylation

down-regulates quantity by destabilization

0.283

Upon virus infection, the kinase IKKɛ directly phosphorylates FAF1 at Ser556 and triggers FAF1 de-aggregation. Moreover, Ser556 phosphorylation promotes FAF1 lysosomal degradation, consequently relieving FAF1-dependent suppression of MAVS.

SIGNOR-277618

Q9BVI0

P31749

0

phosphorylation

down-regulates

0.552

Akt phosphorylates phf20 at ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of phf20 function.

SIGNOR-252529

P67775

O15344

0

ubiquitination

down-regulates quantity by destabilization

0.453

MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation

SIGNOR-271467

A1L390

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.354

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-260585

O95644

P35354

1

transcriptional regulation

up-regulates quantity by expression

0.316

NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration

SIGNOR-264026

Q99717

O00238

0

phosphorylation

up-regulates activity

0.68

Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.

SIGNOR-255260

P41212

Q16549

0

phosphorylation

down-regulates

0.2

In vivo p38-dependent phosphorylation reduced trans-repressional abilities of tel through ets-binding consensus site

SIGNOR-95622

Q9H2G9

Q9NTX7

0

ubiquitination

down-regulates quantity by destabilization

0.409

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

SIGNOR-263340

P04637

Q13627

0

phosphorylation

up-regulates

0.417

Dyrk1a phosphorylates p53 and inhibits proliferation of embryonic neuronal cells. we found that dyrk1a phosphorylates p53 at ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor h19-7 cells. In addition, dyrk1a-induced p53 phosphorylation at ser-15 led to a robust induction of p53 target genes

SIGNOR-167407

P17252

Q14432

1

phosphorylation

up-regulates

0.2

Protein kinase c-mediated phosphorylation and activation of pde3a regulate camp levels in human platelets. together, these results demonstrate that platelet activation stimulates pkc-dependent phosphorylation of pde3a on ser(312), ser(428), ser(438), ser(465), and ser(492) leading to a subsequent increase in camp hydrolysis and 14-3-3 binding.

SIGNOR-184452

Q13114

O43318

1

ubiquitination

up-regulates activity

0.457

Biological investigations demonstrated that TRAF3 activates TAK1 protein kinase activity via a direct binding to TAK1, then the RING finger of TRAF3 ubiquitinates TAK1, leading to TAK1 phosphorylation and activation.|TRAF3 activates TAK1 through ubiquitination.

SIGNOR-278787

Q96AX2

P17252

0

phosphorylation

down-regulates activity

0.2

We also show that Rab37 is phosphorylated by protein kinase Cα (PKCα) at threonine 172 (T172), leading to attenuation of its GTP-bound state, and impairment of the Rab37-mediated exocytosis of TIMP1, and thus reduces its suppression activity on lung cancer cell motility.

SIGNOR-273803

Q13094

Q92918

0

phosphorylation

up-regulates

0.778

The serine/threonine kinase hpk-1 phosphorylates serine 376 of slp-76 and induces the interaction with 14-3-3 proteins

SIGNOR-153613

P29401

P31749

0

phosphorylation

up-regulates activity

0.282

Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis.

SIGNOR-265101

P15884

P30874

1

transcriptional regulation

up-regulates quantity by expression

0.358

Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain.

SIGNOR-261618

Q93009

O15151

1

deubiquitination

up-regulates

0.757

Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins.

SIGNOR-139453

P31751

Q13043

1

phosphorylation

down-regulates

0.262

Full activation of mst1 requires an activation cleavage that is prevented by the phosphorylation of thr-387 by akt.

SIGNOR-201125

P06493

O75170

1

phosphorylation

down-regulates activity

0.261

We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit.

SIGNOR-273587

Q12906

P05771

0

phosphorylation

up-regulates activity

0.2

Upon T cell activation, NF90 translocates from the nucleus into the cytoplasm, where it binds to the AU-rich element-containing 3' untranslated regions of IL-2 mRNA and stabilizes it.|Our results support a model in which PMA stimulation activates PKCβI to phosphorylate NF90-Ser647, and this phosphorylation triggers NF90 relocation to the cytoplasm and stabilize IL-2 mRNA.

SIGNOR-168173

Q13177

Q9NYV4

0

phosphorylation

up-regulates activity

0.2

Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway

SIGNOR-273110

Q9NZQ7

Q9BZS1

0

transcriptional regulation

up-regulates quantity by expression

0.468

FOXP3 expression additionally increased programmed death ligand 1 (PD-L1) expression, which, when inhibited with CCL5, decreased the tumor burden and Treg infiltration in orthotopic murine, Pan-02 PDAC tumors

SIGNOR-277728

P49959

P68400

0

phosphorylation

up-regulates activity

0.2

Here we show that MRE11 directly interacts with PIH1D1, a subunit of heat-shock protein 90 cochaperone R2TP complex, which is required for the assembly of large protein complexes, such as RNA polymerase II, small nucleolar ribonucleoproteins and mammalian target of rapamycin complex 1. The MRE11-PIH1D1 interaction is dependent on casein kinase 2 (CK2) phosphorylation of two acidic sequences within the MRE11 C terminus containing serines 558/561 and 688/689.

SIGNOR-265893

P33981

P53350

0

phosphorylation

up-regulates activity

0.381

Here, we demonstrate that Plk1 promotes checkpoint signaling at kinetochores through the phosphorylation of at least two Mps1 substrates, including KNL-1 and Mps1 itself. As a result, Plk1 activity enhances Mps1 catalytic activity as well as the recruitment of the SAC components Mad1:C-Mad2 and Bub3:BubR1 to kinetochores. Plk1 Targets Mps1 Autophosphorylation Sites In Vitro

SIGNOR-276199

P49840

Q07869

1

phosphorylation

up-regulates activity

0.2

GSK-3alpha phosphorylates PPARalpha at Ser280, located in the ligand binding domain.|These results suggest that GSK-3alpha positively regulates PPARalpha activity through Ser280 phosphorylation.

SIGNOR-278515

P48730

Q16665

1

phosphorylation

down-regulates

0.324

In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha

SIGNOR-167476

P68431

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-265413

Q12968

P48729

0

phosphorylation

down-regulates activity

0.59

Dominant-negative cki alpha Induces nuclear import of nf-at4 these results demonstrated that the cki alpha Phosphorylation sites identified in vitro were also specifically phosphorylated by cki alpha In vivo, and that these residues were crucial for the masking of the nls of nf-at4.

SIGNOR-109781

Q13315

Q8N163

1

phosphorylation

up-regulates activity

0.587

Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.

SIGNOR-267661

O60260

Q16665

1

ubiquitination

down-regulates quantity by destabilization

0.2

These results indicate that Parkin inhibits HIF-1alpha transcriptional activity.|Ubiquitination of HIF-1alpha at lysine 477 by Parkin.

SIGNOR-278542

Q14457

P31749

0

phosphorylation

down-regulates activity

0.564

In addition, pharmacological inhibition of AKT1 enhanced BECN1 stability in both assays, leaving about twice the amount of BECN1 at 90 min compared to control (Fig. 4i\u2013l).|The oncogenic kinase AKT1 phosphorylates BECN1 at positions S234, S295, which leads to sequestration of this peripheral membrane binding protein xref to the cytoskeleton with the result of inhibition of autophagy xref .

SIGNOR-279666

P49841

Q13418

0

phosphorylation

down-regulates activity

0.69

ILK can also directly phosphorylates GSK-3\u03b2 at Ser 9, inactivate it, and lead to activation of some transcription factors [ ].|ILK knockdown activates GSK-3beta.

SIGNOR-278252

O43462

Q96BA8

1

cleavage

up-regulates

0.568

Cleavage of oasis by site-1 and site-2 proteases / oasis is cleaved at the membrane under er stress conditions and that its cleaved n-terminal domain translocates into the nucleus;and then activates transcription of target genes

SIGNOR-143820

Q12866

Q8NB16

1

phosphorylation

up-regulates quantity by stabilization

0.2

TAM kinases phosphorylate MLKL to promote necroptosis. MLKL is then recruited to the plasma membrane, where TAM kinases phosphorylate MLKL at Tyr376 (Figure 5G, step 5), promoting its oligomerization and formation of membrane-rupturing pores that result in necrotic cell death (Figure 5G, step 6).

SIGNOR-274118

Q9P1W9

Q13200

1

phosphorylation

up-regulates activity

0.2

Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).

SIGNOR-273896

P42574

P49137

0

phosphorylation

up-regulates activity

0.311

MK2 Phosphorylates Caspase-3, Facilitates Nuclear Translocation of Caspase 3, and Regulates Apoptosis.|Over-expression of MK2 led to an increase in nuclear caspase-3 activity.

SIGNOR-278960

P14859

P35580

1

transcriptional regulation

up-regulates quantity by expression

0.2

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238772

P20226

Q7Z6Z7

0

ubiquitination

down-regulates quantity

0.337

Having established that Huwe1 mediates TBP ubiquitination in vitro, we then asked which E2 conjugating enzymes work best with Huwe1 in this reaction.|Upregulation of Huwe1 expression during myogenesis induces TBP degradation and myotube differentiation.

SIGNOR-278696

Q7Z6J0

P31749

0

phosphorylation

down-regulates

0.394

We report here that posh is a direct substrate for phosphorylation by akt in vivo and in vitro, and we identify a major site of akt phosphorylation as serine 304 of posh, which lies within the rac-binding domain. We further show that phosphorylation of posh results in a decreased ability to bind activated rac, as does phosphomimetic s304d and s304e mutation of posh.

SIGNOR-252501

O95835

Q13043

0

phosphorylation

up-regulates

0.623

We show that Mst2 and hWW45 interact with each other in human cells and that both Mst2 and Mst1 are able to phosphorylate Lats1 and Lats2, thereby stimulating Lats kinase activity.

SIGNOR-133551

P27361

P51168

1

phosphorylation

down-regulates quantity by destabilization

0.278

Using a number of different approaches it was demonstrated that the protein kinase acting on betaThr-613 and gammaThr-623 is the extracellular regulated kinase (ERK). It is suggested that an ERK-mediated phosphorylation of betaThr-613 and gammaThr-623 down-regulates the channel by facilitating its interaction with Nedd4.

SIGNOR-249447

P23396

O14920

0

phosphorylation

up-regulates activity

0.332

IKKbeta overexpression activated NF-kappaB measured by luciferase assays , and also induced the nuclear translocation of wild-type, but not S209A, RPS3 (XREF_FIG).|Therefore, RPS3 S209 phosphorylation by IKK\u03b2 is apparently required for RPS3 in directing NF-\u03baB to a specific subset of target genes.

SIGNOR-278360

P49841

P26358

1

phosphorylation

down-regulates quantity

0.272

We determined that in a human lung cell line, glycogen synthase kinase 3beta (GSK3beta) phosphorylated DNMT1 to recruit beta-transducin repeat-containing protein (betaTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3beta function and thereby attenuating DNMT1 degradation.

SIGNOR-279181

P63279

O95243

1

sumoylation

up-regulates activity

0.2

MBD4 is sumoylated at three main sites: K137, K215 and K377.|Sumoylation increases the G:T repair activity of MBD4 in cell extracts.|we conducted an in vitrosumoylation assay, employing recombinant activating E1 (Aos1-Uba2) and conjugating E2 (Ubc9) enzymes, along with recombinant YFP-SUMO1 and MBD4 or, as positive control for sumoylation, TDG (Fig. 2D). These results indicate that MBD4 is sumoylated in vivo and in vitro.

SIGNOR-275678

P17661

P06493

0

phosphorylation

down-regulates quantity by destabilization

0.2

In line with this, we found that in Drp/MC mice desmin was hyperphosphorylated in Ser-31 by a hyperactivated Cdk-1.

SIGNOR-278331

Q13490

O15519

1

ubiquitination

down-regulates quantity

0.663

Moreover, API-1 increased c-FLIP ubiquitination and decreased c-FLIP stability.|Thus, we conclude that API-1 reduces c-FLIP levels by facilitating its degradation through the ubiquitin and proteasome dependent pathway.

SIGNOR-278687

P08631

Q13905

1

phosphorylation

up-regulates

0.498

We also showed that ctla-4 receptor signaling mediates tyrosine phosphorylation in the c3g protein, and that this is required for augmented activation of rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (lfa-1). ctla-4 signaling leads to phosphorylation of c3g tyrosine 504. the src family member hck phosphorylates c3g downstream of ctla-4.

SIGNOR-203613

P06493

O94901

1

phosphorylation

down-regulates activity

0.358

Here, we show that SUN1, located in the INM, undergoes mitosis-specific phosphorylation on at least 3 sites within its nucleoplasmic N-terminus. We further identify Cdk1 as the kinase responsible for serine 48 and 333 phosphorylation, while serine 138 is phosphorylated by Plk1. Together, these data support a model whereby mitotic phosphorylation of SUN1 disrupts interactions with nucleoplasmic binding partners, promoting disassembly of the nuclear lamina and, potentially, its chromatin interactions.

SIGNOR-263099

Q9NRM7

Q4VCS5

1

phosphorylation

up-regulates quantity by stabilization

0.516

Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130

SIGNOR-275846

Q00535

P48730

0

phosphorylation

up-regulates activity

0.555

We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro.

SIGNOR-250798

Q9P275

Q9H6R0

1

deubiquitination

up-regulates quantity by stabilization

0.508

Loss of the deubiquitinase USP36 destabilizes the RNA helicase DHX33 and causes preimplantation lethality in mice.

SIGNOR-272289

P31749

P29375

1

phosphorylation

up-regulates activity

0.303

We immunoprecipitated ectopically expressed wild-type KDM5A or KDM5Amut5A and performed an in vitro kinase assay using recombinant AKT1 in the presence or absence of AKT inhibition.Wild-type KDM5A is phosphorylated by AKT1 and this modification is sensitive to AKT inhibition, whereas KDM5Amut5A is not phosphorylated in the presence of AKT1 (Figure 3C).These results suggest that AKT-mediated KDM5A phosphorylation enhances KDM5A promoter recruitment.

SIGNOR-274062

P69905

P30519

0

null

down-regulates activity

0.254

Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular hemoprotein, hemoglobin, and heme

SIGNOR-251814

P60484

P98170

0

ubiquitination

down-regulates quantity

0.691

Finally, we found that XIAP can directly ubiquitinate PTEN in vitro.|Overexpression of XIAP induces polyubiquitination of PTEN and proteasome dependent decrease of PTEN protein levels.

SIGNOR-278751

P27361

O75581

1

phosphorylation

up-regulates

0.313

We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6.

SIGNOR-169004

P11362

Q8WU20

1

phosphorylation

up-regulates activity

0.867

As shown in xref , wild type FGFR1c phosphorylated FRS2\u03b1 on tyrosine 196 whereas the V429E mutant did not.

SIGNOR-280013

P35236

Q04759

0

phosphorylation

up-regulates activity

0.2

PKC θ is required for HePTP translocation to the immune synapse. PKC θ phosphorylates HePTP at S225 in primary T cells.

SIGNOR-276045