GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q92793	Q9NR30	1	acetylation	down-regulates activity	0.245	Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.\|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21.	SIGNOR-275904
P29590	P63165	0	sumoylation	up-regulates	0.78	We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins\|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites\| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation.	SIGNOR-261786
Q8N9B8	P01116	1	guanine nucleotide exchange factor	up-regulates	0.427	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183826
P38936	Q13207	0	transcriptional regulation	down-regulates quantity by repression	0.345	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249593
P49674	P35222	1	phosphorylation	down-regulates activity	0.657	Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45).	SIGNOR-244102
P17612	P07101	1	phosphorylation	up-regulates activity	0.368	HTH1 was phosphorylated at Ser40 by PKA. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. phosphorylationof hTH1‚4 at Ser40, to a stoichiometry of up to 1.0 molphosphate per mol TH subunit, dramatically increases their binding to 14-3-3 proteins.	SIGNOR-250061
Q8TDB6	P62805	1	monoubiquitination	down-regulates activity	0.2	Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. In response to DNA damage, BBAP expression increases and the E3 ligase selectively monoubiquitylates H4K91. Disruption of BBAP-mediated monoubiquitylation of H4K91 is associated with loss of chromatin-associated PR-Set7/Set8 and mono- and dimethyl H4K20, delayed kinetics of 53BP1 foci formation and increased sensitivity to DNA damage.	SIGNOR-271897
Q76N89	O14640	1	ubiquitination	down-regulates quantity by destabilization	0.641	We have also found that NEDL1 targets Dishevelled-1 (Dvl1) for ubiquitination-mediated degradation and that mutant (but not wild-type) SOD1 affects the function of Dvl1.	SIGNOR-271499
P19174	P29317	0	phosphorylation	up-regulates activity	0.276	EphA2 activates PLC\u03b31 in human lung cancer cells.\|The result here showed that only wild-type EphA2, but not K646M\nor Y588F mutants, could phosphorylate PLC\u03b31, demonstrating that\nPLC\u03b31 phosphorylation is dependent on the kinase activity of EphA2.	SIGNOR-279708
P55957	Q13315	0	phosphorylation	down-regulates activity	0.463	Taken together, these results are consistent with the idea that at low levels of DNA damage ATM phosphorylates Bid to keep it away from the mitochondria resulting in low levels of ROS.\|Thus, Bid accumulation at the mitochondria, which is negatively regulated by ATM, triggers a metabolic change in mitochondria that includes an increase in ROS and perhaps changes in other metabolites that signal back to the nucleus to regulate gene transcription leading to cell cycle progression (XREF_FIG).	SIGNOR-279790
Q92731	P06850	1	transcriptional regulation	up-regulates quantity by expression	0.386	Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.\|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro.	SIGNOR-268722
P45985	P53779	1	phosphorylation	up-regulates	0.744	Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19).	SIGNOR-137605
Q9GZY8	Q9BZL6	0	phosphorylation	up-regulates activity	0.2	The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.\|PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-275947
P49810	P55212	0	cleavage	up-regulates activity	0.363	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261750
P06400	Q16539	0	phosphorylation	down-regulates	0.539	P38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates rb on ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not cdks, triggers an interaction between rb and the human homolog of murine double minute 2 (hdm2), leading to degradation of rb, release of e2f1 and cell death.	SIGNOR-168178
P16949	Q8TAS1	0	phosphorylation	down-regulates	0.51	This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of kis-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation.	SIGNOR-182489
P46934	P10523	1	polyubiquitination	down-regulates quantity by destabilization	0.373	Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.	SIGNOR-272843
O14757	P49593	0	dephosphorylation	down-regulates activity	0.2	As a result, inactivation of Chk1 by POPX2 leads to impaired G1S checkpoint activation and cells are able to proceed from G1 to S phase despite DNA damage.\|We also determined that POPX2 can dephosphorylate Chk1Ser317 and -Ser345 and is a potential regulator of Chk1 function in the cell.	SIGNOR-276988
P05976	P27361	0	phosphorylation	up-regulates	0.287	Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein.	SIGNOR-148002
P99999	P31751	0	phosphorylation	down-regulates activity	0.293	Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.	SIGNOR-277236
P28482	P51170	1	phosphorylation	down-regulates quantity by destabilization	0.36	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-249448
Q05655	P10588	1	phosphorylation	down-regulates	0.2	Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6.	SIGNOR-180017
P19652	P16066	0	phosphorylation	up-regulates activity	0.2	On TORC1 inhibition by rapamycin treatment or nutrient limitation, Npr1 phosphorylates and activates Orm1 and Orm2, which in turn promotes synthesis of complex sphingolipids downstream of SPT.\|Thus Npr1 directly phosphorylates Orm1 and Orm2 downstream of TORC1.	SIGNOR-279747
P06730	P67775	0	dephosphorylation	down-regulates	0.347	A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function.	SIGNOR-168306
P30405	P49841	0	phosphorylation	up-regulates activity	0.378	Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion\|We conclude that CypD phosphorylation at S191 residue leads to its binding to OSCP and thus sensitizes mPTP opening for the subsequent cell death.\|Under baseline condition (WT group), the phosphorylation of CypD by a kinase (e.g. GSK3beta) at S191 induces its translocation to the OSCP, to favor mPTP opening and subsequent cell death at reperfusion.	SIGNOR-264880
P49841	P19793	1	phosphorylation	up-regulates activity	0.275	GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.	SIGNOR-277371
P31751	Q12778	1	phosphorylation	down-regulates activity	0.658	Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus.	SIGNOR-68652
O43255	P12931	0	phosphorylation	up-regulates activity	0.334	In human breast cancer cell lines, the protein kinase Src has been shown to activate Siah2 by phosphorylation of tyrosines 86, 140, and 263.\|This function is promoted by Src phosphorylation of Siah2, which increases C/EBPdelta binding, ubiquitination, and degradation.	SIGNOR-279555
Q02156	Q16612	1	phosphorylation	down-regulates quantity by destabilization	0.2	Site-directed mutagenesis of S59A retarded P311 degradation and induced glioma cell motility. In contrast, S59D mutation resulted in the rapid degradation of P311 and reduced glioma cell migration.Taken together, our results show that the serine phosphorylation of P311 is dependent on the function of both PKCε and PKCz.	SIGNOR-273830
Q9UBN4	Q96J02	0	ubiquitination	down-regulates activity	0.35	Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane.	SIGNOR-272624
Q92574	O43524	0	transcriptional regulation	up-regulates quantity	0.448	FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1	SIGNOR-259382
P36873	Q00987	1	dephosphorylation	up-regulates quantity by stabilization	0.2	Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity.	SIGNOR-248504
P25116	P08246	0	cleavage	up-regulates activity	0.43	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus	SIGNOR-263565
P24941	P10244	1	phosphorylation	up-regulates activity	0.718	Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. \| Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. \| These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity.	SIGNOR-250735
O95947	Q9HCE7	0	polyubiquitination	down-regulates quantity by destabilization	0.257	Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase.	SIGNOR-272784
Q16584	Q13526	1	phosphorylation	up-regulates	0.263	Here we demonstrate that mixed-lineage kinase 3 (mlk3), a map3k family member, phosphorylates pin1 on a ser138 site to increase its catalytic activity and nuclear translocation.	SIGNOR-205586
P05771	Q8WV44	0	polyubiquitination	down-regulates quantity by destabilization	0.317	RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear.	SIGNOR-271667
P10275	Q00535	0	phosphorylation	up-regulates	0.371	Cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins	SIGNOR-175696
P03956	Q9ULU4	0	transcriptional regulation	down-regulates quantity by repression	0.2	Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported	SIGNOR-262042
O60763	P67870	0	phosphorylation	up-regulates activity	0.335	Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. \| Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae	SIGNOR-251082
P0DTC2	Q9NRS4	0	cleavage	up-regulates activity	0.2	TMPRSS2 and TMPRSS4 serine proteases mediate this process by inducing cleavage of the S protein and enhancing membrane fusion.	SIGNOR-262306
Q5SQI0	P68363	1	acetylation	up-regulates quantity by stabilization	0.252	Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.\|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules	SIGNOR-272245
Q16512	P18669	1	phosphorylation	down-regulates	0.254	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-91602
Q587J8	Q13315	0	phosphorylation	up-regulates activity	0.2	Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions.	SIGNOR-273505
O96020	Q9HCK8	0	transcriptional regulation	up-regulates quantity by expression	0.417	In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes.	SIGNOR-268804
P05771	O15519	1	phosphorylation	up-regulates quantity by stabilization	0.2	Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins	SIGNOR-276146
O00401	Q05397	0	phosphorylation	up-regulates activity	0.69	In addition, FAK can phosphorylate N-WASP and promote actin polymerization, and inhibition of FAK kinase activity suppresses N-WASP activity.	SIGNOR-278977
Q68DV7	P12830	1	ubiquitination	down-regulates quantity by destabilization	0.267	To identify the E-cadherin ubiquitination site, we individually mutated three lysines in its cytoplasmic domain, including K816A, K855A, and K871A, of which E-cad K816A failed to restore E-cadherin ubiquitination (Additional file xref : Figure S3D), indicating that RNF43 ubiquitinated E-cadherin at the cytoplasmic lysine 816.\|Together , these results suggest that RNF43 potentially downregulates E-cadherin in lung adenocarcinoma in the context of c-Src activation .	SIGNOR-278598
Q14493	Q99879	1	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-265390
Q9Y6N7	Q12857	0	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268893
O15357	P12931	0	phosphorylation	up-regulates	0.535	Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo.	SIGNOR-92935
P17252	P49841	1	phosphorylation	down-regulates	0.357	Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).	SIGNOR-188581
Q96GD4	P42575	1	phosphorylation	up-regulates activity	0.244	Furthermore, in vitro phosphorylation using GST-Casp2 363-423 WT or S384A confirmed that S384 of caspase-2 is phosphorylated by AURKB.	SIGNOR-279496
O14757	O60610	1	phosphorylation	down-regulates activity	0.2	Chk1 Phosphorylates Drf1 for beta-Trcp-Dependent Degradation.\|From this we conclude that Chk1 inhibits Drf1, but not the other three limiting factors at the MBT.	SIGNOR-279026
O14867	P52789	1	transcriptional regulation	up-regulates quantity	0.2	BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells.	SIGNOR-259338
O14733	O43283	0	phosphorylation	up-regulates	0.584	Lzk directly phosphorylated and activated mkk7.	SIGNOR-112349
Q12923	P98172	1	dephosphorylation	up-regulates activity	0.708	Loss of PTPN13 function increases EFNB1 phosphorylation, enhances EFNB1 's interaction with ERBB1 and correlates with potentiated ERK1/2 activation.\|Moreover, acquisition of PTPN13 loss-of-function mutations or its decreased expression (due to HPV infection or epigenetic silencing) may further enhance ERBB1 and EFNB1 mediated signals.	SIGNOR-277002
Q9NZQ7	P40763	0	transcriptional regulation	up-regulates quantity by expression	0.464	STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia.The protein-DNA binding assay revealed that pSTAT3 was bound to the PD-L1 promoter region in H23 cells transfected with EML4-ALK.	SIGNOR-259188
P57678	P35637	0	relocalization	up-regulates activity	0.2	Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.\|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 \|Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells	SIGNOR-262105
P00740	P01008	0	cleavage	down-regulates activity	0.897	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264140
P48735	Q9NXA8	0	catalytic activity	up-regulates activity	0.409	Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes.	SIGNOR-261212
P17612	P11168	1	phosphorylation	down-regulates activity	0.309	GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity.	SIGNOR-250050
P12931	P63010	1	phosphorylation	down-regulates	0.272	The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin.	SIGNOR-181743
Q9UQC2	Q06124	0	dephosphorylation	down-regulates	0.742	Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2.	SIGNOR-124958
P00519	Q9P0J1	1	phosphorylation	down-regulates activity	0.268	Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.	SIGNOR-276641
Q9H2X9	Q9H4A3	0	phosphorylation	down-regulates activity	0.461	The activity of the neuronal specific KCC2 had recently been shown to be regulated by the WNK1 kinase, where phosphorylation decreased KCC2 activation .\|WNK1 phosphorylation of KCC2 occurs in immature neurons but is absent in adult neurons , , emphasizing a developmental role.	SIGNOR-280163
Q13464	P04637	1	phosphorylation	up-regulates quantity	0.409	Besides, ROCK1 phosphorylated p53 at ser15 to up-regulate its protein level.	SIGNOR-280108
O43293	Q00987	1	phosphorylation	up-regulates quantity by stabilization	0.342	Zip kinase was able to phosphorylate mdm2 at ser166, a site previously reported to be modified by akt kinase, thus demonstrating that zip kinase is a bona fide mdm2-binding protein.	SIGNOR-123159
O95271	O15169	1	ubiquitination	down-regulates quantity by destabilization	0.774	Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.	SIGNOR-187972
Q15139	P17252	0	phosphorylation	up-regulates	0.441	These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748.	SIGNOR-66666
P19484	P11802	0	phosphorylation	up-regulates activity	0.2	CDK4 and CDK6 phosphorylate TFEB and TFE3.	SIGNOR-279450
P34947	P50502	1	phosphorylation	up-regulates activity	0.268	An in vitro screen for novel GRK substrates revealed Hsp70 interacting protein (Hip) as a substrate. GRK5, but not GRK2, bound to and stoichiometrically phosphorylated Hip in vitro. The primary binding domain of GRK5 was mapped to residues 303-319 on Hip, while the major site of phosphorylation was identified to be Ser-346. GRK5 also bound to and phosphorylated Hip on Ser-346 in cells.we found that the phosphorylation of Ser-346 was required for proper agonist-induced internalization of the chemokine receptor CXCR4.	SIGNOR-262877
P46531	P49768	0	cleavage	up-regulates	0.797	Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains.	SIGNOR-72886
P16234	P19174	1	phosphorylation	up-regulates	0.65	Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production.	SIGNOR-28176
O00571	P06493	0	phosphorylation	down-regulates	0.297	Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis.	SIGNOR-141569
P05129	Q16625	1	phosphorylation	up-regulates activity	0.307	Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X.	SIGNOR-249107
P24385	P49841	0	phosphorylation	down-regulates	0.783	Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover.	SIGNOR-144818
Q96RU2	P12830	1	deubiquitination	up-regulates quantity by stabilization	0.2	Usp28 deubiquitylates and consequently stabilizes Claspin in response to DNA damage	SIGNOR-274057
P48729	P07910	1	phosphorylation	down-regulates	0.354	A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c.	SIGNOR-133528
O15530	Q14680	0	phosphorylation	down-regulates activity	0.267	The results showed that MPK38 interacted with and inhibited PDK1 activity via Thr(354) phosphorylation.	SIGNOR-276414
Q9BYP7	Q9H2X9	1	phosphorylation	down-regulates activity	0.46	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities\|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264628
P20042	Q9NR50	0	guanine nucleotide exchange factor	up-regulates activity	0.848	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-269131
Q06187	P12931	0	phosphorylation	up-regulates activity	0.529	This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation.	SIGNOR-251100
Q8NI51	Q99933	1	transcriptional regulation	up-regulates quantity by expression	0.28	DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation	SIGNOR-254107
O15550	Q99607	1	transcriptional regulation	down-regulates quantity by repression	0.279	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-260031
P29590	Q9H2X6	0	phosphorylation	up-regulates	0.438	In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death.	SIGNOR-182428
P49840	P13807	1	phosphorylation	down-regulates	0.411	Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase	SIGNOR-118927
O15111	O75925	1	phosphorylation	up-regulates activity	0.38	In addition, we show that IKKalpha is associated with PIAS1 and mediates the S90 phosphorylation of PIAS1.\|Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription.	SIGNOR-278926
Q14524	Q9UQM7	0	phosphorylation	up-regulates activity	0.398	Among the sites identified, only six were previously suggested to be the targets for specific kinases using in silico and/or in vitro analyses: S36 and S525 were attributed to the regulation by PKA; S484 and S664 were assigned to the serum- and glucocorticoid-inducible kinase 3 (SGK3); and S516 and S571 were ascribed to CaMKII (reviewed in Marionneau and Abriel, 2015). In marked contrast, several previously described phosphorylation sites were not detected in the present study, including the PKA-dependent S528, the CaMKII-associated T594, the PKC-dependent S1506, the adenosine monophosphate‚Äìactivated protein kinase (AMPK)‚Äìdependent T101 (Liu et al., 2019), and the six Fyn-dependent tyrosines (Ahern et al., 2005; Iqbal et al., 2018).\|The simplest interpretation of these findings is that these three phosphorylation clusters, at positions S457-S460, S483-T486, and S664-S671, are likely involved in regulating the basal and/or gating properties of native cardiac NaV1.5 channels. Conversely, the other phosphorylation sites, with lower stoichiometries, may play spatially or temporally distinct roles in the physiological or more pathophysiological regulation of channel expression or gating. \| Remarkably, this MS analysis also revealed that the vast majority of identified phosphorylation sites (at least 26) are clustered, suggesting concomitant phosphorylation and roles in regulating channel expression and/or function. Unexpectedly, however, except for S664, S667, and S671, no apparent effects of phosphomimetic or phosphosilent mutations were observed on heterologously expressed (in HEK-293 cells) NaV1.5	SIGNOR-275772
Q13315	P48729	0	phosphorylation	down-regulates quantity by destabilization	0.2	Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest.	SIGNOR-277918
P31939	P50552	0	phosphorylation	up-regulates activity	0.342	ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity.	SIGNOR-276172
P06748	P31269	1	transcriptional regulation	down-regulates quantity by repression	0.352	In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation.	SIGNOR-260138
Q96P70	Q13315	0	phosphorylation	up-regulates activity	0.2	In line with our previous results, IR exposure induced the nuclear accumulation of RanBP9, which was prevented by ATM inhibition using KU-55933.\|Taken together these data indicate that RanBP9 is a novel target of ATM and that ATM phosphorylates at least two different residues (S181 and S603) of RanBP9 following IR exposure.	SIGNOR-278910
P08311	P01019	1	cleavage	up-regulates activity	0.643	Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.	SIGNOR-256312
P04150	P53041	0	dephosphorylation	down-regulates activity	0.541	Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.\|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription.	SIGNOR-248538
P15056	Q8NC42	0	polyubiquitination	down-regulates quantity by destabilization	0.337	We showed that RNF149 bound directly to the C-terminal kinase-containing domain of wild-type BRAF and induced ubiquitination, followed by proteasome-dependent degradation, of the latter protein. Functionally, RNF149 attenuated the increase in cell growth induced by wild-type BRAF.	SIGNOR-272043
P49137	P53667	1	phosphorylation	up-regulates	0.36	Mk2 activated limk1 by phosphorylation at ser-323.	SIGNOR-144333
P36888	O75874	1	phosphorylation	up-regulates activity	0.424	Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity	SIGNOR-267630
Q07955	P51955	0	phosphorylation	down-regulates activity	0.385	First, NEK2 interacts with and phosphorylates SRSF1.	SIGNOR-279344
Q9H093	Q9Y484	1	phosphorylation	up-regulates activity	0.262	WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes.	SIGNOR-268481

Q92793

Q9NR30

1

acetylation

down-regulates activity

0.245

Significantly, the activity of DDX21 is regulated by acetylation. Acetylation by CBP inhibits DDX21 activity, while deacetylation by SIRT7 augments helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.|acetylation of K18, K137, and K600 impairs the helicase activity of DDX21.

SIGNOR-275904

P29590

P63165

0

sumoylation

up-regulates

0.78

We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation.

SIGNOR-261786

Q8N9B8

P01116

1

guanine nucleotide exchange factor

up-regulates

0.427

Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.

SIGNOR-183826

P38936

Q13207

0

transcriptional regulation

down-regulates quantity by repression

0.345

TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS

SIGNOR-249593

P49674

P35222

1

phosphorylation

down-regulates activity

0.657

Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces Beta-catenin phosphorylation at a single site: serine 45 (S45).

SIGNOR-244102

P17612

P07101

1

phosphorylation

up-regulates activity

0.368

HTH1 was phosphorylated at Ser40 by PKA. Tyrosine hydroxylase (TH) has been reported to require binding of 14-3-3 proteins for optimal activation by phosphorylation. phosphorylationof hTH1‚4 at Ser40, to a stoichiometry of up to 1.0 molphosphate per mol TH subunit, dramatically increases their binding to 14-3-3 proteins.

SIGNOR-250061

Q8TDB6

P62805

1

monoubiquitination

down-regulates activity

0.2

Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. In response to DNA damage, BBAP expression increases and the E3 ligase selectively monoubiquitylates H4K91. Disruption of BBAP-mediated monoubiquitylation of H4K91 is associated with loss of chromatin-associated PR-Set7/Set8 and mono- and dimethyl H4K20, delayed kinetics of 53BP1 foci formation and increased sensitivity to DNA damage.

SIGNOR-271897

Q76N89

O14640

1

ubiquitination

down-regulates quantity by destabilization

0.641

We have also found that NEDL1 targets Dishevelled-1 (Dvl1) for ubiquitination-mediated degradation and that mutant (but not wild-type) SOD1 affects the function of Dvl1.

SIGNOR-271499

P19174

P29317

0

phosphorylation

up-regulates activity

0.276

EphA2 activates PLC\u03b31 in human lung cancer cells.|The result here showed that only wild-type EphA2, but not K646M\nor Y588F mutants, could phosphorylate PLC\u03b31, demonstrating that\nPLC\u03b31 phosphorylation is dependent on the kinase activity of EphA2.

SIGNOR-279708

P55957

Q13315

0

phosphorylation

down-regulates activity

0.463

Taken together, these results are consistent with the idea that at low levels of DNA damage ATM phosphorylates Bid to keep it away from the mitochondria resulting in low levels of ROS.|Thus, Bid accumulation at the mitochondria, which is negatively regulated by ATM, triggers a metabolic change in mitochondria that includes an increase in ROS and perhaps changes in other metabolites that signal back to the nucleus to regulate gene transcription leading to cell cycle progression (XREF_FIG).

SIGNOR-279790

Q92731

P06850

1

transcriptional regulation

up-regulates quantity by expression

0.386

Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.|Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro.

SIGNOR-268722

P45985

P53779

1

phosphorylation

up-regulates

0.744

Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19).

SIGNOR-137605

Q9GZY8

Q9BZL6

0

phosphorylation

up-regulates activity

0.2

The mitochondrial fission factor (MFF), the main mitochondrial receptor for the Dynamin-related protein 1 (DRP1), is directly phosphorylated by Protein Kinase D (PKD) specifically during mitosis. PKD-dependent MFF phosphorylation is required and sufficient for mitochondrial fission in mitotic but not in interphasic cells.|PKD directly phosphorylates MFF on serines 155, 172, and 275

SIGNOR-275947

P49810

P55212

0

cleavage

up-regulates activity

0.363

In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.

SIGNOR-261750

P06400

Q16539

0

phosphorylation

down-regulates

0.539

P38 bypasses the cell cycle-associated hierarchical phosphorylation and directly phosphorylates rb on ser567, which is not phosphorylated during the normal cell cycle. Phosphorylation by p38, but not cdks, triggers an interaction between rb and the human homolog of murine double minute 2 (hdm2), leading to degradation of rb, release of e2f1 and cell death.

SIGNOR-168178

P16949

Q8TAS1

0

phosphorylation

down-regulates

0.51

This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of kis-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation.

SIGNOR-182489

P46934

P10523

1

polyubiquitination

down-regulates quantity by destabilization

0.373

Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.

SIGNOR-272843

O14757

P49593

0

dephosphorylation

down-regulates activity

0.2

As a result, inactivation of Chk1 by POPX2 leads to impaired G1S checkpoint activation and cells are able to proceed from G1 to S phase despite DNA damage.|We also determined that POPX2 can dephosphorylate Chk1Ser317 and -Ser345 and is a potential regulator of Chk1 function in the cell.

SIGNOR-276988

P05976

P27361

0

phosphorylation

up-regulates

0.287

Activation of raf/mek/erk cascade can also result in the phosphorylation of the antiapoptotic mcl-1 protein and the pro-apoptotic bim protein.

SIGNOR-148002

P99999

P31751

0

phosphorylation

down-regulates activity

0.293

Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain.

SIGNOR-277236

P28482

P51170

1

phosphorylation

down-regulates quantity by destabilization

0.36

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-249448

Q05655

P10588

1

phosphorylation

down-regulates

0.2

Ser-83 on recombinant nr2f6is a pkc substrate site;mutation of ser-83 (but not ser-89) to alanine strongly reduced pkc-mediated nr2f6 phosphorylation, confirming ser-83 as the major pkc phosphorylation site in nr2f6;the dna-binding capacity of nr2f6 is antagonized by a (p)ser-83 switch on nr2f6.

SIGNOR-180017

P19652

P16066

0

phosphorylation

up-regulates activity

0.2

On TORC1 inhibition by rapamycin treatment or nutrient limitation, Npr1 phosphorylates and activates Orm1 and Orm2, which in turn promotes synthesis of complex sphingolipids downstream of SPT.|Thus Npr1 directly phosphorylates Orm1 and Orm2 downstream of TORC1.

SIGNOR-279747

P06730

P67775

0

dephosphorylation

down-regulates

0.347

A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function.

SIGNOR-168306

P30405

P49841

0

phosphorylation

up-regulates activity

0.378

Phosphorylation of cyclophilin D at serine 191 regulates mitochondrial permeability transition pore opening and cell death after ischemia-reperfusion|We conclude that CypD phosphorylation at S191 residue leads to its binding to OSCP and thus sensitizes mPTP opening for the subsequent cell death.|Under baseline condition (WT group), the phosphorylation of CypD by a kinase (e.g. GSK3beta) at S191 induces its translocation to the OSCP, to favor mPTP opening and subsequent cell death at reperfusion.

SIGNOR-264880

P49841

P19793

1

phosphorylation

up-regulates activity

0.275

GSK3β-induced RXRα phosphorylation decreased for RXRα-S49A, RXRα-S66A and RXRα-S78A in HEK293 cells compared with RXRα WT by western blot analysis.

SIGNOR-277371

P31751

Q12778

1

phosphorylation

down-regulates activity

0.658

Our results demonstrate that pkb/akt directly phosphorylates fkhr1, a member of the closely related fkhr subclass of the forkhead family of transcription factors, on at least two residues (threonine-24 and serine-253). These results indicate that phosphorylation by pkbyakt negatively regulates fkhr1 by promoting export from the nucleus.

SIGNOR-68652

O43255

P12931

0

phosphorylation

up-regulates activity

0.334

In human breast cancer cell lines, the protein kinase Src has been shown to activate Siah2 by phosphorylation of tyrosines 86, 140, and 263.|This function is promoted by Src phosphorylation of Siah2, which increases C/EBPdelta binding, ubiquitination, and degradation.

SIGNOR-279555

Q02156

Q16612

1

phosphorylation

down-regulates quantity by destabilization

0.2

Site-directed mutagenesis of S59A retarded P311 degradation and induced glioma cell motility. In contrast, S59D mutation resulted in the rapid degradation of P311 and reduced glioma cell migration.Taken together, our results show that the serine phosphorylation of P311 is dependent on the function of both PKCε and PKCz.

SIGNOR-273830

Q9UBN4

Q96J02

0

ubiquitination

down-regulates activity

0.35

Ubiquitination of TRPV4 is dramatically increased by the HECT (homologous to E6-AP carboxyl terminus)-family ubiquitin ligase AIP4 without inducing degradation of this channel. Instead, AIP4 promotes the endocytosis of TRPV4 and decreases its amount at the plasma membrane.

SIGNOR-272624

Q92574

O43524

0

transcriptional regulation

up-regulates quantity

0.448

FoxO3a binds to and transactivates the TSC1 promoter, indicating a key role for FoxO3a in regulating TSC1 expression. Together, these data demonstrate that FoxO3a regulates glycolysis downstream of Akt through transcriptional control of Tsc1

SIGNOR-259382

P36873

Q00987

1

dephosphorylation

up-regulates quantity by stabilization

0.2

Three phosphorylation sites identified are Ser342, Ser367, and Ser403. In the present study, we identify protein phosphatase 1 (PP1) as a negative regulator in the p53 signaling pathway. PP1 directly interacts with Mdmx and specifically dephosphorylates Mdmx at Ser367. The dephosphorylation of Mdmx increases its stability and thereby inhibits p53 activity.

SIGNOR-248504

P25116

P08246

0

cleavage

up-regulates activity

0.43

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus

SIGNOR-263565

P24941

P10244

1

phosphorylation

up-regulates activity

0.718

Ten phosphorylation sites carboxyl-terminal to the DNA-binding domain were identified by this method: threonines at positions 267, 408, 497, 519, 522, and 524 and serines at positions 283, 396, 455, and 581. | Our results indicate that B-Myb can be phosphorylated in a cell-free system by both cyclin A-Cdk2 and cyclin E-Cdk2 complexes. | These data suggest that B-Myb is a target for phosphorylation by cyclin-Cdk2 and that phosphorylation of B-Myb regulates its transcriptional activity.

SIGNOR-250735

O95947

Q9HCE7

0

polyubiquitination

down-regulates quantity by destabilization

0.257

Smad6 mediates Tbx6 ubiquitination and proteasomal degradation. Tbx6 forms a ternary complex with Smad6 and Smurf1. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase.

SIGNOR-272784

Q16584

Q13526

1

phosphorylation

up-regulates

0.263

Here we demonstrate that mixed-lineage kinase 3 (mlk3), a map3k family member, phosphorylates pin1 on a ser138 site to increase its catalytic activity and nuclear translocation.

SIGNOR-205586

P05771

Q8WV44

0

polyubiquitination

down-regulates quantity by destabilization

0.317

RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear.

SIGNOR-271667

P10275

Q00535

0

phosphorylation

up-regulates

0.371

Cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins

SIGNOR-175696

P03956

Q9ULU4

0

transcriptional regulation

down-regulates quantity by repression

0.2

Our quantitative ChIP experiments confirmed that ZMYND8 and JARID1D were co-localized at Slug, CD44, VEGFA, and EGFR genes (Figures 4F–4I). Our ChIP results also showed that ZMYND8 repressed and occupied other JARID1D target genes, such as the matrix metalloproteinase 1 (MMP1) and MMP3, that we previously reported

SIGNOR-262042

O60763

P67870

0

phosphorylation

up-regulates activity

0.335

Phosphorylation is mediated by casein kinase II (CKII) or a CKII-like kinase. | Serine 941 in the Acidic Domain of p115 Is Essential for Reassembly of Golgi Cisternae

SIGNOR-251082

P0DTC2

Q9NRS4

0

cleavage

up-regulates activity

0.2

TMPRSS2 and TMPRSS4 serine proteases mediate this process by inducing cleavage of the S protein and enhancing membrane fusion.

SIGNOR-262306

Q5SQI0

P68363

1

acetylation

up-regulates quantity by stabilization

0.252

Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules

SIGNOR-272245

Q16512

P18669

1

phosphorylation

down-regulates

0.254

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-91602

Q587J8

Q13315

0

phosphorylation

up-regulates activity

0.2

Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions.

SIGNOR-273505

O96020

Q9HCK8

0

transcriptional regulation

up-regulates quantity by expression

0.417

In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5' region of both CCNE2 and TYMS genes.

SIGNOR-268804

P05771

O15519

1

phosphorylation

up-regulates quantity by stabilization

0.2

Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins. c-FLIP S193 phosphorylation is mediated by PKCa and PKCb.S193 phosphorylation increases the stability of the short c-FLIP proteins

SIGNOR-276146

O00401

Q05397

0

phosphorylation

up-regulates activity

0.69

In addition, FAK can phosphorylate N-WASP and promote actin polymerization, and inhibition of FAK kinase activity suppresses N-WASP activity.

SIGNOR-278977

Q68DV7

P12830

1

ubiquitination

down-regulates quantity by destabilization

0.267

To identify the E-cadherin ubiquitination site, we individually mutated three lysines in its cytoplasmic domain, including K816A, K855A, and K871A, of which E-cad K816A failed to restore E-cadherin ubiquitination (Additional file xref : Figure S3D), indicating that RNF43 ubiquitinated E-cadherin at the cytoplasmic lysine 816.|Together , these results suggest that RNF43 potentially downregulates E-cadherin in lung adenocarcinoma in the context of c-Src activation .

SIGNOR-278598

Q14493

Q99879

1

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-265390

Q9Y6N7

Q12857

0

transcriptional regulation

up-regulates quantity

0.2

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268893

O15357

P12931

0

phosphorylation

up-regulates

0.535

Ship2 could be phosphorylated in vitro by recombinant src kinase and tyrosines 986-987 in the npxy motif of ship2 appear to be the major sites of phosphorylation for src both in vitro and in vivo.

SIGNOR-92935

P17252

P49841

1

phosphorylation

down-regulates

0.357

Gsk3 is different from most kinases in that it is constitutively partially active and the most common regulatory mechanism is inhibition by phosphorylation of ser21 in gsk3_ or ser9 in gsk3_. This inhibitory phosphorylation can be mediated by several kinases, such as akt/protein kinase b (pkb), protein kinase c (pkc) and protein kinase a (pka).

SIGNOR-188581

Q96GD4

P42575

1

phosphorylation

up-regulates activity

0.244

Furthermore, in vitro phosphorylation using GST-Casp2 363-423 WT or S384A confirmed that S384 of caspase-2 is phosphorylated by AURKB.

SIGNOR-279496

O14757

O60610

1

phosphorylation

down-regulates activity

0.2

Chk1 Phosphorylates Drf1 for beta-Trcp-Dependent Degradation.|From this we conclude that Chk1 inhibits Drf1, but not the other three limiting factors at the MBT.

SIGNOR-279026

O14867

P52789

1

transcriptional regulation

up-regulates quantity

0.2

BACH1 activates transcription of Hexokinase 2 and Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion, thereby stimulating glycolysis-dependent metastasis of mouse and human lung cancer cells.

SIGNOR-259338

O14733

O43283

0

phosphorylation

up-regulates

0.584

Lzk directly phosphorylated and activated mkk7.

SIGNOR-112349

Q12923

P98172

1

dephosphorylation

up-regulates activity

0.708

Loss of PTPN13 function increases EFNB1 phosphorylation, enhances EFNB1 's interaction with ERBB1 and correlates with potentiated ERK1/2 activation.|Moreover, acquisition of PTPN13 loss-of-function mutations or its decreased expression (due to HPV infection or epigenetic silencing) may further enhance ERBB1 and EFNB1 mediated signals.

SIGNOR-277002

Q9NZQ7

P40763

0

transcriptional regulation

up-regulates quantity by expression

0.464

STAT3 and HIF-1α cooperatively enhance PD-L1 expression in EML4-ALK-translocated pADC cells under hypoxia.The protein-DNA binding assay revealed that pSTAT3 was bound to the PD-L1 promoter region in H23 cells transfected with EML4-ALK.

SIGNOR-259188

P57678

P35637

0

relocalization

up-regulates activity

0.2

Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells

SIGNOR-262105

P00740

P01008

0

cleavage

down-regulates activity

0.897

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

SIGNOR-264140

P48735

Q9NXA8

0

catalytic activity

up-regulates activity

0.409

Here, we report that SIRT5 desuccinylates and deglutarylates isocitrate dehydrogenase 2 (IDH2) and glucose-6-phosphate dehydrogenase (G6PD), respectively, and thus activates both NADPH-producing enzymes.

SIGNOR-261212

P17612

P11168

1

phosphorylation

down-regulates activity

0.309

GLUT2 is rapidly phosphorylated by protein kinase A following activation of adenylyl cyclase by forskolin. serines 489 and 501/503 and threonine 510 in the carboxyl-terminal tail of the transporter are the in vitro and in vivo sites of phosphorylation. Stimulation of GLUT2 phosphorylation in beta cells reduces the initial rate of 3-O-methyl glucose uptake by approximately 48% but does not change the Michaelis constant. a consequence of GLUT2 phosphorylation is a reduction of its catalytic activity.

SIGNOR-250050

P12931

P63010

1

phosphorylation

down-regulates

0.272

The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin.

SIGNOR-181743

Q9UQC2

Q06124

0

dephosphorylation

down-regulates

0.742

Expression of the gab2 tyr-614-->phe (y614f) mutant, defective in shp-2 association, prevents erk (extracellular-signal-regulated kinase) activation and expression of a luciferase reporter plasmid driven by the c-fos sre (serum response element), indicating that interaction of shp-2 with gab2 is required for erk activation in response to il-2.

SIGNOR-124958

P00519

Q9P0J1

1

phosphorylation

down-regulates activity

0.268

Here we report that phosphorylation at another tyrosine residue, Tyr-94, inhibits PDP1 by reducing the binding ability of PDP1 to lipoic acid, which is covalently attached to the L2 domain of dihydrolipoyl acetyltransferase (E2) to recruit PDP1 to PDC. We found that multiple oncogenic tyrosine kinases directly phosphorylated PDP1 at Tyr-94, and Tyr-94 phosphorylation of PDP1 was common in diverse human cancer cells and primary leukemia cells from patients.

SIGNOR-276641

Q9H2X9

Q9H4A3

0

phosphorylation

down-regulates activity

0.461

The activity of the neuronal specific KCC2 had recently been shown to be regulated by the WNK1 kinase, where phosphorylation decreased KCC2 activation .|WNK1 phosphorylation of KCC2 occurs in immature neurons but is absent in adult neurons , , emphasizing a developmental role.

SIGNOR-280163

Q13464

P04637

1

phosphorylation

up-regulates quantity

0.409

Besides, ROCK1 phosphorylated p53 at ser15 to up-regulate its protein level.

SIGNOR-280108

O43293

Q00987

1

phosphorylation

up-regulates quantity by stabilization

0.342

Zip kinase was able to phosphorylate mdm2 at ser166, a site previously reported to be modified by akt kinase, thus demonstrating that zip kinase is a bona fide mdm2-binding protein.

SIGNOR-123159

O95271

O15169

1

ubiquitination

down-regulates quantity by destabilization

0.774

Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.

SIGNOR-187972

Q15139

P17252

0

phosphorylation

up-regulates

0.441

These results provide direct evidence that pkd becomes activated in vivo as a consequence of pkc-mediated phosphorylation of serines 744 and 748.

SIGNOR-66666

P19484

P11802

0

phosphorylation

up-regulates activity

0.2

CDK4 and CDK6 phosphorylate TFEB and TFE3.

SIGNOR-279450

P34947

P50502

1

phosphorylation

up-regulates activity

0.268

An in vitro screen for novel GRK substrates revealed Hsp70 interacting protein (Hip) as a substrate. GRK5, but not GRK2, bound to and stoichiometrically phosphorylated Hip in vitro. The primary binding domain of GRK5 was mapped to residues 303-319 on Hip, while the major site of phosphorylation was identified to be Ser-346. GRK5 also bound to and phosphorylated Hip on Ser-346 in cells.we found that the phosphorylation of Ser-346 was required for proper agonist-induced internalization of the chemokine receptor CXCR4.

SIGNOR-262877

P46531

P49768

0

cleavage

up-regulates

0.797

Presenilin-1 (ps1), a polytopic membrane protein primarily localized to the endoplasmic reticulum, is required for efficient proteolysis of both notch and beta-amyloid precursor protein (app) within their trans- membrane domains.

SIGNOR-72886

P16234

P19174

1

phosphorylation

up-regulates

0.65

Tyrosine phosphorylation has been shown to increase the enzymatic activity of plc-? / we show that the human pdgf ?- And ?-Receptors differ quantitatively in their abilities to associate with and phosphorylate plc-? And to stimulate inositol phosphate production.

SIGNOR-28176

O00571

P06493

0

phosphorylation

down-regulates

0.297

Thr204 to glu204 ddx3 mutant protein lost its function, suggesting that phosphorylation at thr204 affects ddx3 function. Thr204 was phosphorylated by cyclin b/cdc2. Thr323 in motif ib was also phosphorylated by cyclin b/cdc2 kinase. We propose a novel function of cyclin b/cdc2 kinase in mitosis, which is to cause a loss of ddx3 function to repress cyclin a expression and to decrease ribosome biogenesis and translation during mitosis.

SIGNOR-141569

P05129

Q16625

1

phosphorylation

up-regulates activity

0.307

Protein kinase C regulates the phosphorylation and cellular localization of occludin. Ser(338) of occludin was identified as an in vitro protein kinase C phosphorylation site using peptide mass fingerprint analysis and electrospray ionization tandem mass spectroscopy. Both the phosphorylation of occludin and its incorporation into tight junctions induced by calcium switch were markedly inhibited by the PKC inhibitor GF-109203X.

SIGNOR-249107

P24385

P49841

0

phosphorylation

down-regulates

0.783

Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover.

SIGNOR-144818

Q96RU2

P12830

1

deubiquitination

up-regulates quantity by stabilization

0.2

Usp28 deubiquitylates and consequently stabilizes Claspin in response to DNA damage

SIGNOR-274057

P48729

P07910

1

phosphorylation

down-regulates

0.354

A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c.

SIGNOR-133528

O15530

Q14680

0

phosphorylation

down-regulates activity

0.267

The results showed that MPK38 interacted with and inhibited PDK1 activity via Thr(354) phosphorylation.

SIGNOR-276414

Q9BYP7

Q9H2X9

1

phosphorylation

down-regulates activity

0.46

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

SIGNOR-264628

P20042

Q9NR50

0

guanine nucleotide exchange factor

up-regulates activity

0.848

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-269131

Q06187

P12931

0

phosphorylation

up-regulates activity

0.529

This interaction of BTK with SRC kinases transphosphorylated BTK on tyrosine at residue 551, which led to BTK activation.

SIGNOR-251100

Q8NI51

Q99933

1

transcriptional regulation

up-regulates quantity by expression

0.28

DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation

SIGNOR-254107

O15550

Q99607

1

transcriptional regulation

down-regulates quantity by repression

0.279

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-260031

P29590

Q9H2X6

0

phosphorylation

up-regulates

0.438

In response to dna damage, hipk2 phosphorylates pml at serines 8 and 38. he n-terminal phosphorylation sites contribute to the dna damage-induced pml sumoylation and are required for the ability of pml to cooperate with hipk2 for the induction of cell death.

SIGNOR-182428

P49840

P13807

1

phosphorylation

down-regulates

0.411

Glycogen synthase kinase-3 (gsk-3) phosphorylates four serine residues in the cooh terminus of glycogen synthase. Phosphorylation of one of these residues, ser640 (site 3a), causes strong inactivation of glycogen synthase

SIGNOR-118927

O15111

O75925

1

phosphorylation

up-regulates activity

0.38

In addition, we show that IKKalpha is associated with PIAS1 and mediates the S90 phosphorylation of PIAS1.|Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription.

SIGNOR-278926

Q14524

Q9UQM7

0

phosphorylation

up-regulates activity

0.398

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

SIGNOR-275772

Q13315

P48729

0

phosphorylation

down-regulates quantity by destabilization

0.2

Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest.

SIGNOR-277918

P31939

P50552

0

phosphorylation

up-regulates activity

0.342

ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity.

SIGNOR-276172

P06748

P31269

1

transcriptional regulation

down-regulates quantity by repression

0.352

In AML cells, NPM1 mutations result in abnormal cytoplasmic localization of the mutant protein (NPM1c); however, it is unknown whether NPM1c is required to maintain the leukemic state. Here, we show that loss of NPM1c from the cytoplasm, either through nuclear relocalization or targeted degradation, results in immediate downregulation of homeobox (HOX) genes followed by differentiation.

SIGNOR-260138

Q96P70

Q13315

0

phosphorylation

up-regulates activity

0.2

In line with our previous results, IR exposure induced the nuclear accumulation of RanBP9, which was prevented by ATM inhibition using KU-55933.|Taken together these data indicate that RanBP9 is a novel target of ATM and that ATM phosphorylates at least two different residues (S181 and S603) of RanBP9 following IR exposure.

SIGNOR-278910

P08311

P01019

1

cleavage

up-regulates activity

0.643

Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.

SIGNOR-256312

P04150

P53041

0

dephosphorylation

down-regulates activity

0.541

Estrogen inhibits glucocorticoid action via protein phosphatase 5 (PP5)-mediated glucocorticoid receptor dephosphorylation.|Inhibition of GR phosphorylation at Ser-211 is associated with decreased nuclear retention of GR and decreased gene transcription.

SIGNOR-248538

P15056

Q8NC42

0

polyubiquitination

down-regulates quantity by destabilization

0.337

We showed that RNF149 bound directly to the C-terminal kinase-containing domain of wild-type BRAF and induced ubiquitination, followed by proteasome-dependent degradation, of the latter protein. Functionally, RNF149 attenuated the increase in cell growth induced by wild-type BRAF.

SIGNOR-272043

P49137

P53667

1

phosphorylation

up-regulates

0.36

Mk2 activated limk1 by phosphorylation at ser-323.

SIGNOR-144333

P36888

O75874

1

phosphorylation

up-regulates activity

0.424

Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity

SIGNOR-267630

Q07955

P51955

0

phosphorylation

down-regulates activity

0.385

First, NEK2 interacts with and phosphorylates SRSF1.

SIGNOR-279344

Q9H093

Q9Y484

1

phosphorylation

up-regulates activity

0.262

WIPI4 is stimulated by AMPK, NUAK2 and BRSK2. This finding is supported by the results of our kinome screening, which identified AMPK and the AMKP-related kinases NUAK2 and BRSK2, all of which function downstream of LKB1 (ref. 69) and stimulate the localization of WIPI4 to nascent autophagosomes.

SIGNOR-268481