GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
O60674	P10912	1	phosphorylation	up-regulates activity	0.766	Jak2 is then phosphorylated and, in turn, phosphorylates the GHR and the signal transducers and activators of transcription (STAT) protein.	SIGNOR-279198
Q05513	P35612	1	phosphorylation	down-regulates	0.275	We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta.	SIGNOR-139914
P42574	Q15173	0	dephosphorylation	up-regulates	0.2	Dephosphorylation of caspase-3 at ser150 site by pp2a increased caspase-3 activity,which was essential to trigger apoptosis in neutrophils.	SIGNOR-131435
Q9NRF2	P40259	1	dephosphorylation	down-regulates activity	0.2	SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.	SIGNOR-268458
Q5S007	P62841	1	phosphorylation	up-regulates activity	0.485	Taken together, these results suggest that phosphorylation of s15 on T136 by LRRK2 mediates enhanced cap-dependent and cap-independent reporter translation and that a stimulatory effect of LRRK2 on mRNA translation contributes to LRRK2 toxicity.	SIGNOR-279058
Q13043	Q7L7X3	0	phosphorylation	up-regulates	0.368	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.	SIGNOR-201324
P78357	P12931	0	phosphorylation	down-regulates activity	0.336	If that is the case, then our genetic results support the notion that p190 is negatively regulated by both Src and integrin.\|The Src family of tyrosine kinases phosphorylate mammalian p190.	SIGNOR-279572
P54252	P49841	0	phosphorylation	up-regulates quantity by stabilization	0.465	Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3\|	SIGNOR-264821
Q92974	Q8TD19	0	phosphorylation	up-regulates activity	0.2	The phosphorylation of ARHGEF2 by NEK9 is the key step of this process.	SIGNOR-279638
P19793	P45985	0	phosphorylation	down-regulates	0.2	Phosphorylation by mkk4/sek1 had profound effects on the biochemical properties of rxr, inhibiting the expression of genes activated by rxr-retinoic acid receptor complexes. Tyr-249 in the rxr de region was required for the inhibitory effect of mkk4/sek1.	SIGNOR-80619
O96017	Q13049	1	phosphorylation	up-regulates activity	0.2	We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy.	SIGNOR-277790
P17252	P13569	1	phosphorylation	up-regulates activity	0.399	Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC.	SIGNOR-248849
O14965	P40337	1	phosphorylation	down-regulates quantity by destabilization	0.406	Conversely, AURKA can phosphorylate VHL at serine 72, a priming phosphorylation for GSK3beta, which regulates VHL 's role in microtubule stability.	SIGNOR-279800
P36952	P10275	0	transcriptional regulation	down-regulates quantity by repression	0.401	In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter	SIGNOR-253685
Q14493	P57053	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-265384
Q969V5	Q86WV6	1	ubiquitination	up-regulates activity	0.2	Identification of MUL1 as an essential activator of dsDNA mediated STING dependent pathway.\|We further report that the mitochondrial E3 ubiquitin protein ligase 1 (MUL1, also known as GIDE/MAPL/MULAN/RNF218) ubiquitinates STING on K224 via K63-linked polyubiquitination, which facilitates optimal STING trafficking and the transcription of host defense genes.	SIGNOR-278634
Q86X55	P40925	1	acetylation	down-regulates activity	0.355	Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer\|Arginine methylation at R248 negatively regulates MDH1 activity\|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization	SIGNOR-267639
Q9HCE7	P36894	1	ubiquitination	down-regulates	0.66	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-153399
P63000	P55283	0	null	up-regulates activity	0.273	Together, these data suggest that R-cadherin expression inhibits myogenesis and induces myoblast transformation through Rac1 activation. Therefore, the properties of R-cadherin make it an attractive target for therapeutic intervention in RMS.	SIGNOR-253103
P23760	Q13207	1	transcriptional regulation	up-regulates quantity by expression	0.346	We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3	SIGNOR-249596
O43524	P53350	0	phosphorylation	down-regulates activity	0.491	Furthermore, PLK1 can directly phosphorylate FOXO3 in an in vitro kinase assay.\|PLK1 induces translocation of FOXO3 from the nucleus to the cytoplasm and suppresses FOXO3 activity, measured by the decrease in the pro-apoptotic Bim protein levels and in the cell cycle inhibitor protein p27.	SIGNOR-279095
P84243	Q9Y4C1	0	demethylation	up-regulates activity	0.2	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.	SIGNOR-276845
P22736	P45983	0	phosphorylation	down-regulates	0.5	We also identified the exact phosphorylation site of jnk to be serine 95 at the n terminus of tr3, around which a classical jnk phosphorylation motif exists. Furthermore, we demonstrated that tr3 phosphorylation by jnk coincided with its ubiquitination and degradation, resulting in the loss of its mitogenic activity.	SIGNOR-149998
Q99661	Q96GD4	0	phosphorylation	up-regulates	0.731	Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres.	SIGNOR-155890
Q05655	P35568	1	phosphorylation	down-regulates activity	0.646	Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).	SIGNOR-249267
P60953	Q8WWN8	0	gtpase-activating protein	down-regulates activity	0.521	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-260457
Q05086	P55036	1	polyubiquitination	down-regulates quantity by destabilization	0.463	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP.	SIGNOR-272746
Q9Y243	P55265	1	phosphorylation	down-regulates activity	0.2	AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively	SIGNOR-276191
P42684	O14818	1	phosphorylation	down-regulates	0.607	Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised	SIGNOR-146589
Q01094	P49336	0	phosphorylation	down-regulates	0.483	E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1.	SIGNOR-181078
Q6NUN9	Q9BXM7	0	phosphorylation	up-regulates activity	0.37	PINK1 directly phosphorylates PARIS at S322 and S613, priming it for ubiquitination by Parkin, which interacts with the C-terminus zinc finger of PARIS and tags it for destruction [ xref \u2013 xref , xref ].\|Thus, by tagging PARIS for destruction, PINK1/Parkin drive the generation of new mitochondria by increasing PGC-1\u03b1 levels (Fig. 1d).	SIGNOR-278268
Q9UBS0	P09651	1	phosphorylation	up-regulates activity	0.416	Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export.	SIGNOR-279569
P51955	Q8N137	1	phosphorylation	down-regulates activity	0.35	The opposite outcomes in NEK2- and centrobin-depleted cells suggest that NEK2 antagonizes biological functions of centrobin.\|These results suggest that NEK2 phosphorylates specific sites of centrobin, which are distinct from the PLK1 phosphorylation sites.	SIGNOR-279545
P02462	Q8IYK4	0	glycosylation	up-regulates activity	0.452	Recombinant GLT25D1 and GLT25D2 enzymes showed a strong galactosyltransferase activity toward various types of collagen and toward the serum mannose-binding lectin MBL, which contains a collagen domain. Amino acid analysis of the products of GLT25D1 and GLT25D2 reactions confirmed the transfer of galactose to hydroxylysine residues.	SIGNOR-261159
P11532	Q01484	0	relocalization	up-regulates quantity	0.53	We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.	SIGNOR-266712
P16298	O00429	1	dephosphorylation	up-regulates activity	0.278	When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.	SIGNOR-248361
Q8IYT8	Q8TDY2	1	phosphorylation	up-regulates activity	0.747	When mTOR is inhibited, ULK1 and ULK2 activate and phosphorylate ATG13 and FIP200.	SIGNOR-280159
Q13237	P42261	1	phosphorylation	up-regulates activity	0.44	In cultured hippocampal neurons, activation of cGKII induces an accumulation of GluR1 on the cellular plasma membrane at extrasynaptic sites, and blockage of cGKII activity prevents the surface increase of GluR1, and also the increase in mEPSC frequency and amplitude, that follows a chemical form of LTP (chemLTP).\|In this complex, cGKII phosphorylates GluR1 at serine 845 (S845), a site known to be phosphorylated also by PKA.	SIGNOR-278427
P17252	Q05682	1	phosphorylation	down-regulates	0.357	Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase.	SIGNOR-36792
Q96EB6	P31749	1	deacetylation	up-regulates activity	0.6	We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation.	SIGNOR-252445
P52948	P06493	0	phosphorylation	down-regulates activity	0.397	We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks.	SIGNOR-172217
Q96GD4	O43683	1	phosphorylation	up-regulates activity	0.749	Although our analysis identified only one of the 15 sites implicated in Bub1-Mad1 interaction, it suggests that following its rapamycin-induced dimerization, Ipl1 phosphorylates Bub1, and potentially Mad1, to drive eSAC signaling.	SIGNOR-279010
P14210	P03951	0	cleavage	up-regulates activity	0.313	the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain.	SIGNOR-256515
P84022	Q9UKB1	0	ubiquitination	up-regulates	0.261	Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3.	SIGNOR-108240
Q9UHD2	P42858	1	phosphorylation	up-regulates activity	0.289	Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity.	SIGNOR-270350
P41240	P06239	1	phosphorylation	down-regulates	0.538	P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity.	SIGNOR-20371
P04049	O60346	0	dephosphorylation	down-regulates activity	0.272	PHLPP1 and PHLPP2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the epithelial-mesenchymal transition. In Apc(Min) mice, loss of PHLPP1 promotes tumor progression.	SIGNOR-237449
P21589	P33981	0	phosphorylation	up-regulates activity	0.2	Intermolecular NTE phosphorylation by Mps1 requires a topology in which sites proximal to the NTE interact with the active Mps1 in order to promote phosphorylation.	SIGNOR-280157
O14920	O95999	1	phosphorylation	up-regulates activity	0.772	Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling.	SIGNOR-276292
P23771	Q969H0	0	ubiquitination	down-regulates quantity by destabilization	0.403	Fbw7 promotes degradation of GATA3 in a Thr-156-dependent manner.	SIGNOR-276635
Q96EB6	P46531	1	deacetylation	down-regulates	0.423	The acetylation marks on notch1-icd are removed by the deacetylase sirt1, suggesting that both deacetylation of notch1-icd and of histones inhibit notch signaling.	SIGNOR-195333
Q13616	P01106	0	transcriptional regulation	up-regulates quantity by expression	0.483	Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2	SIGNOR-102749
P27361	P10636-2	1	phosphorylation	down-regulates activity	0.501	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.	SIGNOR-275434
P12931	Q00535	0	phosphorylation	up-regulates	0.39	These results present compelling evidence that cdk5/p35 kinase is responsible for the novel phosphorylation of c-src at ser75 in neuronal cells, raising the intriguing possibility that c-src acts as an effector of cdk5/p35 kinase during neuronal development.	SIGNOR-71950
O15234	Q9H2K2	0	ADP-ribosylation	down-regulates quantity by destabilization	0.2	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-263382
P00519	P29350	1	phosphorylation	up-regulates activity	0.414	The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites.	SIGNOR-260820
P27361	P17302	1	phosphorylation	down-regulates activity	0.637	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-249466
P37231	P14373	0	ubiquitination	down-regulates quantity by destabilization	0.289	Mechanically, TRIM27 ubiquitinates and degrades PPARgamma, following induces cleaved Caspase-3 and IL-1beta expression.	SIGNOR-278734
P15172	Q8IXJ6	0	deacetylation	down-regulates	0.376	Sir2-mediated deacetylation of myod can be expected to inhibit its transcriptional capabilities.	SIGNOR-104251
P17612	Q5S007	1	phosphorylation	down-regulates activity	0.406	Furthermore, our work establishes S1444 as a PKA-regulated 14-3-3 docking site.Strikingly, 14-3-3 binding to phospho-S1444 decreased LRRK2 kinase activity in vitro.	SIGNOR-237444
Q13153	Q16584	0	phosphorylation	up-regulates activity	0.304	Although, MLK3 can phosphorylate PAK1 on Ser133 and Ser204 sites, PAK1S133A mutant is constitutively active, whereas, PAK1S204A is not activated by MLK3.\|MLK3 was able to directly phosphorylate PAK1 on two Serine residues of which Ser204 is critical for MLK3-induced PAK1 activation and downstream functions.	SIGNOR-279418
Q9H0K1	Q9BV73	1	phosphorylation	down-regulates	0.321	Here, we show that the salt inducible kinase 2 (sik2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, c-nap1, through s2392 phosphorylation	SIGNOR-167488
P46531	P49840	0	phosphorylation	down-regulates	0.319	Taken together, our results indicate that gsk-3alfa is a negative regulator of notch1/nicd.	SIGNOR-183969
Q05193	P12931	0	phosphorylation	up-regulates activity	0.637	Endocytosis of ligand-activated receptors requires dynamin-mediated GTP hydrolysis, which is regulated by dynamin self-assembly. Here, we demonstrate that phosphorylation of dynamin I by c-Src induces its self-assembly and increases its GTPase activity. Electron microscopic analyses reveal that tyrosine-phosphorylated dynamin I spontaneously self-assembles into large stacks of rings. Tyrosine 597 was identified as being phosphorylated both in vitro and in cultured cells following epidermal growth factor receptor stimulation.	SIGNOR-247129
Q96PU5	Q12809	1	ubiquitination	down-regulates quantity by destabilization	0.399	As quantified in Fig. 5 B, only Nedd4-2 significantly increased the basal ubiquitylation of hERG1, while Nedd4-2-C801S and the other ubiquitin ligases had no effect.\|The major findings of this study are as follows : 1) hERG1 interacts via its PY motif with the ubiquitin ligase Nedd4-2, 2) this interaction promotes the down-regulation of the functional form of the channel at the plasma membrane through Nedd4-2 ubiquitylation of the channel, and 3) I hERG1 is strongly decreased by Nedd4-2 catalytic dependent activity.The hERG1 PY motif is a highly conserved sequence across animal species lines, highlighting its crucial role in the regulation of the hERG1 channel at the cell surface.	SIGNOR-278771
P49841	Q9Y4K3	1	phosphorylation	down-regulates quantity by destabilization	0.479	TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling.	SIGNOR-277438
P98177	Q96EB6	0	deacetylation	up-regulates	0.744	Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes.	SIGNOR-124714
P46531	Q00526	0	phosphorylation	down-regulates quantity by destabilization	0.243	Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues	SIGNOR-273167
P68400	P07910	1	phosphorylation	down-regulates activity	0.357	In contrast, 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-133540
O75365	P60484	1	dephosphorylation	down-regulates quantity by destabilization	0.296	As expected, PRL3 clearly reduced PTEN phosphorylation at the tyrosine residue and PTEN protein in PRL3 overexpressing LO2 and HepG2 cell lines, with no significant changes in PRL3 (C104S) mutant cells.\|PRL3 down-regulates PTEN expression, a negative regulator of the Akt pathway.11 Phosphorylation of PTEN at Tyr336 is required for maintenance of PTEN protein stability and prevention of PTEN degradation.17 We therefore speculated that PRL3 might dephosphorylate PTEN at tyrosine sites and consequently reduce the PTEN protein level.	SIGNOR-277010
Q13418	Q13153	0	phosphorylation	up-regulates	0.41	We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin.	SIGNOR-154303
Q9UPY6	P00519	0	phosphorylation	up-regulates activity	0.582	WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3.	SIGNOR-259077
P17302	P28482	0	phosphorylation	down-regulates activity	0.608	These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.	SIGNOR-249401
Q99574	Q9UKV5	0	polyubiquitination	down-regulates quantity by destabilization	0.296	In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin.	SIGNOR-272756
P11137	Q9HCK8	0	transcriptional regulation	down-regulates quantity	0.2	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268916
P25963	Q14164	0	phosphorylation	down-regulates quantity by destabilization	0.484	The activated ikk complex then phosphorylates ikbalfa (an inhibitor of nf-kb) thereby targeting it for ubiquitination and proteasomal degradation.	SIGNOR-167524
Q86TM6	P04035	1	polyubiquitination	down-regulates quantity by destabilization	0.562	In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols.	SIGNOR-272594
Q7L2Z9	P53350	0	phosphorylation	down-regulates quantity by destabilization	0.588	Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites.	SIGNOR-265227
Q8WU17	P36956	1	ubiquitination	down-regulates quantity	0.298	Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner	SIGNOR-271957
Q14247	P29350	0	dephosphorylation	down-regulates activity	0.2	Shp1 interacts with cortactin and reduces cortactin phosphorylation at tyrosine 421; 3.\|induction of Shp1-cortactin complex formation impairs cortactin scaffolding-activity and negatively affects invadopodia behaviour; 4.	SIGNOR-277003
Q9C0H5	P60953	1	gtpase-activating protein	down-regulates activity	0.577	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-260495
Q86VP1	O15111	0	phosphorylation	up-regulates activity	0.383	Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, but not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1).	SIGNOR-175062
P42680	Q08881	0	phosphorylation	up-regulates	0.407	Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated	SIGNOR-98090
Q9GZU7	Q15796	1	dephosphorylation	down-regulates activity	0.515	SCP1 Dephosphorylates Smad2/3 in the Linkers\|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248795
P53355	Q13526	1	phosphorylation	down-regulates activity	0.369	DAPK1 inhibits Pin1 nuclear localization and cellular function.\|DAPK1 interacts with and phosphorylates Pin1 on Ser71 in vitro and in vivo.	SIGNOR-278160
P67775	Q9BUB5	1	dephosphorylation	down-regulates	0.514	Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e.	SIGNOR-168314
O43896	Q9H0N0	1	relocalization	up-regulates quantity	0.245	Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation.	SIGNOR-266879
P49792	P06493	0	phosphorylation	up-regulates activity	0.474	Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.	SIGNOR-259118
Q9UIF3	Q92949	0	transcriptional regulation	up-regulates quantity by expression	0.324	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266937
Q92934	P51812	0	phosphorylation	down-regulates	0.385	The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival.	SIGNOR-184595
Q9UEW8	Q13621	1	phosphorylation	up-regulates activity	0.577	We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).	SIGNOR-276308
Q7KZF4	P36956	0	transcriptional regulation	down-regulates quantity by repression	0.2	These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression.	SIGNOR-259137
Q13526	P53355	0	phosphorylation	down-regulates activity	0.369	DAPK1 inhibits Pin1 nuclear localization and cellular function.\|DAPK1 interacts with and phosphorylates Pin1 on Ser71 in vitro and in vivo.	SIGNOR-278160
P17936	P68400	0	phosphorylation	up-regulates quantity by stabilization	0.338	The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro \| These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment.	SIGNOR-250903
O15033	O43464	1	ubiquitination	down-regulates quantity by destabilization	0.406	Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists	SIGNOR-267669
Q14493	Q71UI9	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-265410
P52333	Q15910	1	phosphorylation	up-regulates activity	0.428	These results demonstrate that phosphorylation of EZH2 by JAK3 on the Y244 increases the interaction with Polymerase II and decreases the association with PRC2 components promoting the expression of non-canonical genes.\|To explore the mechanism of JAK3 mediated EZH2 activation, the authors performed co-immunoprecipitation assays, which revealed interaction of EZH2 with JAK3 and polymerase II.	SIGNOR-278518
Q13555	P18846	1	phosphorylation	up-regulates activity	0.299	Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site.	SIGNOR-250692
O15264	Q15139	1	phosphorylation	down-regulates	0.2	P38delta catalyzes an inhibitory phosphorylation of pkd1, thereby attenuating stimulated insulin secretion.	SIGNOR-183280
Q96SN8	Q13257	1	transcriptional regulation	up-regulates quantity by expression	0.309	These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter	SIGNOR-260313

O60674

P10912

1

phosphorylation

up-regulates activity

0.766

Jak2 is then phosphorylated and, in turn, phosphorylates the GHR and the signal transducers and activators of transcription (STAT) protein.

SIGNOR-279198

Q05513

P35612

1

phosphorylation

down-regulates

0.275

We now demonstrate that ptn stimulates the phosphorylation of serines 713 and 726 in the myristoylated alanine-rich protein kinase (pk) c substrate domain of beta-adducin through activation of either pkc alpha or beta.

SIGNOR-139914

P42574

Q15173

0

dephosphorylation

up-regulates

0.2

Dephosphorylation of caspase-3 at ser150 site by pp2a increased caspase-3 activity,which was essential to trigger apoptosis in neutrophils.

SIGNOR-131435

Q9NRF2

P40259

1

dephosphorylation

down-regulates activity

0.2

SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.

SIGNOR-268458

Q5S007

P62841

1

phosphorylation

up-regulates activity

0.485

Taken together, these results suggest that phosphorylation of s15 on T136 by LRRK2 mediates enhanced cap-dependent and cap-independent reporter translation and that a stimulatory effect of LRRK2 on mRNA translation contributes to LRRK2 toxicity.

SIGNOR-279058

Q13043

Q7L7X3

0

phosphorylation

up-regulates

0.368

In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2.

SIGNOR-201324

P78357

P12931

0

phosphorylation

down-regulates activity

0.336

If that is the case, then our genetic results support the notion that p190 is negatively regulated by both Src and integrin.|The Src family of tyrosine kinases phosphorylate mammalian p190.

SIGNOR-279572

P54252

P49841

0

phosphorylation

up-regulates quantity by stabilization

0.465

Phosphorylation of ataxin-3 by glycogen synthase kinase 3beta at serine 256 regulates the aggregation of ataxin-3|

SIGNOR-264821

Q92974

Q8TD19

0

phosphorylation

up-regulates activity

0.2

The phosphorylation of ARHGEF2 by NEK9 is the key step of this process.

SIGNOR-279638

P19793

P45985

0

phosphorylation

down-regulates

0.2

Phosphorylation by mkk4/sek1 had profound effects on the biochemical properties of rxr, inhibiting the expression of genes activated by rxr-retinoic acid receptor complexes. Tyr-249 in the rxr de region was required for the inhibitory effect of mkk4/sek1.

SIGNOR-80619

O96017

Q13049

1

phosphorylation

up-regulates activity

0.2

We show that CHK2 binds and phosphorylates TRIM32 at the S55 site, which then mediates K63-linked ubiquitination of ATG7 at the K45 site to initiate autophagy.

SIGNOR-277790

P17252

P13569

1

phosphorylation

up-regulates activity

0.399

Direct amino acid sequencing and peptide mapping of CF-2 revealed that serines 660, 700, 737, and 813 as well as serine 768, serine 795, or both were phosphorylated by PKA and PKG, and serines 686 and 790 were phosphorylated by PKC.

SIGNOR-248849

O14965

P40337

1

phosphorylation

down-regulates quantity by destabilization

0.406

Conversely, AURKA can phosphorylate VHL at serine 72, a priming phosphorylation for GSK3beta, which regulates VHL 's role in microtubule stability.

SIGNOR-279800

P36952

P10275

0

transcriptional regulation

down-regulates quantity by repression

0.401

In addition, androgen receptor (AR) can recognize and bind to the ARE element, and then inhibit the activity of maspin promoter

SIGNOR-253685

Q14493

P57053

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-265384

Q969V5

Q86WV6

1

ubiquitination

up-regulates activity

0.2

Identification of MUL1 as an essential activator of dsDNA mediated STING dependent pathway.|We further report that the mitochondrial E3 ubiquitin protein ligase 1 (MUL1, also known as GIDE/MAPL/MULAN/RNF218) ubiquitinates STING on K224 via K63-linked polyubiquitination, which facilitates optimal STING trafficking and the transcription of host defense genes.

SIGNOR-278634

Q86X55

P40925

1

acetylation

down-regulates activity

0.355

Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer|Arginine methylation at R248 negatively regulates MDH1 activity|PRMT4/CARM1 methylates MDH1 at R248 and inhibits its dimerization

SIGNOR-267639

Q9HCE7

P36894

1

ubiquitination

down-regulates

0.66

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

SIGNOR-153399

P63000

P55283

0

null

up-regulates activity

0.273

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

SIGNOR-253103

P23760

Q13207

1

transcriptional regulation

up-regulates quantity by expression

0.346

We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3

SIGNOR-249596

O43524

P53350

0

phosphorylation

down-regulates activity

0.491

Furthermore, PLK1 can directly phosphorylate FOXO3 in an in vitro kinase assay.|PLK1 induces translocation of FOXO3 from the nucleus to the cytoplasm and suppresses FOXO3 activity, measured by the decrease in the pro-apoptotic Bim protein levels and in the cell cycle inhibitor protein p27.

SIGNOR-279095

P84243

Q9Y4C1

0

demethylation

up-regulates activity

0.2

Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.

SIGNOR-276845

P22736

P45983

0

phosphorylation

down-regulates

0.5

We also identified the exact phosphorylation site of jnk to be serine 95 at the n terminus of tr3, around which a classical jnk phosphorylation motif exists. Furthermore, we demonstrated that tr3 phosphorylation by jnk coincided with its ubiquitination and degradation, resulting in the loss of its mitogenic activity.

SIGNOR-149998

Q99661

Q96GD4

0

phosphorylation

up-regulates

0.731

Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres.

SIGNOR-155890

Q05655

P35568

1

phosphorylation

down-regulates activity

0.646

Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).

SIGNOR-249267

P60953

Q8WWN8

0

gtpase-activating protein

down-regulates activity

0.521

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-260457

Q05086

P55036

1

polyubiquitination

down-regulates quantity by destabilization

0.463

S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10). Two additional Lys residues (Lys-126 and -135) were ubiquitinated by E6AP.

SIGNOR-272746

Q9Y243

P55265

1

phosphorylation

down-regulates activity

0.2

AKT-dependent phosphorylation of the adenosine deaminases ADAR-1 and -2 inhibits deaminase activity. Coimmunoprecipitation studies and in vitro kinase assays revealed that AKT-1, -2, and -3 interact with both ADAR1p110 and ADAR2 and phosphorylate these RNA editases. Using site-directed mutagenesis of suspected AKT phosphorylation sites, AKT was found to primarily phosphorylate ADAR1p110 and ADAR2 on T738 and T553, respectively

SIGNOR-276191

P42684

O14818

1

phosphorylation

down-regulates

0.607

Proteasome-mediated proteolysis is a primary protein degradation pathway in cells. The present study demonstrates that c-abl and arg (abl-related gene) tyrosine kinases associate with and phosphorylate the proteasome psma7 (alpha4) subunit at tyr-153. Consequently, proteasome-dependent proteolysis is compromised

SIGNOR-146589

Q01094

P49336

0

phosphorylation

down-regulates

0.483

E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1.

SIGNOR-181078

Q6NUN9

Q9BXM7

0

phosphorylation

up-regulates activity

0.37

PINK1 directly phosphorylates PARIS at S322 and S613, priming it for ubiquitination by Parkin, which interacts with the C-terminus zinc finger of PARIS and tags it for destruction [ xref \u2013 xref , xref ].|Thus, by tagging PARIS for destruction, PINK1/Parkin drive the generation of new mitochondria by increasing PGC-1\u03b1 levels (Fig. 1d).

SIGNOR-278268

Q9UBS0

P09651

1

phosphorylation

up-regulates activity

0.416

Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export.

SIGNOR-279569

P51955

Q8N137

1

phosphorylation

down-regulates activity

0.35

The opposite outcomes in NEK2- and centrobin-depleted cells suggest that NEK2 antagonizes biological functions of centrobin.|These results suggest that NEK2 phosphorylates specific sites of centrobin, which are distinct from the PLK1 phosphorylation sites.

SIGNOR-279545

P02462

Q8IYK4

0

glycosylation

up-regulates activity

0.452

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

SIGNOR-261159

P11532

Q01484

0

relocalization

up-regulates quantity

0.53

We present evidence for an ankyrin-based mechanism for sarcolemmal localization of dystrophin and beta-DG. Ankyrin-B thus is an adaptor required for sarcolemmal localization of dystrophin, as well as dynactin-4.

SIGNOR-266712

P16298

O00429

1

dephosphorylation

up-regulates activity

0.278

When mitochondrial depolarization is associated with sustained cytosolic Ca(2+) rise, it activates the cytosolic phosphatase calcineurin that normally interacts with Drp1. Calcineurin-dependent dephosphorylation of Drp1, and in particular of its conserved serine 637, regulates its translocation to mitochondria as substantiated by site directed mutagenesis.

SIGNOR-248361

Q8IYT8

Q8TDY2

1

phosphorylation

up-regulates activity

0.747

When mTOR is inhibited, ULK1 and ULK2 activate and phosphorylate ATG13 and FIP200.

SIGNOR-280159

Q13237

P42261

1

phosphorylation

up-regulates activity

0.44

In cultured hippocampal neurons, activation of cGKII induces an accumulation of GluR1 on the cellular plasma membrane at extrasynaptic sites, and blockage of cGKII activity prevents the surface increase of GluR1, and also the increase in mEPSC frequency and amplitude, that follows a chemical form of LTP (chemLTP).|In this complex, cGKII phosphorylates GluR1 at serine 845 (S845), a site known to be phosphorylated also by PKA.

SIGNOR-278427

P17252

Q05682

1

phosphorylation

down-regulates

0.357

Phosphorylation of both intact caldesmon and of its c-terminal fragment (658c), containing residues 658-756, significantly decreased their ability to inhibit acto-heavy meromyosin atpase.

SIGNOR-36792

Q96EB6

P31749

1

deacetylation

up-regulates activity

0.6

We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation.

SIGNOR-252445

P52948

P06493

0

phosphorylation

down-regulates activity

0.397

We show that npc disassembly is a phosphorylation-driven process, dependent on cdk1 activity and supported by members of the nima-related kinase (nek) family. mitotic hyperphosphorylation of nup98 is accomplished by multiple kinases, including cdk1 and neks.

SIGNOR-172217

Q96GD4

O43683

1

phosphorylation

up-regulates activity

0.749

Although our analysis identified only one of the 15 sites implicated in Bub1-Mad1 interaction, it suggests that following its rapamycin-induced dimerization, Ipl1 phosphorylates Bub1, and potentially Mad1, to drive eSAC signaling.

SIGNOR-279010

P14210

P03951

0

cleavage

up-regulates activity

0.313

the ability of plasma kallikrein and FXIa to activate pro-HGF in vitro raises the possibility that mediators of inflammation and blood coagulation may also regulate processes that involve the HGF/c-Met pathway, such as tissue repair and angiogenesis.Unlike other known activators, both FXIa and kallikrein processed pro-HGF by cleavage at two sites. Using N-terminal sequencing they were identified as the normal cleavage site Arg(494)-Val(495) and the novel site Arg(424)-His(425) located in the K4 domain of the alpha-chain.

SIGNOR-256515

P84022

Q9UKB1

0

ubiquitination

up-regulates

0.261

Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3.

SIGNOR-108240

Q9UHD2

P42858

1

phosphorylation

up-regulates activity

0.289

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

SIGNOR-270350

P41240

P06239

1

phosphorylation

down-regulates

0.538

P50csk tyrosine kinase phosphorylates p56lck at tyr-505 and down regulates its catalytic activity.

SIGNOR-20371

P04049

O60346

0

dephosphorylation

down-regulates activity

0.272

PHLPP1 and PHLPP2 dephosphorylate RAF1 to reduce its signaling, increase the invasive and migratory activities of CRC cells, and activate the epithelial-mesenchymal transition. In Apc(Min) mice, loss of PHLPP1 promotes tumor progression.

SIGNOR-237449

P21589

P33981

0

phosphorylation

up-regulates activity

0.2

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

SIGNOR-280157

O14920

O95999

1

phosphorylation

up-regulates activity

0.772

Here we show that the putative downstream kinase IKKbeta is required for initial CBM complex formation. Further, upon engagement of IKKbeta/Malt1/Bcl10 with Carma1, IKKbeta phosphorylates Bcl10 in the C terminus and thereby interferes with Bcl10/Malt1 association and Bcl10-mediated IKKgamma ubiquitination. Since only mutation of all serines 134, 136, 138, 141, and 144 completely prevented signal-induced Bcl10 phosphorylation, the Bcl10 5×S/A mutant was used to elucidate the effects of C-terminal Bcl10 phosphorylation on downstream signaling.

SIGNOR-276292

P23771

Q969H0

0

ubiquitination

down-regulates quantity by destabilization

0.403

Fbw7 promotes degradation of GATA3 in a Thr-156-dependent manner.

SIGNOR-276635

Q96EB6

P46531

1

deacetylation

down-regulates

0.423

The acetylation marks on notch1-icd are removed by the deacetylase sirt1, suggesting that both deacetylation of notch1-icd and of histones inhibit notch signaling.

SIGNOR-195333

Q13616

P01106

0

transcriptional regulation

up-regulates quantity by expression

0.483

Furthermore, c-myc activation can also promote the degradation of p27kip1 protein by directly activating the cul1 gene, which encodes a critical component of the ubiquitin ligase scfskp2

SIGNOR-102749

P27361

P10636-2

1

phosphorylation

down-regulates activity

0.501

We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.

SIGNOR-275434

P12931

Q00535

0

phosphorylation

up-regulates

0.39

These results present compelling evidence that cdk5/p35 kinase is responsible for the novel phosphorylation of c-src at ser75 in neuronal cells, raising the intriguing possibility that c-src acts as an effector of cdk5/p35 kinase during neuronal development.

SIGNOR-71950

O15234

Q9H2K2

0

ADP-ribosylation

down-regulates quantity by destabilization

0.2

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-263382

P00519

P29350

1

phosphorylation

up-regulates activity

0.414

The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites.

SIGNOR-260820

P27361

P17302

1

phosphorylation

down-regulates activity

0.637

These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.

SIGNOR-249466

P37231

P14373

0

ubiquitination

down-regulates quantity by destabilization

0.289

Mechanically, TRIM27 ubiquitinates and degrades PPARgamma, following induces cleaved Caspase-3 and IL-1beta expression.

SIGNOR-278734

P15172

Q8IXJ6

0

deacetylation

down-regulates

0.376

Sir2-mediated deacetylation of myod can be expected to inhibit its transcriptional capabilities.

SIGNOR-104251

P17612

Q5S007

1

phosphorylation

down-regulates activity

0.406

Furthermore, our work establishes S1444 as a PKA-regulated 14-3-3 docking site.Strikingly, 14-3-3 binding to phospho-S1444 decreased LRRK2 kinase activity in vitro.

SIGNOR-237444

Q13153

Q16584

0

phosphorylation

up-regulates activity

0.304

Although, MLK3 can phosphorylate PAK1 on Ser133 and Ser204 sites, PAK1S133A mutant is constitutively active, whereas, PAK1S204A is not activated by MLK3.|MLK3 was able to directly phosphorylate PAK1 on two Serine residues of which Ser204 is critical for MLK3-induced PAK1 activation and downstream functions.

SIGNOR-279418

Q9H0K1

Q9BV73

1

phosphorylation

down-regulates

0.321

Here, we show that the salt inducible kinase 2 (sik2) localizes at the centrosome, plays a key role in the initiation of mitosis, and regulates the localization of the centrosome linker protein, c-nap1, through s2392 phosphorylation

SIGNOR-167488

P46531

P49840

0

phosphorylation

down-regulates

0.319

Taken together, our results indicate that gsk-3alfa is a negative regulator of notch1/nicd.

SIGNOR-183969

Q05193

P12931

0

phosphorylation

up-regulates activity

0.637

Endocytosis of ligand-activated receptors requires dynamin-mediated GTP hydrolysis, which is regulated by dynamin self-assembly. Here, we demonstrate that phosphorylation of dynamin I by c-Src induces its self-assembly and increases its GTPase activity. Electron microscopic analyses reveal that tyrosine-phosphorylated dynamin I spontaneously self-assembles into large stacks of rings. Tyrosine 597 was identified as being phosphorylated both in vitro and in cultured cells following epidermal growth factor receptor stimulation.

SIGNOR-247129

Q96PU5

Q12809

1

ubiquitination

down-regulates quantity by destabilization

0.399

As quantified in Fig. 5 B, only Nedd4-2 significantly increased the basal ubiquitylation of hERG1, while Nedd4-2-C801S and the other ubiquitin ligases had no effect.|The major findings of this study are as follows : 1) hERG1 interacts via its PY motif with the ubiquitin ligase Nedd4-2, 2) this interaction promotes the down-regulation of the functional form of the channel at the plasma membrane through Nedd4-2 ubiquitylation of the channel, and 3) I hERG1 is strongly decreased by Nedd4-2 catalytic dependent activity.The hERG1 PY motif is a highly conserved sequence across animal species lines, highlighting its crucial role in the regulation of the hERG1 channel at the cell surface.

SIGNOR-278771

P49841

Q9Y4K3

1

phosphorylation

down-regulates quantity by destabilization

0.479

TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling.

SIGNOR-277438

P98177

Q96EB6

0

deacetylation

up-regulates

0.744

Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes.

SIGNOR-124714

P46531

Q00526

0

phosphorylation

down-regulates quantity by destabilization

0.243

Mapping of cyclin C-dependent phosphosites on ICN1, using mass spectrometry revealed that several of them are located within the PEST-domain of Notch1, which controls ICN1 degradation38,39 (Fig. 5g and Supplementary Table 1). Three of them (T2512, S2514 and S2517) are localized within the consensus motif, “Cdc4 phosphodegron”, which is shared by most substrates of Fbw7 (Cdc4) ubiquitin ligase38. Two of these residues (S2514 and S2517) were previously shown by Fryer et al.20 to be phosphorylated by cyclin C-CDK8 in vitro, and all three were shown to play a role in controlling ICN1 stability via Fbw740. We verified that cyclin C-CDK8, C-CDK19 and C-CDK3 phosphorylate ICN1 on these three residues

SIGNOR-273167

P68400

P07910

1

phosphorylation

down-regulates activity

0.357

In contrast, 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-133540

O75365

P60484

1

dephosphorylation

down-regulates quantity by destabilization

0.296

As expected, PRL3 clearly reduced PTEN phosphorylation at the tyrosine residue and PTEN protein in PRL3 overexpressing LO2 and HepG2 cell lines, with no significant changes in PRL3 (C104S) mutant cells.|PRL3 down-regulates PTEN expression, a negative regulator of the Akt pathway.11 Phosphorylation of PTEN at Tyr336 is required for maintenance of PTEN protein stability and prevention of PTEN degradation.17 We therefore speculated that PRL3 might dephosphorylate PTEN at tyrosine sites and consequently reduce the PTEN protein level.

SIGNOR-277010

Q13418

Q13153

0

phosphorylation

up-regulates

0.41

We found that pak1 phosphorylates ilk at threonine-173 and serine-246 in vitro and in vivo. together, these results suggest that ilk is a pak1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin.

SIGNOR-154303

Q9UPY6

P00519

0

phosphorylation

up-regulates activity

0.582

WAVE3-Abl interaction promotes the tyrosine phosphorylation of WAVE3 by Abl, and STI-571, a specific inhibitor of Abl kinase activity, abrogates the Abl-mediated phosphorylation of WAVE3.

SIGNOR-259077

P17302

P28482

0

phosphorylation

down-regulates activity

0.608

These studies confirm that connexin-43 is a MAP kinase substrate in vivo and that phosphorylation on Ser255, Ser279, and/or Ser282 initiates the down-regulation of gap junctional communication. Studies with connexin-43 mutants suggest that MAP kinase phosphorylation at one or more of the tandem Ser279/Ser282 sites is sufficient to disrupt gap junctional intercellular communication.

SIGNOR-249401

Q99574

Q9UKV5

0

polyubiquitination

down-regulates quantity by destabilization

0.296

In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin.

SIGNOR-272756

P11137

Q9HCK8

0

transcriptional regulation

down-regulates quantity

0.2

Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells

SIGNOR-268916

P25963

Q14164

0

phosphorylation

down-regulates quantity by destabilization

0.484

The activated ikk complex then phosphorylates ikbalfa (an inhibitor of nf-kb) thereby targeting it for ubiquitination and proteasomal degradation.

SIGNOR-167524

Q86TM6

P04035

1

polyubiquitination

down-regulates quantity by destabilization

0.562

In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols.

SIGNOR-272594

Q7L2Z9

P53350

0

phosphorylation

down-regulates quantity by destabilization

0.588

Notably, although Plk1 did not alter the level of PBIP1 and CENP-Q ubiquitination, Plk1-dependent phosphorylation and delocalization of these proteins from kinetochores appeared to indirectly lead to their degradation in the cytosol. From these analyses, we identified nine CENP-Q residues (Thr-123, Thr-135, Ser-138, Ser-139, Ser-248, Ser-249, Ser-253, Ser-255, and Thr-256) that were phosphorylated in both in vitro and in vivo samples (Fig. 4B), suggesting that Plk1 phosphorylates these sites.

SIGNOR-265227

Q8WU17

P36956

1

ubiquitination

down-regulates quantity

0.298

Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. TRC8 destablizes SREBP precursors in a RING and proteasome-dependent manner

SIGNOR-271957

Q14247

P29350

0

dephosphorylation

down-regulates activity

0.2

Shp1 interacts with cortactin and reduces cortactin phosphorylation at tyrosine 421; 3.|induction of Shp1-cortactin complex formation impairs cortactin scaffolding-activity and negatively affects invadopodia behaviour; 4.

SIGNOR-277003

Q9C0H5

P60953

1

gtpase-activating protein

down-regulates activity

0.577

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-260495

Q86VP1

O15111

0

phosphorylation

up-regulates activity

0.383

Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, but not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1).

SIGNOR-175062

P42680

Q08881

0

phosphorylation

up-regulates

0.407

Tec family protein tyrosine kinases (tfks) play a central role in hematopoietic cellular signaling. Initial activation takes place through specific tyrosine phosphorylation situated in the activation loop. Further activation occurs within the sh3 domain via a transphosphorylation mechanism. Here, we could confirm that y223 is the only site in the btk-sh3 domain being detectably phosphorylated

SIGNOR-98090

Q9GZU7

Q15796

1

dephosphorylation

down-regulates activity

0.515

SCP1 Dephosphorylates Smad2/3 in the Linkers|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity

SIGNOR-248795

P53355

Q13526

1

phosphorylation

down-regulates activity

0.369

DAPK1 inhibits Pin1 nuclear localization and cellular function.|DAPK1 interacts with and phosphorylates Pin1 on Ser71 in vitro and in vivo.

SIGNOR-278160

P67775

Q9BUB5

1

dephosphorylation

down-regulates

0.514

Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e.

SIGNOR-168314

O43896

Q9H0N0

1

relocalization

up-regulates quantity

0.245

Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation.

SIGNOR-266879

P49792

P06493

0

phosphorylation

up-regulates activity

0.474

Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.

SIGNOR-259118

Q9UIF3

Q92949

0

transcriptional regulation

up-regulates quantity by expression

0.324

FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).

SIGNOR-266937

Q92934

P51812

0

phosphorylation

down-regulates

0.385

The rsks catalyze the phosphorylation of the pro-apoptotic protein bad at serine 112 to promote cell survival.

SIGNOR-184595

Q9UEW8

Q13621

1

phosphorylation

up-regulates activity

0.577

We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91.Using these phosphorylation-specific antibodies we establish that hypotonic low-chloride stimulation induces marked phosphorylation of overexpressed NKCC2 in HEK-293 cells at Ser91, Thr100, Thr105 and Ser130 (Fig. 3A).

SIGNOR-276308

Q7KZF4

P36956

0

transcriptional regulation

down-regulates quantity by repression

0.2

These findings reveal that SREBP-2 and SREBP-1 bind to specific sites in SND1 promoter and regulate SND1 transcription in opposite ways; it is induced by SREBP-2 activating conditions and repressed by SREBP-1 overexpression.

SIGNOR-259137

Q13526

P53355

0

phosphorylation

down-regulates activity

0.369

DAPK1 inhibits Pin1 nuclear localization and cellular function.|DAPK1 interacts with and phosphorylates Pin1 on Ser71 in vitro and in vivo.

SIGNOR-278160

P17936

P68400

0

phosphorylation

up-regulates quantity by stabilization

0.338

The importance of Ser111 and Ser113 as targets for CK2 has also been shown in our laboratory, as mutation of either residue to alanine caused a major decrease in IGFBP-3 phosphorylation by this enzyme in vitro | These results indicate that IGFBP-3 interaction with acid-labile subunit and with the cell surface, both of which involve basic carboxyl-terminal residues, may be modulated by phosphorylation. Relative resistance to proteolysis and poor binding to cells suggest that CK2-phospho-IGFBP-3 may be a significant inhibitor of IGF activity in the extracellular environment.

SIGNOR-250903

O15033

O43464

1

ubiquitination

down-regulates quantity by destabilization

0.406

Furthermore, the ubiquitination and degradation of SMAC, HtrA2, and ARTS were significantly enhanced in AREL1-expressing cells following apoptotic stimulation, indicating that AREL1 binds to and ubiquitinates cytosolic but not mitochondria-associated forms of IAP antagonists

SIGNOR-267669

Q14493

Q71UI9

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-265410

P52333

Q15910

1

phosphorylation

up-regulates activity

0.428

These results demonstrate that phosphorylation of EZH2 by JAK3 on the Y244 increases the interaction with Polymerase II and decreases the association with PRC2 components promoting the expression of non-canonical genes.|To explore the mechanism of JAK3 mediated EZH2 activation, the authors performed co-immunoprecipitation assays, which revealed interaction of EZH2 with JAK3 and polymerase II.

SIGNOR-278518

Q13555

P18846

1

phosphorylation

up-regulates activity

0.299

Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site.

SIGNOR-250692

O15264

Q15139

1

phosphorylation

down-regulates

0.2

P38delta catalyzes an inhibitory phosphorylation of pkd1, thereby attenuating stimulated insulin secretion.

SIGNOR-183280

Q96SN8

Q13257

1

transcriptional regulation

up-regulates quantity by expression

0.309

These data indicate that CDK5RAP2 is a positive regulator of both the BUBR1 promoter and the MAD2 promoter

SIGNOR-260313