GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
O14965	P00533	1	phosphorylation	up-regulates activity	0.393	Because AURKA associated with EGFR, we next investigated whether AURKA phosphorylates EGFR at Thr654 and Ser1046.\|Protein phosphorylation profiling using an in situ proximity ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung cancer cells.	SIGNOR-279589
P08581	P08047	0	transcriptional regulation	up-regulates quantity by expression	0.319	Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.	SIGNOR-241490
P19338	P60484	0	dephosphorylation	up-regulates activity	0.27	The fact that PTEN\u03b2 interacts with nucleolin and dephosphorylates nucleolin at Thr84 raised a question as to whether nucleolin mediates PTEN\u03b2 regulation of rDNA transcription, and thus represents a direct mechanism by which PTEN\u03b2 controls ribosomal biogenesis.	SIGNOR-277166
Q15796	P11309	0	phosphorylation	up-regulates activity	0.2	We further showed that PIM1 could interact with and phosphorylate Smad2 or Smad3 in the nucleus to induce transcription factor (ZEB1, ZEB2, Snail1, Snail2 and Twist) expression and EMT.	SIGNOR-279090
P54727	Q05086	0	polyubiquitination	down-regulates quantity by destabilization	0.405	Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP. E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B.	SIGNOR-272551
P29590	P68400	0	phosphorylation	down-regulates	0.342	Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517.	SIGNOR-148306
Q9NY61	Q13315	0	phosphorylation	up-regulates quantity by stabilization	0.355	The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. \|DNA damage stabilizes Che-1 protein\|In addition, substitution of Che-1 Ser187 with an alanine (Che-1S187A) prevented Che-1 phosphorylation by ATM (Figure 2F), supporting this residue as an ATM-target site.	SIGNOR-264415
Q99942	P13569	1	ubiquitination	down-regulates quantity by destabilization	0.665	JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation.	SIGNOR-271494
P06401	P27361	0	phosphorylation	down-regulates	0.561	Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation.	SIGNOR-74716
O00418	P13639	1	phosphorylation	down-regulates	0.788	Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58.	SIGNOR-38556
P35222	P68400	0	phosphorylation	up-regulates activity	0.556	The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability.	SIGNOR-250849
Q9NZQ7	Q9NX76	0	stabilization	up-regulates quantity by stabilization	0.47	Furthermore, the observations that (i) CMTM6 affects PD-L1 protein stability at late time points after biosynthesis; (ii) CMTM6, CMTM4 and PD-L1 interact, as shown by co-immunoprecipitation; and that (iii) CMTM6 is largely located at the cell surface, collectively suggest a model in which CMTM6 interacts with PD-L1 at the tumour cell surface and thereby protects it from degradation	SIGNOR-274980
P06493	P23396	1	phosphorylation	up-regulates	0.362	These results suggest that the phosphorylation of rps3 by cdk1 occurs at thr221 during g2/m phase and, moreover, that this event is important for nuclear accumulation of rps3.	SIGNOR-176131
P17096	P06493	0	phosphorylation	down-regulates	0.384	Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation.	SIGNOR-158604
P18846	P17612	0	phosphorylation	up-regulates activity	0.451	PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1.	SIGNOR-250336
P05108	Q9NTG7	0	deacetylation	up-regulates quantity by stabilization	0.2	Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.\|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis.	SIGNOR-268718
P09467	P37275	0	transcriptional regulation	down-regulates quantity by repression	0.2	Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells\|we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells.	SIGNOR-267596
P53350	O14757	0	phosphorylation	down-regulates activity	0.314	Chk1 directly phosphorylates Plk1 to disturb its interaction with Sgo1.	SIGNOR-277914
P06493	Q01094	1	phosphorylation	up-regulates	0.7	Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro.	SIGNOR-36026
Q15672	P17252	0	phosphorylation	up-regulates quantity by stabilization	0.2	Because most of these sites were predicted to be phosphorylated by protein kinase C (PKC), we overexpressed PKCα in several cell lines and found that it phosphorylates Twist1 on Ser-144. we observed that PKCα-mediated Twist1 phosphorylation at Ser-144 inhibits Twist1 ubiquitination and consequently stabilizes it.	SIGNOR-277429
P31749	O15151	1	phosphorylation	up-regulates quantity by stabilization	0.509	We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2.	SIGNOR-252517
O60229	Q00535	0	phosphorylation	up-regulates activity	0.4	We then demonstrated that Cdk5 phosphorylates Kalirin 7 on Thr 1590 , increasing its GEF activity slightly and changing its solubility properties.	SIGNOR-279603
Q13153	Q99661	1	phosphorylation	down-regulates	0.385	Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes	SIGNOR-199084
P22681	O94875	1	ubiquitination	down-regulates	0.512	Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl	SIGNOR-96325
Q9NXA8	P54868	1	post translational modification	up-regulates activity	0.343	We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.\|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity\|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5	SIGNOR-267641
Q13164	O00141	1	phosphorylation	up-regulates	0.388	Bmk1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinasebmk1 activates sgk by phosphorylation at serine 78.	SIGNOR-105728
Q13464	O14974	1	phosphorylation	down-regulates activity	0.774	Phosphorylation by Rho-kinase inhibited MP activity and this reflected a decrease in V(max). Activity of MP with different substrates also was inhibited by phosphorylation. Two major sites of phosphorylation on MYPT1 were Thr(695) and Thr(850).	SIGNOR-249034
P42262	Q5JU85	0	relocalization	up-regulates quantity	0.2	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264913
P15173	P15172	0	transcriptional regulation	up-regulates quantity by expression	0.46	We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation.	SIGNOR-255640
Q15797	O96004	1	transcriptional regulation	up-regulates quantity	0.2	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268936
P05771	P08670	1	phosphorylation	up-regulates quantity	0.2	PKCbeta induces vimentin phosphorylation in MCP-1-activated human monocytes.	SIGNOR-278984
P04049	Q05639	1	phosphorylation	down-regulates quantity by destabilization	0.2	Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.	SIGNOR-276407
P85298	P45983	0	phosphorylation	up-regulates activity	0.327	Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation.	SIGNOR-275550
P05771	Q6ZVD8	0	dephosphorylation	down-regulates quantity	0.328	Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle	SIGNOR-237039
P08581	P51608	0	post transcriptional regulation	down-regulates quantity by repression	0.27	MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2	SIGNOR-264683
O60684	P46531	1	relocalization	up-regulates	0.2	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling.	SIGNOR-165343
P07737	Q13464	0	phosphorylation	down-regulates	0.272	We previously identified pfn1 as a huntingtin aggregation inhibitor, and others have implicated it as a tumor-suppressor. Rho-associated kinase (rock) directly phosphorylates pfn1 at ser-137 to prevent its binding to polyproline sequences. This negatively regulates its anti-aggregation activity.	SIGNOR-196820
P22307	Q2T9J0	0	cleavage	up-regulates activity	0.503	Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1.	SIGNOR-261055
P28482	Q07666	1	phosphorylation	up-regulates	0.666	In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites	SIGNOR-96414
P68400	Q12972	1	phosphorylation	up-regulates activity	0.471	Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2.	SIGNOR-250931
P18858	P68400	0	phosphorylation	up-regulates activity	0.34	Moreover, these data confirmed the occurrence of Ser66 phosphorylation, which was previously studied with a specific monoclonal antibody (23).	SIGNOR-103258
Q92813	P60604	0	ubiquitination	down-regulates quantity by destabilization	0.2	ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.	SIGNOR-267484
P06239	P40763	1	phosphorylation	up-regulates activity	0.699	Lck was able to induce tyrosine phosphorylation of STAT3 to a level equal to or greater than that induced by Jak2.\|This finding, along with the previous data, gives strong evidence that Lck can directly and positively affect STAT3 activity.Our data provide strong evidence that Lck can activate STAT3 via phosphorylation in baculovirus infected insect cells.	SIGNOR-279201
P00747	P02749	1	cleavage	down-regulates activity	0.458	Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form\| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI.	SIGNOR-266996
P06239	P07766	1	phosphorylation	up-regulates activity	0.692	Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways.	SIGNOR-251369
P60953	O60890	0	gtpase-activating protein	up-regulates activity	0.637	OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro	SIGNOR-268398
P03956	Q8TF68	0	transcriptional regulation	up-regulates quantity by expression	0.307	Luciferase activity driven by the MMP-1 promoter also increased by 2.5- to 3-fold. In contrast, CIZ had no effect on the luciferase activity from the MMP-1 promoter that was mutated at the CIZ binding consensus sequence. These results show that the CIZ transactivates the MMP-1 promoter through this sequence.	SIGNOR-266229
Q92985	O15111	0	phosphorylation	up-regulates	0.688	Ikkalfa associated with and phosphorylated and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production.	SIGNOR-146116
P63000	P52565	0	guanine nucleotide exchange factor	down-regulates activity	0.811	Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma.	SIGNOR-268436
P43403	O43561	1	phosphorylation	up-regulates activity	0.77	In the presence of the catalytically inactive LckK273R, the phosphorylation of LAT Y132 and Y191 residues by Zap70K362E were considerably increased	SIGNOR-274562
P46527	P54753	0	phosphorylation	down-regulates activity	0.2	In accord with this concept are the findings of Vlach et al. , who have studied point mutants of p27 deficient in their interactions with EK2, and have found that T187 phosphorylation of p27 by EK2 requires an interaction of p27 with the cyclin E subunit, while inhibition of the kinase activity requires an additional interaction with the CDK2 subunit.\|The question considered here is the theoretical question whether deactivation of p27 by EK2 can produce binary EK2 release, and if so what biochemical kinetic features are required for this behavior.	SIGNOR-279406
P27361	Q15349	1	phosphorylation	up-regulates	0.719	Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms	SIGNOR-44949
Q6IE81	Q8IUQ4	0	polyubiquitination	down-regulates quantity by destabilization	0.291	Siah-1 decreases Jade-1 abundance and enhances Jade-1 ubiquitination	SIGNOR-272915
Q8IY63	Q9P2P5	0	ubiquitination	up-regulates activity	0.419	These results clearly indicate that HECW2 ubiquitinates AMOTL1 with K63-linked polyubiquitin chains.\|Unlike NEDD4.2, HECW2 targeted AMOTL1 and promoted its stability.	SIGNOR-278811
P27361	O60885	1	null	down-regulates activity	0.312	The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity.	SIGNOR-262048
P53355	Q13224	1	phosphorylation	up-regulates activity	0.497	DAPK1 Activation Enhances the NR1 and NR2B Channel Conductance.\|Thus, an activated DAPK1 enhances NR1 and NR2B receptor channel conductance by phosphorylating NR2B subunit at Ser 1303.	SIGNOR-278397
P04035	P13674	0	transcriptional regulation	up-regulates quantity by expression	0.2	In this study, we found that the prolyl 4-hydroxylase (P4H) subunit P4HA1 protects NPC cells from erastin-induced ferroptosis by activating HMGCS1, a key enzyme in the mevalonate pathway. Our results show that HMGCS1 and HMGCR are regulated by P4HA subunits at the transcriptional level (Fig. S4).	SIGNOR-279854
P04275	Q8IXL6	0	phosphorylation	up-regulates activity	0.2	In vitro phosphorylation of von Willebrand factor by FAM20c enhances its ability to support platelet adhesion.	SIGNOR-279331
Q9P1W9	P38936	1	phosphorylation	up-regulates quantity by stabilization	0.402	Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo	SIGNOR-164646
P42224	O60674	0	phosphorylation	up-regulates	0.806	Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation.	SIGNOR-235709
P23471	Q9NRY4	1	dephosphorylation	down-regulates activity	0.417	Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP\| Furthermore, Ptprz selectively dephosphorylated pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at Y1105 controls p190 RhoGAP activity in vivo.	SIGNOR-248451
Q02156	P61586	1	phosphorylation	up-regulates activity	0.439	Our laboratory reported that PKCepsilon modulates RhoA activity in HNSCC presumably through posttranslation phosphorylation .\|Phosphopeptide mapping revealed that PKCepsilon phosphorylates RhoA at T127 and S188.	SIGNOR-279478
Q96IZ0	P31749	0	phosphorylation	down-regulates activity	0.39	Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy	SIGNOR-279668
P04637	Q9Y4K3	0	ubiquitination	up-regulates activity	0.61	Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK.\|We mutated every conserved lysine (K) residue on p53 and found that TRAF6 preferentially ubiquitinates p53 at K24 in the in vivo ubiquitination assay (XREF_FIG, XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).	SIGNOR-278728
P60484	Q8NFU7	0	transcriptional regulation	up-regulates quantity by expression	0.373	We also found that TET1 directly binds to the promoter region of PTEN and activates its transcription through demethylation of CpG islands	SIGNOR-259096
O43541	Q9C0C9	0	ubiquitination	down-regulates	0.464	We showed that ube2o functions as an e2-e3 hybrid to monoubiquitinate smad6 at lysine 174	SIGNOR-192255
P07948	P46934	0	polyubiquitination	down-regulates quantity by destabilization	0.459	These findings suggest that LMP2A recruits Nedd4-like ubiquitin-protein ligases and B-cell signal transduction molecules, resulting in the degradation of LMP2A and Lyn by a ubiquitin-dependent mechanism.	SIGNOR-272558
P06241	Q15831	1	phosphorylation	down-regulates activity	0.327	Moreover, Fyn kinase directly phosphorylated LKB1 on tyrosine 261 and 365 residues and mutations of these sites resulted in LKB1 export into the cytoplasm and increased AMPK phosphorylation.	SIGNOR-278477
P17612	Q9UD71	1	phosphorylation	up-regulates activity	0.504	DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚	SIGNOR-250031
Q9UKV5	O15503	1	ubiquitination	down-regulates quantity by destabilization	0.525	The ubiquitination of Insig-1 is mediated by gp78 and regulated by sterols.\|gp78 mediates the degradation of Insig-1 and Insig-2.	SIGNOR-278567
P29350	Q8NER1	1	dephosphorylation	down-regulates activity	0.2	Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.\|These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.	SIGNOR-277129
P63000	P98171	0	gtpase-activating protein	down-regulates activity	0.479	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260460
Q9Y4P1	O95166	1	cleavage	up-regulates activity	0.861	In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly	SIGNOR-141929
P28482	O75581	1	phosphorylation	up-regulates	0.301	We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription.	SIGNOR-169001
P49674	Q13114	1	phosphorylation	up-regulates activity	0.307	CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3.	SIGNOR-277212
P40763	P42345	0	phosphorylation	up-regulates	0.748	Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor	SIGNOR-146915
P25963	Q969T4	0	sumoylation	up-regulates quantity by stabilization	0.346	In the presence of an E1 SUMO-1-activating enzyme, Ubch9 conjugated SUMO-1 to IkappaBalpha primarily on K21, which is also utilized for ubiquitin modification. Thus, SUMO-1-modified IkappaBalpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation.	SIGNOR-270545
P10636	Q16539	0	phosphorylation	up-regulates	0.316	A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins.	SIGNOR-166611
Q15121	P17252	0	phosphorylation	down-regulates	0.384	Pea-15 is phosphorylated on two ser residues, ser104 and ser116. Protein kinase c (pkc) phosphorylates ser104 / we report that phosphorylation of pea-15 blocks its interaction with erk1/2 in vitro and in vivo and that phosphorylation of both ser104 and ser116 is required for this effect.	SIGNOR-137841
Q9Y2K7	Q04206	1	demethylation	down-regulates	0.459	Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.	SIGNOR-163384
P07288	Q9UQ80	0	transcriptional regulation	down-regulates quantity by repression	0.2	Ectopic expression of ebp1, a member of the PA2G4 family, inhibits the proliferation and induces the differentiation of human breast and prostate cancer cell lines. Ebp1 inhibits transcription of E2F1 and androgen receptor regulated genes such as prostate specific antigen (PSA) through its interactions with histone deacetylases (HDACs)	SIGNOR-253662
P03372	Q00526	0	phosphorylation	up-regulates activity	0.259	CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3	SIGNOR-273187
Q9UDX5	P06730	0	translation regulation	up-regulates activity	0.2	In this study, we demonstrate that mTORC1 stimulates mitochondrial fission via 4E-BP-mediated translational regulation of the mitochondrial fission factor MTFP1. Suppression of mTORC1 activity by pharmacological or genetic means causes mitochondrial hyperfusion, branching, and circularization. This is a consequence of downregulation of MTFP1 levels via the mTORC1/4E-BP pathway, thereby eliciting changes in phosphorylation and localization of the mitochondrial fission factor DRP1	SIGNOR-275429
Q04206	Q68CZ1	0	demethylation	down-regulates	0.2	Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.	SIGNOR-163320
P04637	P55957	1	transcriptional regulation	up-regulates quantity by expression	0.519	Bid is a p53 primary-response gene.	SIGNOR-140248
P52333	P35222	1	phosphorylation	up-regulates activity	0.444	Jak3 phosphorylates Tyr 30, Tyr 64, and Tyr 86 of beta-catenin in intestinal epithelial cells.	SIGNOR-278180
P10586	Q86YJ5	0	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271536
P14136	Q13464	0	phosphorylation	down-regulates activity	0.312	We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro.	SIGNOR-100192
P38936	P17252	0	phosphorylation	up-regulates activity	0.375	Binding of calmodulin to the carboxy-terminal region of p21 induces nuclear accumulation via inhibition of protein kinase c-mediated phosphorylation of ser153\| When phosphorylated at Ser153, p21 is located at the cytoplasm and disrupts stress fibers.	SIGNOR-139302
O00257	P48729	0	phosphorylation	down-regulates quantity by destabilization	0.2	The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.	SIGNOR-277512
P31749	Q05397	1	phosphorylation	up-regulates activity	0.43	In mouse embryonic fibroblasts, AKT1 phosphorylates S695 and T700 on FAK ( xref ) and in human colon cancer cells AKT1 phosphorylates S517, S601, and S695 on FAK ( xref , xref ).\|This suggests that further activation of FAK by AKT1 ( beyond that of Pten loss alone ) is required to promote FA turnover , increase tumor invasion , and ultimately elicit brain metastasis .	SIGNOR-279777
P49841	Q9NRR4	1	phosphorylation	up-regulates activity	0.278	Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.	SIGNOR-264846
Q92769	P25490	1	deacetylation	down-regulates activity	0.769	Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.	SIGNOR-268836
P40763	Q06187	0	phosphorylation	down-regulates activity	0.382	Phosphorylation of STAT-3 by BTK may also alter the conformation of STAT-3 in such a way as to make it inaccessible as a substrate of activating kinases such as JAK3.\|The ability of BTK to negatively regulate STAT-3 activity suggests several possible models for a mechanism of BTK action.	SIGNOR-279011
P01042	P03952	0	cleavage	up-regulates activity	0.779	Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1).	SIGNOR-263548
O14757	P38936	1	phosphorylation	down-regulates quantity by destabilization	0.531	Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21(Waf1) on T145 and S146 residues and induces its proteasome-dependent proteolysis.	SIGNOR-279325
P06493	P52926	1	phosphorylation	down-regulates	0.374	Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone.	SIGNOR-74098
P27361	P41182	1	phosphorylation	down-regulates	0.405	Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.	SIGNOR-58493
O14976	P12931	0	phosphorylation	up-regulates activity	0.274	GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149.	SIGNOR-263197
P12931	P84022	1	phosphorylation	up-regulates activity	0.377	Although the role of ERK in mediating phosphorylation of Smad2/3 remains to be investigated, our data indicate that early Smad3 phosphorylation is independent of transient EGFR transactivation and ERK1/2 activation initiated by HB-EGF release, whereas Src mediated chronic EGFR transactivation and ERK1/2 activation involve late Smad3 activation induced by TGF-beta1.\|Inhibition of Src not only decreases Smad3 phosphorylation but also decreases phosphorylation dependent nuclear translocation of Smad2/3, suggesting that Src kinase could modulate Smad3 activity.	SIGNOR-279292

O14965

P00533

1

phosphorylation

up-regulates activity

0.393

Because AURKA associated with EGFR, we next investigated whether AURKA phosphorylates EGFR at Thr654 and Ser1046.|Protein phosphorylation profiling using an in situ proximity ligation assay: phosphorylation of AURKA-elicited EGFR-Thr654 and EGFR-Ser1046 in lung cancer cells.

SIGNOR-279589

P08581

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.319

Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.

SIGNOR-241490

P19338

P60484

0

dephosphorylation

up-regulates activity

0.27

The fact that PTEN\u03b2 interacts with nucleolin and dephosphorylates nucleolin at Thr84 raised a question as to whether nucleolin mediates PTEN\u03b2 regulation of rDNA transcription, and thus represents a direct mechanism by which PTEN\u03b2 controls ribosomal biogenesis.

SIGNOR-277166

Q15796

P11309

0

phosphorylation

up-regulates activity

0.2

We further showed that PIM1 could interact with and phosphorylate Smad2 or Smad3 in the nucleus to induce transcription factor (ZEB1, ZEB2, Snail1, Snail2 and Twist) expression and EMT.

SIGNOR-279090

P54727

Q05086

0

polyubiquitination

down-regulates quantity by destabilization

0.405

Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP. E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B.

SIGNOR-272551

P29590

P68400

0

phosphorylation

down-regulates

0.342

Here we show that ck2 regulates pml protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at ser517.

SIGNOR-148306

Q9NY61

Q13315

0

phosphorylation

up-regulates quantity by stabilization

0.355

The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. |DNA damage stabilizes Che-1 protein|In addition, substitution of Che-1 Ser187 with an alanine (Che-1S187A) prevented Che-1 phosphorylation by ATM (Figure 2F), supporting this residue as an ATM-target site.

SIGNOR-264415

Q99942

P13569

1

ubiquitination

down-regulates quantity by destabilization

0.665

JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation.

SIGNOR-271494

P06401

P27361

0

phosphorylation

down-regulates

0.561

Specifically, down-regulation of mature prs occurs by a mechanism in which ligand binding activates pr phosphorylation by mapks at a unique serine residue, which then targets the receptors for degradation.

SIGNOR-74716

O00418

P13639

1

phosphorylation

down-regulates

0.788

Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58.

SIGNOR-38556

P35222

P68400

0

phosphorylation

up-regulates activity

0.556

The major CK2 phosphorylation site in this domain is Thr393, a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces beta-catenin phosphorylation, cotranscriptional activity, and stability.

SIGNOR-250849

Q9NZQ7

Q9NX76

0

stabilization

up-regulates quantity by stabilization

0.47

Furthermore, the observations that (i) CMTM6 affects PD-L1 protein stability at late time points after biosynthesis; (ii) CMTM6, CMTM4 and PD-L1 interact, as shown by co-immunoprecipitation; and that (iii) CMTM6 is largely located at the cell surface, collectively suggest a model in which CMTM6 interacts with PD-L1 at the tumour cell surface and thereby protects it from degradation

SIGNOR-274980

P06493

P23396

1

phosphorylation

up-regulates

0.362

These results suggest that the phosphorylation of rps3 by cdk1 occurs at thr221 during g2/m phase and, moreover, that this event is important for nuclear accumulation of rps3.

SIGNOR-176131

P17096

P06493

0

phosphorylation

down-regulates

0.384

Here, we found that hipk2 phosphorylates hmga1a at ser-35, thr-52, and thr-77, and hmga1b at thr-41 and thr-66. In addition, we demonstrated that cdc2, which is known to phosphorylate hmga1 proteins, could induce the phosphorylation of hmga1 proteins at the same ser/thr sites. we found that the hipk2-phosphorylated hmga1a reduced the binding affinity of hmga1a to human germ line promoter, and the drop in binding affinity induced by hipk2 phosphorylation was lower than that introduced by cdc2 phosphorylation.

SIGNOR-158604

P18846

P17612

0

phosphorylation

up-regulates activity

0.451

PKA catalytic subunit phosphorylates ATF-1 at Ser63 and that phosphorylation is essential for efficient DNA binding by ATF-1.

SIGNOR-250336

P05108

Q9NTG7

0

deacetylation

up-regulates quantity by stabilization

0.2

Resveratrol stimulates cortisol biosynthesis by activating SIRT-dependent deacetylation of P450scc.|Stable overexpression of SIRT3 abrogates the cellular content of acetylated P450scc, concomitant with an increase in P450scc protein expression and cortisol secretion. Mutation of K148 and K149 to alanine stabilizes the expression of P450scc and results in a 1.5-fold increase in pregnenolone biosynthesis.

SIGNOR-268718

P09467

P37275

0

transcriptional regulation

down-regulates quantity by repression

0.2

Down-regulation of FBP1 by ZEB1-mediated repression confers to growth and invasion in lung cancer cells|we confirmed DNA methylation in the promoter contributed to the decrease of FBP1 expression in lung cancer cells. We identified Zinc finger E-box-binding homeobox 1 (ZEB1) bond to FBP1 promoter to enhance DNA methylation in lung cancer cells.

SIGNOR-267596

P53350

O14757

0

phosphorylation

down-regulates activity

0.314

Chk1 directly phosphorylates Plk1 to disturb its interaction with Sgo1.

SIGNOR-277914

P06493

Q01094

1

phosphorylation

up-regulates

0.7

Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro.

SIGNOR-36026

Q15672

P17252

0

phosphorylation

up-regulates quantity by stabilization

0.2

Because most of these sites were predicted to be phosphorylated by protein kinase C (PKC), we overexpressed PKCα in several cell lines and found that it phosphorylates Twist1 on Ser-144. we observed that PKCα-mediated Twist1 phosphorylation at Ser-144 inhibits Twist1 ubiquitination and consequently stabilizes it.

SIGNOR-277429

P31749

O15151

1

phosphorylation

up-regulates quantity by stabilization

0.509

We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2.

SIGNOR-252517

O60229

Q00535

0

phosphorylation

up-regulates activity

0.4

We then demonstrated that Cdk5 phosphorylates Kalirin 7 on Thr 1590 , increasing its GEF activity slightly and changing its solubility properties.

SIGNOR-279603

Q13153

Q99661

1

phosphorylation

down-regulates

0.385

Here we found that mcak is a cognate substrate of pak1 wherein pak1 phosphorylates mcak on serines 192 and 111 both in vivo and in vitro. Furthermore, we found that pak1 phosphorylation of mcak on serines 192 and 111 preferentially regulates its microtubule depolymerization activity and localization to centrosomes

SIGNOR-199084

P22681

O94875

1

ubiquitination

down-regulates

0.512

Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl

SIGNOR-96325

Q9NXA8

P54868

1

post translational modification

up-regulates activity

0.343

We demonstrate that SIRT5 regu-lates succinylation of the rate-limiting ketogenicenzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2) both in vivo and in vitro.|Succinylation of Lysine Residues within the SubstrateBinding Pocket Inhibits HMGCS2 Activity|Here, we use a label-freequantitative proteomic approach to characterizethe lysine succinylome in liver mitochondria and itsregulation by the desuccinylase SIRT5

SIGNOR-267641

Q13164

O00141

1

phosphorylation

up-regulates

0.388

Bmk1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinasebmk1 activates sgk by phosphorylation at serine 78.

SIGNOR-105728

Q13464

O14974

1

phosphorylation

down-regulates activity

0.774

Phosphorylation by Rho-kinase inhibited MP activity and this reflected a decrease in V(max). Activity of MP with different substrates also was inhibited by phosphorylation. Two major sites of phosphorylation on MYPT1 were Thr(695) and Thr(850).

SIGNOR-249034

P42262

Q5JU85

0

relocalization

up-regulates quantity

0.2

BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.

SIGNOR-264913

P15173

P15172

0

transcriptional regulation

up-regulates quantity by expression

0.46

We conclude that MyoD is the major MRF that binds to the E-box from the myogenin promoter during differentiation.

SIGNOR-255640

Q15797

O96004

1

transcriptional regulation

up-regulates quantity

0.2

Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation

SIGNOR-268936

P05771

P08670

1

phosphorylation

up-regulates quantity

0.2

PKCbeta induces vimentin phosphorylation in MCP-1-activated human monocytes.

SIGNOR-278984

P04049

Q05639

1

phosphorylation

down-regulates quantity by destabilization

0.2

Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.

SIGNOR-276407

P85298

P45983

0

phosphorylation

up-regulates activity

0.327

Furthermore, we identify that BPGAP1 (a BCH domain-containing, Cdc42GAP-like Rho GTPase-activating protein) promotes MEK partner 1 (MP1)-induced ERK activation on late endosome through scaffolding MP1/MEK1 complex. This regulatory function requires phosphorylation of BPGAP1 by JNK at its C terminal tail (Ser424) to unlock its autoinhibitory conformation.

SIGNOR-275550

P05771

Q6ZVD8

0

dephosphorylation

down-regulates quantity

0.328

Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC betaII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle

SIGNOR-237039

P08581

P51608

0

post transcriptional regulation

down-regulates quantity by repression

0.27

MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2

SIGNOR-264683

O60684

P46531

1

relocalization

up-regulates

0.2

Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7. importins alpha3, alpha4 (and to a lesser extent, alpha7) mediate nuclear import of nicd and thus are directly involved in notch signaling.

SIGNOR-165343

P07737

Q13464

0

phosphorylation

down-regulates

0.272

We previously identified pfn1 as a huntingtin aggregation inhibitor, and others have implicated it as a tumor-suppressor. Rho-associated kinase (rock) directly phosphorylates pfn1 at ser-137 to prevent its binding to polyproline sequences. This negatively regulates its anti-aggregation activity.

SIGNOR-196820

P22307

Q2T9J0

0

cleavage

up-regulates activity

0.503

Here, we demonstrate that Tysnd1, a previously uncharacterized protein, is responsible both for the removal of the leader peptide from PTS2 proteins and for the specific processing of PTS1 proteins. All of the identified Tysnd1 substrates catalyze peroxisomal β-oxidation. In vitro cleavage of Acox1, Scp2 and prethiolase by recombinant Tysnd1.

SIGNOR-261055

P28482

Q07666

1

phosphorylation

up-regulates

0.666

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

SIGNOR-96414

P68400

Q12972

1

phosphorylation

up-regulates activity

0.471

Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2.

SIGNOR-250931

P18858

P68400

0

phosphorylation

up-regulates activity

0.34

Moreover, these data confirmed the occurrence of Ser66 phosphorylation, which was previously studied with a specific monoclonal antibody (23).

SIGNOR-103258

Q92813

P60604

0

ubiquitination

down-regulates quantity by destabilization

0.2

ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.

SIGNOR-267484

P06239

P40763

1

phosphorylation

up-regulates activity

0.699

Lck was able to induce tyrosine phosphorylation of STAT3 to a level equal to or greater than that induced by Jak2.|This finding, along with the previous data, gives strong evidence that Lck can directly and positively affect STAT3 activity.Our data provide strong evidence that Lck can activate STAT3 via phosphorylation in baculovirus infected insect cells.

SIGNOR-279201

P00747

P02749

1

cleavage

down-regulates activity

0.458

Plasmin can reduce the function of human beta2 glycoprotein I by cleaving domain V into a nicked form| The cleavage site of r-Domain V and beta2GPI by plasmin was proved to be Lys 317-Thr 318 by amino acid sequence analysis of the digest and of the C-terminal peptide isolated by high-performance liquid chromatography. The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI.

SIGNOR-266996

P06239

P07766

1

phosphorylation

up-regulates activity

0.692

Tyrosine Phosphorylation of CD8- Chimeras by Lck and ZAP-70 in COS Cells. both Y170F and Y181F chimeric proteins could be efficiently phosphorylated by Lck in vivo. phosphorylation of Y170 and Y181 within CD3- –ITAM provides to CD3- the potential to interact with multiple downstream effectors and signaling pathways.

SIGNOR-251369

P60953

O60890

0

gtpase-activating protein

up-regulates activity

0.637

OPHN-1 colocalized with the actin cytoskeleton in neuronal and glial cells. We have previously shown that OPHN1 stimulates GTPases activity of RhoA, Cdc42, and Rac1 in vitro

SIGNOR-268398

P03956

Q8TF68

0

transcriptional regulation

up-regulates quantity by expression

0.307

Luciferase activity driven by the MMP-1 promoter also increased by 2.5- to 3-fold. In contrast, CIZ had no effect on the luciferase activity from the MMP-1 promoter that was mutated at the CIZ binding consensus sequence. These results show that the CIZ transactivates the MMP-1 promoter through this sequence.

SIGNOR-266229

Q92985

O15111

0

phosphorylation

up-regulates

0.688

Ikkalfa associated with and phosphorylated and activate interferon regulatory factor-7 (irf7), which is required for interferon-alfa (ifnalfa) production.

SIGNOR-146116

P63000

P52565

0

guanine nucleotide exchange factor

down-regulates activity

0.811

Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. direct interaction of RhoGDIα and the cytoplasmic domain of plexin-B3 (plexin-B3CD) was confirmed by GST pulldown assays.RhoGDIα is required for Sema5A-induced Rac1 inactivation and inhibition of cell invasion in C6 glioma.

SIGNOR-268436

P43403

O43561

1

phosphorylation

up-regulates activity

0.77

In the presence of the catalytically inactive LckK273R, the phosphorylation of LAT Y132 and Y191 residues by Zap70K362E were considerably increased

SIGNOR-274562

P46527

P54753

0

phosphorylation

down-regulates activity

0.2

In accord with this concept are the findings of Vlach et al. , who have studied point mutants of p27 deficient in their interactions with EK2, and have found that T187 phosphorylation of p27 by EK2 requires an interaction of p27 with the cyclin E subunit, while inhibition of the kinase activity requires an additional interaction with the CDK2 subunit.|The question considered here is the theoretical question whether deactivation of p27 by EK2 can produce binary EK2 release, and if so what biochemical kinetic features are required for this behavior.

SIGNOR-279406

P27361

Q15349

1

phosphorylation

up-regulates

0.719

Several lines of investigation have suggested that rsk is phosphorylated and activated by erk1/2 mapk isoforms

SIGNOR-44949

Q6IE81

Q8IUQ4

0

polyubiquitination

down-regulates quantity by destabilization

0.291

Siah-1 decreases Jade-1 abundance and enhances Jade-1 ubiquitination

SIGNOR-272915

Q8IY63

Q9P2P5

0

ubiquitination

up-regulates activity

0.419

These results clearly indicate that HECW2 ubiquitinates AMOTL1 with K63-linked polyubiquitin chains.|Unlike NEDD4.2, HECW2 targeted AMOTL1 and promoted its stability.

SIGNOR-278811

P27361

O60885

1

null

down-regulates activity

0.312

The MYC stabilizing kinase, ERK1, regulates MYC levels directly and indirectly by inhibiting BRD4 kinase activity.

SIGNOR-262048

P53355

Q13224

1

phosphorylation

up-regulates activity

0.497

DAPK1 Activation Enhances the NR1 and NR2B Channel Conductance.|Thus, an activated DAPK1 enhances NR1 and NR2B receptor channel conductance by phosphorylating NR2B subunit at Ser 1303.

SIGNOR-278397

P04035

P13674

0

transcriptional regulation

up-regulates quantity by expression

0.2

In this study, we found that the prolyl 4-hydroxylase (P4H) subunit P4HA1 protects NPC cells from erastin-induced ferroptosis by activating HMGCS1, a key enzyme in the mevalonate pathway. Our results show that HMGCS1 and HMGCR are regulated by P4HA subunits at the transcriptional level (Fig. S4).

SIGNOR-279854

P04275

Q8IXL6

0

phosphorylation

up-regulates activity

0.2

In vitro phosphorylation of von Willebrand factor by FAM20c enhances its ability to support platelet adhesion.

SIGNOR-279331

Q9P1W9

P38936

1

phosphorylation

up-regulates quantity by stabilization

0.402

Pim-2 phosphorylation of p21(cip1/waf1) enhances its stability and inhibits cell proliferation in hct116 cellsere we demonstrate that like pim-1, pim-2 also phosphorylates the cell cycle inhibitor p21(cip1/waf1) (p21) on thr145 in vitro and in vivo

SIGNOR-164646

P42224

O60674

0

phosphorylation

up-regulates

0.806

Phosphorylation at tyr701 by the janus family of tyrosine kinases (jak) leads to stat1 dimerization via its src homology 2 domains, exposure of a dimer-specific nuclear localization signal, and subsequent nuclear translocation.

SIGNOR-235709

P23471

Q9NRY4

1

dephosphorylation

down-regulates activity

0.417

Protein tyrosine phosphatase receptor type Z is involved in hippocampus-dependent memory formation through dephosphorylation at Y1105 on p190 RhoGAP| Furthermore, Ptprz selectively dephosphorylated pY1105 of p190 RhoGAP in vitro, and the tyrosine phosphorylation at Y1105 controls p190 RhoGAP activity in vivo.

SIGNOR-248451

Q02156

P61586

1

phosphorylation

up-regulates activity

0.439

Our laboratory reported that PKCepsilon modulates RhoA activity in HNSCC presumably through posttranslation phosphorylation .|Phosphopeptide mapping revealed that PKCepsilon phosphorylates RhoA at T127 and S188.

SIGNOR-279478

Q96IZ0

P31749

0

phosphorylation

down-regulates activity

0.39

Prostate apoptosis response protein-4 (Par-4) sensitizes cells to chemotherapy

SIGNOR-279668

P04637

Q9Y4K3

0

ubiquitination

up-regulates activity

0.61

Here, we show that TRAF6 E3 ligase is a crucial factor to restrict mitochondrial translocation of p53 and spontaneous apoptosis by promoting K63-linked ubiquitination of p53 at K24 in cytosol, and such ubiquitination limits the interaction between p53 and MCL-1/BAK.|We mutated every conserved lysine (K) residue on p53 and found that TRAF6 preferentially ubiquitinates p53 at K24 in the in vivo ubiquitination assay (XREF_FIG, XREF_SUPPLEMENTARY, XREF_SUPPLEMENTARY and XREF_SUPPLEMENTARY).

SIGNOR-278728

P60484

Q8NFU7

0

transcriptional regulation

up-regulates quantity by expression

0.373

We also found that TET1 directly binds to the promoter region of PTEN and activates its transcription through demethylation of CpG islands

SIGNOR-259096

O43541

Q9C0C9

0

ubiquitination

down-regulates

0.464

We showed that ube2o functions as an e2-e3 hybrid to monoubiquitinate smad6 at lysine 174

SIGNOR-192255

P07948

P46934

0

polyubiquitination

down-regulates quantity by destabilization

0.459

These findings suggest that LMP2A recruits Nedd4-like ubiquitin-protein ligases and B-cell signal transduction molecules, resulting in the degradation of LMP2A and Lyn by a ubiquitin-dependent mechanism.

SIGNOR-272558

P06241

Q15831

1

phosphorylation

down-regulates activity

0.327

Moreover, Fyn kinase directly phosphorylated LKB1 on tyrosine 261 and 365 residues and mutations of these sites resulted in LKB1 export into the cytoplasm and increased AMPK phosphorylation.

SIGNOR-278477

P17612

Q9UD71

1

phosphorylation

up-regulates activity

0.504

DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.‚

SIGNOR-250031

Q9UKV5

O15503

1

ubiquitination

down-regulates quantity by destabilization

0.525

The ubiquitination of Insig-1 is mediated by gp78 and regulated by sterols.|gp78 mediates the degradation of Insig-1 and Insig-2.

SIGNOR-278567

P29350

Q8NER1

1

dephosphorylation

down-regulates activity

0.2

Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.|These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.

SIGNOR-277129

P63000

P98171

0

gtpase-activating protein

down-regulates activity

0.479

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260460

Q9Y4P1

O95166

1

cleavage

up-regulates activity

0.861

In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly

SIGNOR-141929

P28482

O75581

1

phosphorylation

up-regulates

0.301

We show that several proline-directed mitogen-activated protein kinases (mapks), such as p38, erk1/2, and jnk1 are sufficient and required for the phosphorylation of ppps/tp motifs of lrp6. External stimuli, which control the activity of mapks, such as phorbol esters and fibroblast growth factor 2 (fgf2) control the choice of the lrp6-ppps/tp kinase and regulate the amplitude of lrp6 phosphorylation and wnt/beta-catenin-dependent transcription.

SIGNOR-169001

P49674

Q13114

1

phosphorylation

up-regulates activity

0.307

CK1ɛ interacted with and phosphorylated TRAF3 at Ser349, which thereby promoted the Lys63 (K63)-linked ubiquitination of TRAF3 and subsequent recruitment of the kinase TBK1 to TRAF3.

SIGNOR-277212

P40763

P42345

0

phosphorylation

up-regulates

0.748

Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor

SIGNOR-146915

P25963

Q969T4

0

sumoylation

up-regulates quantity by stabilization

0.346

In the presence of an E1 SUMO-1-activating enzyme, Ubch9 conjugated SUMO-1 to IkappaBalpha primarily on K21, which is also utilized for ubiquitin modification. Thus, SUMO-1-modified IkappaBalpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation.

SIGNOR-270545

P10636

Q16539

0

phosphorylation

up-regulates

0.316

A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins.

SIGNOR-166611

Q15121

P17252

0

phosphorylation

down-regulates

0.384

Pea-15 is phosphorylated on two ser residues, ser104 and ser116. Protein kinase c (pkc) phosphorylates ser104 / we report that phosphorylation of pea-15 blocks its interaction with erk1/2 in vitro and in vivo and that phosphorylation of both ser104 and ser116 is required for this effect.

SIGNOR-137841

Q9Y2K7

Q04206

1

demethylation

down-regulates

0.459

Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.

SIGNOR-163384

P07288

Q9UQ80

0

transcriptional regulation

down-regulates quantity by repression

0.2

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

SIGNOR-253662

P03372

Q00526

0

phosphorylation

up-regulates activity

0.259

CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3

SIGNOR-273187

Q9UDX5

P06730

0

translation regulation

up-regulates activity

0.2

In this study, we demonstrate that mTORC1 stimulates mitochondrial fission via 4E-BP-mediated translational regulation of the mitochondrial fission factor MTFP1. Suppression of mTORC1 activity by pharmacological or genetic means causes mitochondrial hyperfusion, branching, and circularization. This is a consequence of downregulation of MTFP1 levels via the mTORC1/4E-BP pathway, thereby eliciting changes in phosphorylation and localization of the mitochondrial fission factor DRP1

SIGNOR-275429

Q04206

Q68CZ1

0

demethylation

down-regulates

0.2

Fbxl11 and nsd1 have opposite effects on nf-kb; both bind to p65 subunit after activation of nf-kb. / nsd1 activates nf-kb and reverses the inhibitory effect of fbxl11 / these data confirm that fbxl11 and nsd1 constitute an enzyme pair that methylates and demethylates p65 on k218 and 221 in response to cytokine stimulation.

SIGNOR-163320

P04637

P55957

1

transcriptional regulation

up-regulates quantity by expression

0.519

Bid is a p53 primary-response gene.

SIGNOR-140248

P52333

P35222

1

phosphorylation

up-regulates activity

0.444

Jak3 phosphorylates Tyr 30, Tyr 64, and Tyr 86 of beta-catenin in intestinal epithelial cells.

SIGNOR-278180

P10586

Q86YJ5

0

ubiquitination

down-regulates quantity by destabilization

0.2

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

SIGNOR-271536

P14136

Q13464

0

phosphorylation

down-regulates activity

0.312

We report here that aurora-b phosphorylates gfap and desmin in vitro, and this phosphorylation leads to a reduction in filament forming ability. The sites phosphorylated by aurora-b;thr-7/ser-13/ser-38 of gfap, and thr-16 of desmin are common with those related to rho-associated kinase (rho-kinase), which has been reported to phosphorylate gfap and desmin at cleavage furrow during cytokinesis. We identified ser-59 of desmin to be a specific site phosphorylated by aurora-b in vitro.

SIGNOR-100192

P38936

P17252

0

phosphorylation

up-regulates activity

0.375

Binding of calmodulin to the carboxy-terminal region of p21 induces nuclear accumulation via inhibition of protein kinase c-mediated phosphorylation of ser153| When phosphorylated at Ser153, p21 is located at the cytoplasm and disrupts stress fibers.

SIGNOR-139302

O00257

P48729

0

phosphorylation

down-regulates quantity by destabilization

0.2

The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα.

SIGNOR-277512

P31749

Q05397

1

phosphorylation

up-regulates activity

0.43

In mouse embryonic fibroblasts, AKT1 phosphorylates S695 and T700 on FAK ( xref ) and in human colon cancer cells AKT1 phosphorylates S517, S601, and S695 on FAK ( xref , xref ).|This suggests that further activation of FAK by AKT1 ( beyond that of Pten loss alone ) is required to promote FA turnover , increase tumor invasion , and ultimately elicit brain metastasis .

SIGNOR-279777

P49841

Q9NRR4

1

phosphorylation

up-regulates activity

0.278

Our findings suggest that phosphorylation of Drosha at multiple sites including S300 promotes its translocation to the cytoplasm. Interestingly, GSK3beta can phosphorylate Drosha at S300 and S302 in vitro. This has been reported to promote the nuclear localization of Drosha under basal condition (Tang et al., 2011). Thus, it appears that phosphorylation of S300 by GSK3beta and p38 MAPK is involved in opposing processes.

SIGNOR-264846

Q92769

P25490

1

deacetylation

down-regulates activity

0.769

Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.

SIGNOR-268836

P40763

Q06187

0

phosphorylation

down-regulates activity

0.382

Phosphorylation of STAT-3 by BTK may also alter the conformation of STAT-3 in such a way as to make it inaccessible as a substrate of activating kinases such as JAK3.|The ability of BTK to negatively regulate STAT-3 activity suggests several possible models for a mechanism of BTK action.

SIGNOR-279011

P01042

P03952

0

cleavage

up-regulates activity

0.779

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

SIGNOR-263548

O14757

P38936

1

phosphorylation

down-regulates quantity by destabilization

0.531

Responsible for this degradation is the checkpoint kinase Chk1, which phosphorylates p21(Waf1) on T145 and S146 residues and induces its proteasome-dependent proteolysis.

SIGNOR-279325

P06493

P52926

1

phosphorylation

down-regulates

0.374

Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone.

SIGNOR-74098

P27361

P41182

1

phosphorylation

down-regulates

0.405

Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.

SIGNOR-58493

O14976

P12931

0

phosphorylation

up-regulates activity

0.274

GAK is phosphorylated by c-Src and translocated from the centrosome to chromatin at the end of telophase. Cyclin G-associated kinase (GAK) harbors a consensus phosphorylation motif (Y412) for c-Src; however, its physiological significance remains elusive. Here, we show that GAK is phosphorylated by c-Src not only at Y412 but also at Y1149.

SIGNOR-263197

P12931

P84022

1

phosphorylation

up-regulates activity

0.377

Although the role of ERK in mediating phosphorylation of Smad2/3 remains to be investigated, our data indicate that early Smad3 phosphorylation is independent of transient EGFR transactivation and ERK1/2 activation initiated by HB-EGF release, whereas Src mediated chronic EGFR transactivation and ERK1/2 activation involve late Smad3 activation induced by TGF-beta1.|Inhibition of Src not only decreases Smad3 phosphorylation but also decreases phosphorylation dependent nuclear translocation of Smad2/3, suggesting that Src kinase could modulate Smad3 activity.

SIGNOR-279292