GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P98174	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.716	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-260551
Q96J92	O00141	0	phosphorylation	up-regulates activity	0.415	In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM.	SIGNOR-276421
P49137	Q15717	1	phosphorylation	up-regulates	0.303	Mk2 and mk3 participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating the are-binding proteins ttp and hur, and by regulating eef2k	SIGNOR-166622
Q12851	Q13200	1	phosphorylation	up-regulates activity	0.2	Seven of these kinases (PIM1/2/3, MAP4K1/2, PKA, and NEK6) directly and robustly phosphorylated recombinant GST-Rpn1 at S361 in vitro (Fig. 3D and SI Appendix, Fig. S3 A and B).	SIGNOR-273900
P60953	P98174	0	guanine nucleotide exchange factor	up-regulates activity	0.716	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-260551
P84243	Q9UPS6	0	methylation	down-regulates activity	0.2	SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.	SIGNOR-265578
P49674	Q9GZV5	1	phosphorylation	down-regulates	0.366	LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)	SIGNOR-230747
P51003	P06493	0	phosphorylation	up-regulates activity	0.258	Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity.	SIGNOR-268338
P00533	Q14164	1	phosphorylation	up-regulates activity	0.257	To understand the mechanism by which IKBKE is activated by mutant EGFR, we first investigated if activating mutation of EGFR is able to form a complex with IKBKE.\|While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179.	SIGNOR-278222
Q14344	O95835	1	phosphorylation	down-regulates activity	0.2	These findings suggest that Galpha13 induced phosphorilation of LATS1 at S909 recruits ITCH to trigger LATS1 degradation, leading to EMT-related phenotypes	SIGNOR-278051
Q9NZN5	Q05397	0	phosphorylation	up-regulates activity	0.303	These results suggest that LARG is phosphorylated on tyrosine by FAK after stimulation with RGMa.	SIGNOR-279310
Q00535	Q00536	1	phosphorylation	up-regulates activity	0.335	Taken together, our findings demonstrate that Pctaire1 interacts with p35, both in vitro and in vivo, and that phosphorylation of Pctaire1 by Cdk5 enhances its kinase activity.	SIGNOR-279149
Q13464	P35611	1	phosphorylation	up-regulates	0.376	Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480	SIGNOR-66996
Q13535	P23508	1	phosphorylation	up-regulates activity	0.2	MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120. Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity.	SIGNOR-273514
O60716	P17252	0	phosphorylation	down-regulates activity	0.251	PKC\u03b1 phosphorylation of p120 at S879 is a critical phospho-switch mediating disassociation of p120 from VE-cadherin that results in AJ disassembly.\|We surmised that PKCalpha may function to disrupt AJs by signaling dissociation of p120 from VE-cadherin.	SIGNOR-278261
P15692	P15172	0	transcriptional regulation	up-regulates quantity by expression	0.391	We further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter.	SIGNOR-257598
P68400	Q15672	1	phosphorylation	up-regulates	0.2	Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist.	SIGNOR-173668
Q05397	P08581	0	phosphorylation	up-regulates	0.497	Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain	SIGNOR-147199
P35869	P53350	0	phosphorylation	down-regulates activity	0.251	In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events.	SIGNOR-277885
P18146	P37231	1	transcriptional regulation	down-regulates quantity by repression	0.62	Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC.	SIGNOR-263508
P0DTC2	O15393	0	cleavage	up-regulates activity	0.2	Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. The Cellular Serine Protease TMPRSS2 Primes SARS-2- S for Entry, and a Serine Protease Inhibitor Blocks SARS-CoV-2 Infection of Lung Cells	SIGNOR-260736
P78527	Q9Y6K9	1	phosphorylation	down-regulates activity	0.296	Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR).	SIGNOR-277508
O75626	P13500	1	transcriptional regulation	down-regulates quantity by repression	0.2	Blimp-1 binds to the proinflammatory cytokine/chemokine genes, Il-6 and Ccl2, and negatively regulates their expression.	SIGNOR-271679
P49418	Q13627	0	phosphorylation	down-regulates	0.396	Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd	SIGNOR-126843
Q9P2D0	P05771	0	phosphorylation	down-regulates	0.328	We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane.	SIGNOR-173387
Q8IYT8	P42345	0	phosphorylation	down-regulates	0.777	Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2	SIGNOR-183961
Q15011	Q7Z6J0	0	ubiquitination	up-regulates activity	0.324	Upon TG induced ER calcium store depletion, POSH promotes Herp lys-63-linked polyubiquitination, which in turn promotes the redistribution of Herp to the ER .\|Upon thapsigargin-induced endoplasmic reticulum calcium store depletion, POSH promotes Herp lys-63-linked polyubiquitination, which in turn promotes the redistribution of Herp to the endoplasmic reticulum .	SIGNOR-278779
Q16665	P27361	0	phosphorylation	up-regulates	0.695	We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_	SIGNOR-178731
P06681	O00187	0	cleavage	up-regulates activity	0.436	The MASPs in the preparations had proteolytic activities against C4, C2, and C3 in the fluid phase	SIGNOR-263416
P28482	P46695	1	phosphorylation	up-regulates	0.552	Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors.	SIGNOR-93740
Q12913	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-271535
P04198	Q7Z6Z7	0	ubiquitination	down-regulates quantity by destabilization	0.423	HUWE1 ubiquitinates and directs MYCN degradation to the proteasome.	SIGNOR-278750
Q14289	Q9UHD2	1	phosphorylation	up-regulates activity	0.266	Mechanistically, we demonstrate that PTK2B directly phosphorylates residue Tyr591 of TBK1, which increases TBK1 oligomerization and activation.	SIGNOR-277910
Q96P48	P60953	1	gtpase-activating protein	down-regulates activity	0.531	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-260452
P30307	Q13535	0	phosphorylation	up-regulates activity	0.643	We also found that activated ATR phosphorylates CDC25C (Cell Division Cycle 25C) at serine 216, which in turn inactivates the cyclin B1/Cyclin-Dependent Kinase 1(CDK1) complex and induces G2-phase arrest.	SIGNOR-279008
P57682	O95600	1	transcriptional regulation	down-regulates quantity by repression	0.255	Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.	SIGNOR-266049
O75385	O75143	1	phosphorylation	up-regulates	0.917	Ulks directly phosphorylate atg13	SIGNOR-183957
Q9NYY3	Q9Y4G8	1	phosphorylation	up-regulates activity	0.357	Here, we report that Plk2 phosphorylates a quartet of Ras and Rap regulators : SynGAP, PDZGEF1, RasGRF1 and SPAR, resulting in powerful bidirectional control over Rap and Ras activity.\|Thus, Plk2 was sufficient to promote the activities of both SynGAP and PDZGEF1 in mammalian cells.	SIGNOR-280066
O95388	P35222	0	transcriptional regulation	up-regulates quantity	0.2	This study identifies WISP-1 as a beta-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and beta-catenin expression.	SIGNOR-256270
P27361	P08235	1	phosphorylation	down-regulates quantity by destabilization	0.35	Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.	SIGNOR-276102
Q99626	Q16819	1	transcriptional regulation	up-regulates quantity by expression	0.471	TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis\|	SIGNOR-253965
Q9UHW9	Q9H4A3	0	phosphorylation	down-regulates	0.453	We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases.	SIGNOR-187564
P53350	P60510	0	dephosphorylation	down-regulates activity	0.416	PPP4C dephosphorylated PLK1 at the S137 site, negatively regulating its activity in the DSB response in early embryonic cells.	SIGNOR-277076
Q05397	P24666	0	dephosphorylation	down-regulates activity	0.276	Lymphocyte function-associated antigen-1-mediated T cell adhesion is impaired by low molecular weight phosphotyrosine phosphatase-dependent inhibition of FAK activity. 4000254={CellProcess=4107155 CellType=10000184}}\|Moreover, in these conditions LMW-PTP causes FAK dephosphorylation, thus preventing the activation of FAK downstream pathways.	SIGNOR-277064
O95835	P58012	1	phosphorylation	up-regulates activity	0.452	LATS1 phosphorylates forkhead L2 and regulates its transcriptional activity.\|Last, we demonstrated that coexpression with LATS1 enhances FOXL2 's activity as a repressor of the StAR promoter, and this results from the kinase activity of LATS1.	SIGNOR-279624
P12259	P68400	0	phosphorylation	down-regulates activity	0.307	Factor Va, the essential cofactor for prothrombinase, is phosphorylated on the acidic COOH terminus of the heavy chain of the cofactor, at Ser692, by a platelet membrane-associated casein kinase II (CKII). \| The phosphorylated cofactor has increased susceptibility to inactivation by activated protein C, since phosphorylated factor Va was found to be inactivated approximately 3-fold faster than its native counterpart.	SIGNOR-250862
Q9H2K2	Q9NTX7	0	ubiquitination	down-regulates quantity	0.614	We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.	SIGNOR-260005
Q9BX84	P0C0S8	1	phosphorylation	down-regulates activity	0.2	We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1.	SIGNOR-276008
O75914	P17600	1	phosphorylation	up-regulates activity	0.334	Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release	SIGNOR-250246
Q9UHD2	Q15025	1	phosphorylation	down-regulates quantity by destabilization	0.375	TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1	SIGNOR-275733
P04150	Q92831	1	relocalization	up-regulates activity	0.549	NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase	SIGNOR-269233
Q96J02	P31749	0	phosphorylation	up-regulates quantity	0.319	AKT1-mediated phosphorylation of ITCH at Ser257 drives its nuclear translocation	SIGNOR-272922
P04150	O15516	0	transcriptional regulation	down-regulates quantity by repression	0.41	We recently reported that the basic helix-loop- helix transcription factor Clock, which is a histone acetyltransferase and a central component of the self-oscillating transcription factor loop that generates circadian rhythms, represses GR transcriptional activity by acetylating lysine residues within the 'lysine cluster' located in the hinge region of the receptor. This Clock-mediated repression of GR transcriptional activity oscillates in inverse phase to the HPA axis, acting as a target tissue counter-regulatory mechanism to the diurnally fluctuating circulating glucocorticoids.	SIGNOR-253699
O00429	P16298	0	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
P31749	Q6ZVD8	0	dephosphorylation	down-regulates	0.773	Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt.	SIGNOR-252602
Q99102	P19419	0	transcriptional regulation	up-regulates quantity by expression	0.2	Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level.	SIGNOR-254096
Q15369	Q02539	1	phosphorylation	up-regulates	0.2	Our results also show the potential function of p-tefb phosphorylation of h1, namely, to increase h1 dissociation from actively transcribed dna. P-tefb preferentially phosphorylates the ser-183 phosphorylation site of histone h1.1	SIGNOR-166120
Q13177	Q99523	1	phosphorylation	down-regulates activity	0.2	PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction.	SIGNOR-273717
P26038	O94804	0	phosphorylation	up-regulates activity	0.385	Evidence in jurkat cells that lok phosphorylates erm and that erm phosphorylation impedes migration.	SIGNOR-184433
P18848	P67870	0	phosphorylation	down-regulates quantity by destabilization	0.2	By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.	SIGNOR-276424
Q9UQM7	P16220	1	phosphorylation	down-regulates	0.594	Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer.	SIGNOR-82501
O15527	Q96PU5	0	ubiquitination	down-regulates quantity by destabilization	0.2	We demonstrate that recombinant NEDD4L stimulates ubiquitylation of OGG1 in vitro, particularly on lysine 341, and that NEDD4L and OGG1 interact in U2OS cells.	SIGNOR-278639
Q15911	Q13315	0	phosphorylation	up-regulates activity	0.346	Indeed, ATM phosphorylates ATBF1 at Ser1180 in HEK293T cells exposed to 10-Gy radiation [ xref ].\|We also found in this study that ATBF1 mediated neuronal death is dependent on ATM signals because the blockage of ATM by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 functions in neuronal death.	SIGNOR-279138
Q9HC98	P23443	1	phosphorylation	up-regulates activity	0.367	Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Analysis of the peptides phosphorylated by NEK6 (Fig 2), performed in the present study has confirmed this, and identified two novel sites on S6K1 (Ser53 and Ser403) as major sites of NEK6 phosphorylation.	SIGNOR-262953
Q86U44	Q13315	0	phosphorylation	up-regulates activity	0.2	Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43.	SIGNOR-265969
P17676	O96013	0	phosphorylation	up-regulates activity	0.2	Importantly, we found that PAK4 enhanced CEBPB phosphorylation on Thr 235.\|In summary, we showed that PAK4 mediated CEBPB activation upregulated CLDN4 expression to promote breast cancer cell migration and invasion.	SIGNOR-280055
Q05923	Q16659	1	dephosphorylation	down-regulates activity	0.376	DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.\|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5.	SIGNOR-277069
Q99576	P98177	1	relocalization	down-regulates activity	0.253	GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells.	SIGNOR-256148
Q7Z6Z7	P38398	1	ubiquitination	down-regulates quantity by destabilization	0.397	Collectively, these data indicate that HUWE1 targets BRCA1, but not BARD1, for polyubiquitination and degradation.Because HUWE1 promotes BRCA1 ubiquitination and degradation, we wondered whether it might contribute to the reduced BRCA1 protein levels in sporadic breast cancer.	SIGNOR-278583
Q13315	Q9BXW9	1	phosphorylation	up-regulates	0.789	These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint	SIGNOR-90117
Q9UBN7	Q01130	1	deacetylation	up-regulates	0.356	Our data support a model in which hdac6 has a key role in the maintenance of srsf2 protein level by inhibiting tip60_mediated acetylation and proteasomal degradation.	SIGNOR-170590
P12830	Q96RU2	0	deubiquitination	up-regulates quantity by stabilization	0.2	Usp28 deubiquitylates and consequently stabilizes Claspin in response to DNA damage	SIGNOR-274057
Q9NTG7	P36888	0	phosphorylation	down-regulates activity	0.2	We also hypothesize that, besides activating ACAT1 through Y407 phosphorylation (Fan et al., 2016), FLT3 might simultaneously phosphorylate and regulate SIRT3. Our mutational studies on all of the seven tyrosine sites of SIRT3 revealed that purified rFLT3 directly phosphorylated purified rSIRT3 in an in vitro kinase assay, leading to decreased SIRT3 deacetylase activity that was assessed by ability to deacetylate K413 of mIDH2 (Figure 4H, first three samples in left, middle, and right panels), whereas replacement of Y226 completely abolished inhibition of SIRT3 by FLT3 (Figure 4H, right).	SIGNOR-267631
Q9BY78	Q86WV6	1	ubiquitination	up-regulates activity	0.2	As a result, knockdown of RNF26 promoted degradation of MITA after viral infection and prevented degradation of IRF3.\|In addition, RNF26 could not induce polyubiquitination of MITA (K150R) in in vitro ubiquitination assays (XREF_FIG).	SIGNOR-278573
P06400	P11802	0	phosphorylation	down-regulates	0.929	Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression.	SIGNOR-200487
Q13489	Q96FA3	0	ubiquitination	up-regulates quantity by stabilization	0.455	Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity.	SIGNOR-259395
Q13286	P06493	0	phosphorylation	down-regulates activity	0.257	(D) Phosphorylation of Cln3 by Cdk1 is independent of Ssa1 T36.\|Thereby, both Cdk1 and Pho85can promote Cln3 degradation, though under distinct circumstances.	SIGNOR-279013
Q07890	P01112	1	guanine nucleotide exchange factor	up-regulates	0.79	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-175262
O15530	P05106	1	phosphorylation	down-regulates activity	0.473	PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3.	SIGNOR-250266
P17252	O60825	1	phosphorylation	up-regulates activity	0.439	The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. \| Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme.	SIGNOR-248844
Q9P1W9	Q13131	1	phosphorylation	down-regulates activity	0.2	Specifically, we found that PIM2 bound to AMPKα1, and directly phosphorylated it on Thr467. Phosphorylation of AMPKα1 by PIM2 led to decreasing AMPKα1 kinase activity, which in turn promoted aerobic glycolysis and tumor growth.	SIGNOR-277471
P06241	P16410	1	phosphorylation	up-regulates quantity by stabilization	0.77	CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.¬† Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4.	SIGNOR-251161
O95163	P42345	0	phosphorylation	up-regulates activity	0.2	Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival \|In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174	SIGNOR-275541
P19784	O60936	1	phosphorylation	up-regulates activity	0.2	Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm.	SIGNOR-262836
Q5UE93	P31749	0	phosphorylation	up-regulates activity	0.45	P84 forms a negative regulatory complex with p110gamma to control PI3Kgamma signalling during cell migration\|However, phosphorylation at this site was confirmed using an in vitro kinase assay in which Akt kinase was shown to readily phosphorylate Thr607 using a p84 peptide (Figure 1e), where Thr607 in conjunction with surrounding residues forms an Akt kinase consensus sequence\|In contrast, although p84-T607A exhibited basal p110γ dimerisation, this interaction could not be further induced with stimulation	SIGNOR-275722
Q9UL68	Q14469	1	transcriptional regulation	down-regulates quantity by repression	0.2	ChIP–seq experiments showed that 80% of Myt1l targets, including the transcription factor Hes1, were co-bound by the repressive Sin3b–HDAC1 complex early during reprogramming	SIGNOR-266775
Q13315	Q01094	1	phosphorylation	up-regulates quantity by stabilization	0.679	Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes.	SIGNOR-109416
Q99502	P16104	1	dephosphorylation	down-regulates	0.2	Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3.	SIGNOR-168879
O14964	P00533	0	phosphorylation	up-regulates activity	0.637	We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation	SIGNOR-100246
P42229	Q15303	0	phosphorylation	up-regulates activity	0.811	ERBB4 directly activates STAT5A, in part, through phosphorylation of STAT5A at the regulatory Tyr-694.\|ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events.	SIGNOR-279711
Q8TAB3	P10589	0	transcriptional regulation	up-regulates quantity by expression	0.2	We demonstrated that high expression of COUP-TFI induces MEC cell fate and protocadherin 19 expression. We next demonstrated that COUP-TFI is able to directly bind to a conserved Sp1/COUP-TFI binding site in the Pcdh19 promoter region by chromatin immunoprecipitation (ChIP) (Fig. 6, E and F).	SIGNOR-267223
Q9H0F5	P04637	1	ubiquitination	down-regulates activity	0.363	Here we demonstrate that RNF38 is a functional ubiquitin protein ligase (E3). We show that RNF38 isoform 1 is localized to the nucleus by a bipartite nuclear localization sequence (NLS). We confirm that RNF38 is a binding partner of p53 and demonstrate that RNF38 can ubiquitinate p53 in vitro and in vivo. Finally, we show that overexpression of RNF38 in HEK293T cells results in relocalization of p53 to discrete foci associated with PML nuclear bodies.	SIGNOR-272130
Q15648	P27361	0	phosphorylation	up-regulates	0.263	Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase	SIGNOR-93993
P53350	O95271	1	phosphorylation	up-regulates quantity by stabilization	0.427	Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.	SIGNOR-276245
Q13526	P01574	1	transcriptional regulation	down-regulates quantity by repression	0.2	To investigate the temporal regulation of IRF3-dependent transcription by Pin1, we used a rapid-response luciferase reporter gene. Real-time reporter gene assays showed that suppression of endogenous Pin1 expression substantially prolonged both IRF3-dependent transcription and IFN-beta promoter activation after poly(I)dotpoly(C) stimulation (Fig. 4c,d). Consistent with the inhibitory effects of Pin1 on the IFN-beta promoter	SIGNOR-252289
P12830	P06493	0	phosphorylation	up-regulates activity	0.368	We show that adequate accumulation of Cin8 and Kip1 requires inactivation of the anaphase promoting complex-activator Cdh1 through sequential phosphorylation by Cdk1 and polo kinase.\|We show that adequate accumulation of Cin8 and Kip1 requires inactivation of the anaphase-promoting complex-activator Cdh1 through sequential phosphorylation by Cdk1 and polo kinase.	SIGNOR-280204
Q04656	P31751	0	phosphorylation	up-regulates quantity by stabilization	0.261	Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus\|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466	SIGNOR-272268
P60981	Q96S53	0	phosphorylation	down-regulates activity	0.422	The present study provides evidence that TESK2 can phosphorylate cofilin and ADF specifically at Ser-3. Since actin-depolymerizing and -severing activities of cofilin/ADF are abrogated by phosphorylation at Ser-3, TESK2 seems to play an important role in actin filament dynamics by inhibiting cofilin/ADF activity.	SIGNOR-246707
P50876	P09874	1	ubiquitination	down-regulates quantity by destabilization	0.2	As RNF144A is a newly characterized E3 ubiquitin ligase , ], we next investigated whether RNF144A could promote PARP1 ubiquitination.\|RNF144A promotes the proteasomal degradation of PARP1.	SIGNOR-278776
P24158	P55085	1	cleavage	down-regulates activity	0.373	PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases \| The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II\|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.\|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3	SIGNOR-263601

P98174

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.716

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-260551

Q96J92

O00141

0

phosphorylation

up-regulates activity

0.415

In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM.

SIGNOR-276421

P49137

Q15717

1

phosphorylation

up-regulates

0.303

Mk2 and mk3 participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating the are-binding proteins ttp and hur, and by regulating eef2k

SIGNOR-166622

Q12851

Q13200

1

phosphorylation

up-regulates activity

0.2

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

SIGNOR-273900

P60953

P98174

0

guanine nucleotide exchange factor

up-regulates activity

0.716

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-260551

P84243

Q9UPS6

0

methylation

down-regulates activity

0.2

SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks.

SIGNOR-265578

P49674

Q9GZV5

1

phosphorylation

down-regulates

0.366

LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)

SIGNOR-230747

P51003

P06493

0

phosphorylation

up-regulates activity

0.258

Once an oocyte resumes meiosis, activated CDK1 and ERK1/2 cooperatively mediate the phosphorylation of three serine residues of PAPalpha, 537, 545 and 558, thereby leading to increased activity.

SIGNOR-268338

P00533

Q14164

1

phosphorylation

up-regulates activity

0.257

To understand the mechanism by which IKBKE is activated by mutant EGFR, we first investigated if activating mutation of EGFR is able to form a complex with IKBKE.|While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179.

SIGNOR-278222

Q14344

O95835

1

phosphorylation

down-regulates activity

0.2

These findings suggest that Galpha13 induced phosphorilation of LATS1 at S909 recruits ITCH to trigger LATS1 degradation, leading to EMT-related phenotypes

SIGNOR-278051

Q9NZN5

Q05397

0

phosphorylation

up-regulates activity

0.303

These results suggest that LARG is phosphorylated on tyrosine by FAK after stimulation with RGMa.

SIGNOR-279310

Q00535

Q00536

1

phosphorylation

up-regulates activity

0.335

Taken together, our findings demonstrate that Pctaire1 interacts with p35, both in vitro and in vivo, and that phosphorylation of Pctaire1 by Cdk5 enhances its kinase activity.

SIGNOR-279149

Q13464

P35611

1

phosphorylation

up-regulates

0.376

Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480

SIGNOR-66996

Q13535

P23508

1

phosphorylation

up-regulates activity

0.2

MCC is phosphorylated at the ATM/ATR consensus sites Ser118 and Ser120. Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity.

SIGNOR-273514

O60716

P17252

0

phosphorylation

down-regulates activity

0.251

PKC\u03b1 phosphorylation of p120 at S879 is a critical phospho-switch mediating disassociation of p120 from VE-cadherin that results in AJ disassembly.|We surmised that PKCalpha may function to disrupt AJs by signaling dissociation of p120 from VE-cadherin.

SIGNOR-278261

P15692

P15172

0

transcriptional regulation

up-regulates quantity by expression

0.391

We further demonstrate that the myogenic transcription factor, MyoD, and its heterodimeric binding proteins E12 and E47, up-regulate the expression of endogenous VEGF through direct interaction with the VEGF promoter.

SIGNOR-257598

P68400

Q15672

1

phosphorylation

up-regulates

0.2

Further investigation revealed that il-6 stabilizes twist in scchn cell lines through casein kinase 2 (ck2) phosphorylation of twist residues s18 and s20, and that this phosphorylation inhibits degradation of twist.

SIGNOR-173668

Q05397

P08581

0

phosphorylation

up-regulates

0.497

Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain

SIGNOR-147199

P35869

P53350

0

phosphorylation

down-regulates activity

0.251

In this study, we demonstrate that PLK1 phosphorylates AHR at S489 in LUAD, leading to epithelial-mesenchymal transition (EMT) and metastatic events.

SIGNOR-277885

P18146

P37231

1

transcriptional regulation

down-regulates quantity by repression

0.62

Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC.

SIGNOR-263508

P0DTC2

O15393

0

cleavage

up-regulates activity

0.2

Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. The Cellular Serine Protease TMPRSS2 Primes SARS-2- S for Entry, and a Serine Protease Inhibitor Blocks SARS-CoV-2 Infection of Lung Cells

SIGNOR-260736

P78527

Q9Y6K9

1

phosphorylation

down-regulates activity

0.296

Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR).

SIGNOR-277508

O75626

P13500

1

transcriptional regulation

down-regulates quantity by repression

0.2

Blimp-1 binds to the proinflammatory cytokine/chemokine genes, Il-6 and Ccl2, and negatively regulates their expression.

SIGNOR-271679

P49418

Q13627

0

phosphorylation

down-regulates

0.396

Recent studies show that phosphorylation of amphiphysin1 prd by cdk5 inhibited the association of amphiphysin1 with ap-2 in synaptic vesicle endocytosis (7, 8) similar to that by mapk (present report). Cdk5 appears to phosphorylate amphiphysin1 at serines 261, 272, 276, and 285 and threonine 310, located in the prd

SIGNOR-126843

Q9P2D0

P05771

0

phosphorylation

down-regulates

0.328

We found that ibtk_ is phosphorylated at serines 87 and 90 by pkc on bcr engagement;this phosphorylation causes the dissociation of the btk:ibtk_ complex and allows btk to translocate to the plasma membrane.

SIGNOR-173387

Q8IYT8

P42345

0

phosphorylation

down-regulates

0.777

Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2

SIGNOR-183961

Q15011

Q7Z6J0

0

ubiquitination

up-regulates activity

0.324

Upon TG induced ER calcium store depletion, POSH promotes Herp lys-63-linked polyubiquitination, which in turn promotes the redistribution of Herp to the ER .|Upon thapsigargin-induced endoplasmic reticulum calcium store depletion, POSH promotes Herp lys-63-linked polyubiquitination, which in turn promotes the redistribution of Herp to the endoplasmic reticulum .

SIGNOR-278779

Q16665

P27361

0

phosphorylation

up-regulates

0.695

We show that at least two different nuclear protein kinases, one of them identified as p42/p44 mapk, can modify hif-1_. Analysis of in vitro phosphorylated hif-1_ by mass spectroscopy revealed residues ser-641 and ser-643 as possible mapk phosphorylation sites these data suggest that phosphorylation of ser-641/643 by mapk promotes the nuclear accumulation and transcriptional activity of hif-1_

SIGNOR-178731

P06681

O00187

0

cleavage

up-regulates activity

0.436

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

SIGNOR-263416

P28482

P46695

1

phosphorylation

up-regulates

0.552

Upon phosphorylation by erks, iex-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, iex-1 potentiates erk activation in response to various growth factors.

SIGNOR-93740

Q12913

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-271535

P04198

Q7Z6Z7

0

ubiquitination

down-regulates quantity by destabilization

0.423

HUWE1 ubiquitinates and directs MYCN degradation to the proteasome.

SIGNOR-278750

Q14289

Q9UHD2

1

phosphorylation

up-regulates activity

0.266

Mechanistically, we demonstrate that PTK2B directly phosphorylates residue Tyr591 of TBK1, which increases TBK1 oligomerization and activation.

SIGNOR-277910

Q96P48

P60953

1

gtpase-activating protein

down-regulates activity

0.531

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-260452

P30307

Q13535

0

phosphorylation

up-regulates activity

0.643

We also found that activated ATR phosphorylates CDC25C (Cell Division Cycle 25C) at serine 216, which in turn inactivates the cyclin B1/Cyclin-Dependent Kinase 1(CDK1) complex and induces G2-phase arrest.

SIGNOR-279008

P57682

O95600

1

transcriptional regulation

down-regulates quantity by repression

0.255

Here we report that Klf8 is repressed by Klf3 in vivo and is up-regulated by Klf1. Transcript analysis indicates that Klf8 has two promoters, both containing multiple CACCC elements. Transactivation assays and chromatin immunoprecipitation experiments indicate that Klf3 represses Klf8 directly and that Klf1 activates Klf8 directly.

SIGNOR-266049

O75385

O75143

1

phosphorylation

up-regulates

0.917

Ulks directly phosphorylate atg13

SIGNOR-183957

Q9NYY3

Q9Y4G8

1

phosphorylation

up-regulates activity

0.357

Here, we report that Plk2 phosphorylates a quartet of Ras and Rap regulators : SynGAP, PDZGEF1, RasGRF1 and SPAR, resulting in powerful bidirectional control over Rap and Ras activity.|Thus, Plk2 was sufficient to promote the activities of both SynGAP and PDZGEF1 in mammalian cells.

SIGNOR-280066

O95388

P35222

0

transcriptional regulation

up-regulates quantity

0.2

This study identifies WISP-1 as a beta-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and beta-catenin expression.

SIGNOR-256270

P27361

P08235

1

phosphorylation

down-regulates quantity by destabilization

0.35

Taken together, these data suggest that ERK1/2 directly phosphorylates the MR on several serine residues present in its NTD, that the upward shift of MR is mainly due to receptor phosphorylation, and finally that these sites represent the major aldosterone-inducible targets for MR phosphorylation.MR phosphorylation limits the transcriptional activity.Taken together, these results provide evidence that MR phosphorylation plays a role in aldosterone-mediated ubiquitylation and degradation.

SIGNOR-276102

Q99626

Q16819

1

transcriptional regulation

up-regulates quantity by expression

0.471

TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis|

SIGNOR-253965

Q9UHW9

Q9H4A3

0

phosphorylation

down-regulates

0.453

We have attempted to identify kinases and phosphatases involved in the modulation of phosphorylation at kcc3 t991 and t1048. the wnk kinases and spak/osr1 are strong candidates for kcc3 regulatory kinases.

SIGNOR-187564

P53350

P60510

0

dephosphorylation

down-regulates activity

0.416

PPP4C dephosphorylated PLK1 at the S137 site, negatively regulating its activity in the DSB response in early embryonic cells.

SIGNOR-277076

Q05397

P24666

0

dephosphorylation

down-regulates activity

0.276

Lymphocyte function-associated antigen-1-mediated T cell adhesion is impaired by low molecular weight phosphotyrosine phosphatase-dependent inhibition of FAK activity. 4000254={CellProcess=4107155 CellType=10000184}}|Moreover, in these conditions LMW-PTP causes FAK dephosphorylation, thus preventing the activation of FAK downstream pathways.

SIGNOR-277064

O95835

P58012

1

phosphorylation

up-regulates activity

0.452

LATS1 phosphorylates forkhead L2 and regulates its transcriptional activity.|Last, we demonstrated that coexpression with LATS1 enhances FOXL2 's activity as a repressor of the StAR promoter, and this results from the kinase activity of LATS1.

SIGNOR-279624

P12259

P68400

0

phosphorylation

down-regulates activity

0.307

Factor Va, the essential cofactor for prothrombinase, is phosphorylated on the acidic COOH terminus of the heavy chain of the cofactor, at Ser692, by a platelet membrane-associated casein kinase II (CKII). | The phosphorylated cofactor has increased susceptibility to inactivation by activated protein C, since phosphorylated factor Va was found to be inactivated approximately 3-fold faster than its native counterpart.

SIGNOR-250862

Q9H2K2

Q9NTX7

0

ubiquitination

down-regulates quantity

0.614

We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.

SIGNOR-260005

Q9BX84

P0C0S8

1

phosphorylation

down-regulates activity

0.2

We found that MSK1 phosphorylated histone H2A on serine 1, and mutation of serine 1 to alanine blocked the inhibition of transcription by MSK1.

SIGNOR-276008

O75914

P17600

1

phosphorylation

up-regulates activity

0.334

Synapsin I is phosphorylated at Ser603 by p21-activated kinases. the Ser603 residue must be one of the pivotal sites for the release

SIGNOR-250246

Q9UHD2

Q15025

1

phosphorylation

down-regulates quantity by destabilization

0.375

TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1

SIGNOR-275733

P04150

Q92831

1

relocalization

up-regulates activity

0.549

NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase

SIGNOR-269233

Q96J02

P31749

0

phosphorylation

up-regulates quantity

0.319

AKT1-mediated phosphorylation of ITCH at Ser257 drives its nuclear translocation

SIGNOR-272922

P04150

O15516

0

transcriptional regulation

down-regulates quantity by repression

0.41

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

SIGNOR-253699

O00429

P16298

0

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

P31749

Q6ZVD8

0

dephosphorylation

down-regulates

0.773

Here, we identify a protein phosphatase, ph domain leucine-rich repeat protein phosphatase (phlpp), that specifically dephosphorylates the hydrophobic motif of akt (ser473 in akt1), triggering apoptosis and suppressing tumor growth.[...] These data are consistent with phlpp terminating akt signaling by directly dephosphorylating and inactivating akt.

SIGNOR-252602

Q99102

P19419

0

transcriptional regulation

up-regulates quantity by expression

0.2

Through promoter screening, overexpressing methods and luciferase reporter studies, we found that transcription factors CREB, Ets-1, Elk-1 and STAT1 can positively regulate MUC4 expression at the promoter and mRNA level.

SIGNOR-254096

Q15369

Q02539

1

phosphorylation

up-regulates

0.2

Our results also show the potential function of p-tefb phosphorylation of h1, namely, to increase h1 dissociation from actively transcribed dna. P-tefb preferentially phosphorylates the ser-183 phosphorylation site of histone h1.1

SIGNOR-166120

Q13177

Q99523

1

phosphorylation

down-regulates activity

0.2

PAKs specifically phosphorylate Ser15 of the sortilin-cd and alter its trafficking. It can be concluded that PAK1-3 may indeed instigate the phosphorylation of sortilin and that they target a single serine residue (Ser15) located in the kinase domain-binding site of the sortilin-cd. Full-length sortilins with the serine at position 793 (residue 15 in the cytoplasmic domain) (for the sequence, see Fig. 2). Phosphorylation (Ser15) downregulates the sortilin–AP-1 interaction.

SIGNOR-273717

P26038

O94804

0

phosphorylation

up-regulates activity

0.385

Evidence in jurkat cells that lok phosphorylates erm and that erm phosphorylation impedes migration.

SIGNOR-184433

P18848

P67870

0

phosphorylation

down-regulates quantity by destabilization

0.2

By using mutants of ATF4 we identified serine 215 as the main CK2 phosphorylation site. The ATF4 S215A mutant turned out to be more stable than the wild-type form.

SIGNOR-276424

Q9UQM7

P16220

1

phosphorylation

down-regulates

0.594

Phosphorylation of creb1 at ser142 and ser143 is selectively activated by ca(2+) influx;phosphorylation of ser142 and ser143, disrupts the interaction of creb with its cofactor cbp. Phosphorylation of serine 142 in creb by camkii leads to dissociation of the creb dimer.

SIGNOR-82501

O15527

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.2

We demonstrate that recombinant NEDD4L stimulates ubiquitylation of OGG1 in vitro, particularly on lysine 341, and that NEDD4L and OGG1 interact in U2OS cells.

SIGNOR-278639

Q15911

Q13315

0

phosphorylation

up-regulates activity

0.346

Indeed, ATM phosphorylates ATBF1 at Ser1180 in HEK293T cells exposed to 10-Gy radiation [ xref ].|We also found in this study that ATBF1 mediated neuronal death is dependent on ATM signals because the blockage of ATM by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 functions in neuronal death.

SIGNOR-279138

Q9HC98

P23443

1

phosphorylation

up-regulates activity

0.367

Here we demonstrate that in addition to phosphorylating S6K1 and SGK1 at their hydrophobic motif, NEK6 also phosphorylates S6K1 at two other sites and phosphorylates SGK1 at one other site in vitro. Analysis of the peptides phosphorylated by NEK6 (Fig 2), performed in the present study has confirmed this, and identified two novel sites on S6K1 (Ser53 and Ser403) as major sites of NEK6 phosphorylation.

SIGNOR-262953

Q86U44

Q13315

0

phosphorylation

up-regulates activity

0.2

Here, we report that, in response to DSBs, the RNA methyltransferase METTL3 is activated by ATM-mediated phosphorylation at S43.

SIGNOR-265969

P17676

O96013

0

phosphorylation

up-regulates activity

0.2

Importantly, we found that PAK4 enhanced CEBPB phosphorylation on Thr 235.|In summary, we showed that PAK4 mediated CEBPB activation upregulated CLDN4 expression to promote breast cancer cell migration and invasion.

SIGNOR-280055

Q05923

Q16659

1

dephosphorylation

down-regulates activity

0.376

DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5.

SIGNOR-277069

Q99576

P98177

1

relocalization

down-regulates activity

0.253

GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells.

SIGNOR-256148

Q7Z6Z7

P38398

1

ubiquitination

down-regulates quantity by destabilization

0.397

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

SIGNOR-278583

Q13315

Q9BXW9

1

phosphorylation

up-regulates

0.789

These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint

SIGNOR-90117

Q9UBN7

Q01130

1

deacetylation

up-regulates

0.356

Our data support a model in which hdac6 has a key role in the maintenance of srsf2 protein level by inhibiting tip60_mediated acetylation and proteasomal degradation.

SIGNOR-170590

P12830

Q96RU2

0

deubiquitination

up-regulates quantity by stabilization

0.2

Usp28 deubiquitylates and consequently stabilizes Claspin in response to DNA damage

SIGNOR-274057

Q9NTG7

P36888

0

phosphorylation

down-regulates activity

0.2

We also hypothesize that, besides activating ACAT1 through Y407 phosphorylation (Fan et al., 2016), FLT3 might simultaneously phosphorylate and regulate SIRT3. Our mutational studies on all of the seven tyrosine sites of SIRT3 revealed that purified rFLT3 directly phosphorylated purified rSIRT3 in an in vitro kinase assay, leading to decreased SIRT3 deacetylase activity that was assessed by ability to deacetylate K413 of mIDH2 (Figure 4H, first three samples in left, middle, and right panels), whereas replacement of Y226 completely abolished inhibition of SIRT3 by FLT3 (Figure 4H, right).

SIGNOR-267631

Q9BY78

Q86WV6

1

ubiquitination

up-regulates activity

0.2

As a result, knockdown of RNF26 promoted degradation of MITA after viral infection and prevented degradation of IRF3.|In addition, RNF26 could not induce polyubiquitination of MITA (K150R) in in vitro ubiquitination assays (XREF_FIG).

SIGNOR-278573

P06400

P11802

0

phosphorylation

down-regulates

0.929

Cyclin d1 is known to activate cdk4, which then phosphorylates the rb protein, leading to cell cycle progression.

SIGNOR-200487

Q13489

Q96FA3

0

ubiquitination

up-regulates quantity by stabilization

0.455

Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity.

SIGNOR-259395

Q13286

P06493

0

phosphorylation

down-regulates activity

0.257

(D) Phosphorylation of Cln3 by Cdk1 is independent of Ssa1 T36.|Thereby, both Cdk1 and Pho85can promote Cln3 degradation, though under distinct circumstances.

SIGNOR-279013

Q07890

P01112

1

guanine nucleotide exchange factor

up-regulates

0.79

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.

SIGNOR-175262

O15530

P05106

1

phosphorylation

down-regulates activity

0.473

PDK1 specifically phosphorylates Thr-753 in 3. Our data argue that phosphorylation of Thr-753, which is conserved in many subunits, reduces the ability of PTB-containing proteins to bind the NXX(pY) motif in 3.

SIGNOR-250266

P17252

O60825

1

phosphorylation

up-regulates activity

0.439

The phosphorylation sites for both cAMP-dependent protein kinase and protein kinase C were located in a single peptide whose sequence was Arg-Arg-Asn-Ser-(P)-Phe-Thr-Pro-Leu-Ser-Ser-Ser-Asn-Thr(P)-Ile-Arg-Arg-Pro. The seryl residue nearest the N terminus was the residue specifically phosphorylated by cAMP-dependent protein kinase, whereas the threonine residue nearest the C terminus was phosphorylated by protein kinase C. | Phosphorylation of bovine heart Fru-6-P,B-kinase by either protein kinase C or CAMP-dependent protein kinase results in activation of the enzyme.

SIGNOR-248844

Q9P1W9

Q13131

1

phosphorylation

down-regulates activity

0.2

Specifically, we found that PIM2 bound to AMPKα1, and directly phosphorylated it on Thr467. Phosphorylation of AMPKα1 by PIM2 led to decreasing AMPKα1 kinase activity, which in turn promoted aerobic glycolysis and tumor growth.

SIGNOR-277471

P06241

P16410

1

phosphorylation

up-regulates quantity by stabilization

0.77

CTLA-4 can associate with the Src kinases Fyn and Lck and that transfection of Fyn or Lck, but not the unrelated kinase ZAP70, can induce tyrosine phosphorylation of CTLA-4 on residues Y201 and Y218.¬† Phosphorylation of CTLA-4 Y201 in Jurkat cells correlated with cell surface accumulation of CTLA-4.

SIGNOR-251161

O95163

P42345

0

phosphorylation

up-regulates activity

0.2

Human ELP1 S1174 phosphorylation was triggered by insulin treatment, as shown by the specific phosphorylated (p)ELP1 (S1174) antibody, and addition of a phosphorylation-mutant variant of the ELP1 protein (ELP1(S1174A)) to ELP1-depleted BRAFV600E melanoma cells failed to rescue cell survival |In line with these findings, mTORC2 activity, but not mTORC1, was required for the insulin-induced phosphorylation of Elp1 S1174

SIGNOR-275541

P19784

O60936

1

phosphorylation

up-regulates activity

0.2

Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm.

SIGNOR-262836

Q5UE93

P31749

0

phosphorylation

up-regulates activity

0.45

P84 forms a negative regulatory complex with p110gamma to control PI3Kgamma signalling during cell migration|However, phosphorylation at this site was confirmed using an in vitro kinase assay in which Akt kinase was shown to readily phosphorylate Thr607 using a p84 peptide (Figure 1e), where Thr607 in conjunction with surrounding residues forms an Akt kinase consensus sequence|In contrast, although p84-T607A exhibited basal p110γ dimerisation, this interaction could not be further induced with stimulation

SIGNOR-275722

Q9UL68

Q14469

1

transcriptional regulation

down-regulates quantity by repression

0.2

ChIP–seq experiments showed that 80% of Myt1l targets, including the transcription factor Hes1, were co-bound by the repressive Sin3b–HDAC1 complex early during reprogramming

SIGNOR-266775

Q13315

Q01094

1

phosphorylation

up-regulates quantity by stabilization

0.679

Selective induction of e2f1 in response to dna damage, mediated by atm-dependent phosphorylation. We identify a site for atm/atr phosphorylation in the amino terminus of e2f1 and we show that this site is required for atm-mediated stabilization of e2f1. Finally, we also show that e2f1 is required for dna damaged induced apoptosis in mouse thymocytes.

SIGNOR-109416

Q99502

P16104

1

dephosphorylation

down-regulates

0.2

Tyr142 is dephosphorylated by the tyr phosphatases eya1 and eya3.

SIGNOR-168879

O14964

P00533

0

phosphorylation

up-regulates activity

0.637

We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation

SIGNOR-100246

P42229

Q15303

0

phosphorylation

up-regulates activity

0.811

ERBB4 directly activates STAT5A, in part, through phosphorylation of STAT5A at the regulatory Tyr-694.|ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events.

SIGNOR-279711

Q8TAB3

P10589

0

transcriptional regulation

up-regulates quantity by expression

0.2

We demonstrated that high expression of COUP-TFI induces MEC cell fate and protocadherin 19 expression. We next demonstrated that COUP-TFI is able to directly bind to a conserved Sp1/COUP-TFI binding site in the Pcdh19 promoter region by chromatin immunoprecipitation (ChIP) (Fig. 6, E and F).

SIGNOR-267223

Q9H0F5

P04637

1

ubiquitination

down-regulates activity

0.363

Here we demonstrate that RNF38 is a functional ubiquitin protein ligase (E3). We show that RNF38 isoform 1 is localized to the nucleus by a bipartite nuclear localization sequence (NLS). We confirm that RNF38 is a binding partner of p53 and demonstrate that RNF38 can ubiquitinate p53 in vitro and in vivo. Finally, we show that overexpression of RNF38 in HEK293T cells results in relocalization of p53 to discrete foci associated with PML nuclear bodies.

SIGNOR-272130

Q15648

P27361

0

phosphorylation

up-regulates

0.263

Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (ppar)-binding protein (pbp). Stimulation of transcriptional regulation by mitogen-activated protein kinase

SIGNOR-93993

P53350

O95271

1

phosphorylation

up-regulates quantity by stabilization

0.427

Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.

SIGNOR-276245

Q13526

P01574

1

transcriptional regulation

down-regulates quantity by repression

0.2

To investigate the temporal regulation of IRF3-dependent transcription by Pin1, we used a rapid-response luciferase reporter gene. Real-time reporter gene assays showed that suppression of endogenous Pin1 expression substantially prolonged both IRF3-dependent transcription and IFN-beta promoter activation after poly(I)dotpoly(C) stimulation (Fig. 4c,d). Consistent with the inhibitory effects of Pin1 on the IFN-beta promoter

SIGNOR-252289

P12830

P06493

0

phosphorylation

up-regulates activity

0.368

We show that adequate accumulation of Cin8 and Kip1 requires inactivation of the anaphase promoting complex-activator Cdh1 through sequential phosphorylation by Cdk1 and polo kinase.|We show that adequate accumulation of Cin8 and Kip1 requires inactivation of the anaphase-promoting complex-activator Cdh1 through sequential phosphorylation by Cdk1 and polo kinase.

SIGNOR-280204

Q04656

P31751

0

phosphorylation

up-regulates quantity by stabilization

0.261

Akt2 (Protein Kinase B Beta) Stabilizes ATP7A, a Copper Transporter for Extracellular Superoxide Dismutase, in Vascular Smooth Muscle: Novel Mechanism to Limit Endothelial Dysfunction in Type 2 Diabetes Mellitus|Immunoprecipitation, in vitro kinase assay, and mass spectrometry analysis reveal that insulin stimulates Akt2 binding to ATP7A to induce phosphorylation at Ser1424/1463/1466

SIGNOR-272268

P60981

Q96S53

0

phosphorylation

down-regulates activity

0.422

The present study provides evidence that TESK2 can phosphorylate cofilin and ADF specifically at Ser-3. Since actin-depolymerizing and -severing activities of cofilin/ADF are abrogated by phosphorylation at Ser-3, TESK2 seems to play an important role in actin filament dynamics by inhibiting cofilin/ADF activity.

SIGNOR-246707

P50876

P09874

1

ubiquitination

down-regulates quantity by destabilization

0.2

As RNF144A is a newly characterized E3 ubiquitin ligase , ], we next investigated whether RNF144A could promote PARP1 ubiquitination.|RNF144A promotes the proteasomal degradation of PARP1.

SIGNOR-278776

P24158

P55085

1

cleavage

down-regulates activity

0.373

PAR1E and PAR2E (10 microM) were incubated in the presence of the different proteases | The enzymes were used at the following concentrations: 0.5 unit/mL thrombin, 2.5 nM trypsin, 20 nM plasmin, 20 nM cathepsin G, 20 nM elastase, 20 nM proteinase 3, and 2 units/mL calpain I and II|Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus.|Mass spectrometry studies of PAR2E predicted activation of PAR2 by trypsin through cleavage at the Arg36-Ser37 site, no effect of thrombin, and inactivation of the receptor by plasmin, calpain and leukocyte elastase, cathepsin G, and proteinase 3

SIGNOR-263601