GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q16566	Q9UNW9	1	phosphorylation	up-regulates quantity	0.255	CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. Conversely, Nova-2 with single or double mutations to alanine (2A and 1A2A) was predominantly nuclear, like the WT (Figures 5H and and5I).5I). In contrast, glutamate mutations at site 3 had no effect on Nova-2 localization (Figures 5H and and5I)5I) or on Nova-2 binding to RNA (Figure S5E). These results showed that active CaMKIV reduces Nova-2 nuclear localization by phosphorylating sites 1 and 2 (S25, T27).	SIGNOR-273521
P29966	P17252	0	phosphorylation	down-regulates activity	0.73	Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin	SIGNOR-249650
P24941	P38936	2	phosphorylation	down-regulates quantity by destabilization	0.954	Cdk2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation at ser-130.	SIGNOR-149416
P03372	P27986	2	binding	up-regulates	0.628	Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k.	SIGNOR-140470
P06241	Q9Y210	1	phosphorylation	up-regulates activity	0.505	Fyn phosphorylates TRPC6 and increases its diacylglycerol stimulated single channel activity.	SIGNOR-279717
P15374	P62979	1	cleavage	up-regulates quantity	0.802	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270828
P61073	Q05655	0	phosphorylation	down-regulates activity	0.2	Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C \| However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization.	SIGNOR-260898
P09471	P25103	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257249
Q14449	P49840	0	phosphorylation	down-regulates activity	0.264	Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor\| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.	SIGNOR-264871
P12931	Q13642	1	phosphorylation	up-regulates activity	0.26	However, overexpression of Src promoted most of the Flag-FHL1-WT to translocate to the nucleus, whereas the Flag-FHL1-Y149-272F mutant (phosphorylation deficient mutant) remained in the cytoplasm (XREF_FIG).\|We found that Src phosphorylates FHL1 at Y149 and Y272, demonstrating that FHL1 is a bona fide novel substrate of Src.	SIGNOR-278213
Q96GD4	Q99661	1	phosphorylation	up-regulates	0.731	Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres.	SIGNOR-155890
P78527	O75030	1	phosphorylation	up-regulates activity	0.2	These results suggest that DNA-PK can target MITF-S325 for phosphorylation. In melanocytes and melanoma cells, MITF is rapidly phosphorylated by DNA-PK and interacts with NBS1–RAD50 but not MRE11, destabilizing the MRN complex.	SIGNOR-277899
Q9ULT8	P07900	1	ubiquitination	down-regulates quantity	0.2	We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Identification of Hsp90 in both proteomic screens suggested that members of the Hsp90 superfamily may be substrates of Hectd1. Myc-Hectd1ANK and HA-Hsp90bd (the fragment identified in the yeast two-hybrid screen) bind in an in vitro binding assay (Fig. 3 D) and when coexpressed in HEK293T cells. Hectd1 is required for K63-linked Ubn of Hsp90. Together, these results demonstrate that Hectd1-dependent Ubn of Hsp90 targets it away from the membrane and the secretory pathway.	SIGNOR-261199
Q92830	P84243	1	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269603
Q9NPD5	P53567	0	transcriptional regulation	up-regulates quantity by expression	0.2	Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter.	SIGNOR-268986
O15530	Q00005	2	binding	down-regulates activity	0.331	Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation.	SIGNOR-243511
P43405	P15498	2	phosphorylation	up-regulates	0.92	Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k.	SIGNOR-107046
P01019-PRO_0000032457	P12821	2	binding	up-regulates activity	0.2	Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I	SIGNOR-260231
Q00535	Q13794	1	phosphorylation	down-regulates	0.356	We show that noxa is phosphorylated on a serine residue (s(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify cdk5 as the noxa kinase	SIGNOR-170357
Q05397	P63000	1	phosphorylation	up-regulates activity	0.574	Both Src and FAK phosphorylate Rac1 at tyrosine 64.\|Our investigations of direct interactions between Rac1, Src, and FAK were motivated by our previous insights into FAK augmentation of Rac1 activation during cell spreading, and the Cerione lab 's work on the interactions between Src and Cdc42 , .	SIGNOR-279652
Q99523	Q13153	0	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-273718
Q92914	Q9UI33	2	binding	down-regulates activity	0.2	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253438
Q6STE5	P15172	2	binding	up-regulates activity	0.538	We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes.	SIGNOR-238289
Q13586	P28482	0	phosphorylation	up-regulates	0.351	The netrin-2-mediated nfatc3 activation was coincident with robust interactions between cdo and stim1 in myoblasts and the erk-mediated stim1 phosphorylation at serine 575	SIGNOR-192788
P78527	P31749	1	phosphorylation	up-regulates activity	0.754	DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform	SIGNOR-252431
P06493	P53350	2	binding	up-regulates activity	0.611	Moreover, CDK1 phosphorylates RSF1 at Ser1375, and this phosphorylation is necessary for PLK1 recruitment. Subsequently, PLK1 phosphorylates RSF1 at Ser1359, stabilizing PLK1 deposition.	SIGNOR-273589
Q04637	P17252	0	phosphorylation	up-regulates activity	0.258	Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186.	SIGNOR-276327
O14640	Q53G59	2	binding	down-regulates quantity by destabilization	0.621	KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation.	SIGNOR-271558
Q05655	P04040	1	phosphorylation	up-regulates activity	0.266	Endothelin-1 stimulates catalase activity through the PKCδ-mediated phosphorylation of serine 167.	SIGNOR-260904
Q9H0K1	O75581	1	phosphorylation	up-regulates activity	0.2	Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation.	SIGNOR-275399
Q9H2X6	P06276	1	phosphorylation	down-regulates quantity	0.2	As shown in XREF_FIG, HIPK2 overexpression strongly reduced Myc-Che-1 levels, whereas it produced little effect on Che-1 T144A expression.\|Notably, we found that HIPK2 phosphorylates a specific residue of Che-1, which is required for its interaction with Pin1 and for its degradation through the proteasome pathway.	SIGNOR-279190
P08246	P05546	1	cleavage	down-regulates activity	0.451	Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC.	SIGNOR-256510
Q96SW2	Q9H3D4	1	polyubiquitination	down-regulates quantity by destabilization	0.2	CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs.When thalidomide binds to CRBN, substrate specificity of CRL4CRBN is altered and CRBN neomorphically binds to ∆Np63, TAp63 and other neosubstrates and ubiquitinates them for proteasomal degradation.	SIGNOR-272214
Q8NHW3	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.257	We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.	SIGNOR-159462
Q05195	P17480	1	transcriptional regulation	down-regulates quantity by repression	0.36	MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation\|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter.	SIGNOR-269646
Q9NP62	Q14012	0	phosphorylation	up-regulates activity	0.388	We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.	SIGNOR-262680
P28336	P19086	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257315
Q71DI3	Q9Y4C1	0	demethylation	up-regulates activity	0.2	Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9.	SIGNOR-276844
O14654	Q9UNE7	0	polyubiquitination	down-regulates quantity by destabilization	0.2	IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP).	SIGNOR-277616
P12931	P78352	1	phosphorylation	up-regulates	0.565	These results indicate that psd-95 phosphorylation by src facilitates the integration of pyk2 to psd-95 signal complex, the activation of pyk2/src, as well as the subsequent tyrosine phosphorylation of nr2a, which ultimately results in the upregulation of nmda receptor function and synaptic transmission.	SIGNOR-205120
Q15276	Q15139	0	phosphorylation	up-regulates activity	0.382	PKD phosphorylates Rabaptin-5 at Ser407, and this controls alphavbeta3 and alpha5beta1 integrin and EGFR recycling.	SIGNOR-278192
Q5VWQ8	P15976	2	binding	up-regulates activity	0.2	DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene	SIGNOR-254770
P50542	O43933	2	binding	up-regulates activity	0.548	Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. (Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner.	SIGNOR-253618
Q13315	Q9Y6K9	1	phosphorylation	down-regulates activity	0.739	Atm phosphorylates serine-85 of nemo to promote its ubiquitin-dependent nuclear export.	SIGNOR-144813
Q8N752	Q8NEG4	2	binding	up-regulates quantity	0.2	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273759
Q13185	P17612	0	phosphorylation	up-regulates	0.2	We demonstrate that p-ser 83-hp1gamma has an exclusively euchromatic localization, interacts with ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation.	SIGNOR-145109
Q09472	P31749	0	phosphorylation	up-regulates	0.697	We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity	SIGNOR-148983
Q9NR28	P53779	0	phosphorylation	down-regulates	0.341	Here we demonstrate that jnk3 can phosphorylate smac. Phosphorylation of smac by jnk3 attenuates its interaction with xiap. These results suggest that jnk3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between smac and xiap.	SIGNOR-157280
P51812	O15297	0	dephosphorylation	down-regulates activity	0.361	RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity	SIGNOR-248322
P01189	P40763	0	transcriptional regulation	up-regulates quantity by expression	0.638	We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter.	SIGNOR-263497
Q7Z6Z7	P43405	0	phosphorylation	up-regulates activity	0.2	Collectively, these data suggest that TNF induced tyrosine phosphorylation of Mule by Syk contributes to its E3 ligase activity.	SIGNOR-280150
Q14814	P23409	1	transcriptional regulation	up-regulates quantity by expression	0.573	Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis.	SIGNOR-238715
P23771	Q969H0	0	ubiquitination	down-regulates quantity by destabilization	0.403	Fbw7 promotes degradation of GATA3 in a Thr-156-dependent manner.	SIGNOR-276635
P49840	Q13554	0	phosphorylation	down-regulates	0.291	Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival.	SIGNOR-167962
P04179	Q16236	0	transcriptional regulation	up-regulates quantity by expression	0.45	BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2	SIGNOR-254652
P42224	O14543	1	transcriptional regulation	up-regulates quantity by expression	0.677	Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways.	SIGNOR-249565
Q16633	P14859	2	binding	up-regulates	0.622	Obf1 enhances transcriptional potential of oct1.	SIGNOR-100968
O75582	Q92934	1	phosphorylation	down-regulates activity	0.344	Phosphorylation of Bad at Ser112 in response to growth factors or cytokines is generally linked to cell survival. Knockdown of MSK1 suppressed Bad phosphorylation after calcium ionophore A23187 treatment in neuronal cells	SIGNOR-262990
P11142	O75061	0	relocalization	up-regulates activity	0.883	Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane.	SIGNOR-260719
P29353	P29317	2	binding	up-regulates	0.616	We also show that the interaction of epha2 with grb2 is indirect and mediated by shc and that this complex is necessary for epha2-mediated activation of erk kinases.	SIGNOR-94804
P28482	Q96RK0	1	phosphorylation	down-regulates	0.372	Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3))[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3	SIGNOR-169875
P08575	P23458	1	dephosphorylation	up-regulates	0.454	These negative regulatory effects on ig class switching were concomitant with the ability of cd45 to dephosphorylate the induced phosphorylation of jak1, jak3,	SIGNOR-87154
P13674	Q01581	1	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-279853
Q8N122	P27361	0	phosphorylation	up-regulates activity	0.469	We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.	SIGNOR-169530
P17252	Q16760	1	phosphorylation	down-regulates activity	0.366	The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain.	SIGNOR-249265
P25101	P19086	2	binding	up-regulates activity	0.25	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257320
Q13905	P46108	2	binding	up-regulates	0.901	The endogenous c3g could be coprecipitated with crk from cell lysates of cells expressing high levels of c-crk or v-crk, suggesting high binding affinity and a possible interaction in vivo.	SIGNOR-33732
Q13547	Q96KB5	0	phosphorylation	up-regulates activity	0.245	TOPK overexpression promotes HDAC1 and HDAC2 phosphorylation and Histone 3 and Histone 4 acetylation in BV2 cells.\|The results of in vitro studies further confirmed the effect of TOPK on HDAC activity by showing that TOPK overexpression significantly up-regulated p-HDAC1 and p-HDAC2, resulting in an increase in the acetylation of histones H3 and H4 in BV2 cells.	SIGNOR-279086
P63000	Q9BRR9	0	gtpase-activating protein	down-regulates activity	0.606	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-260464
O15357	Q9ULV8	2	binding	down-regulates	0.2	This association between ship2 and cbl could sequester cbl from the egfr, thereby regulating the kinetics of egfr-cbl association and subsequent internalization and degradation of the receptor.	SIGNOR-133388
P00519	P37231	1	phosphorylation	up-regulates quantity	0.341	We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ.	SIGNOR-262297
Q92835	P16885	1	dephosphorylation	down-regulates activity	0.312	An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.	SIGNOR-268455
P53350	Q96FF9	1	phosphorylation	down-regulates activity	0.705	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.	SIGNOR-276122
O14920	Q9NQC7	1	phosphorylation	down-regulates activity	0.548	Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.	SIGNOR-204716
Q00535	P00352	1	phosphorylation	up-regulates quantity	0.2	Cdk5 Phosphorylates ALDH1A1 at S75 and S274.\|These results demonstrate that Cdk5 increases ALDH1A1 levels in neurotoxin exposed neuronal cells both at transcriptional level and by direct phosphorylation at S75 and S274 sites.	SIGNOR-279399
Q96LA8	Q9NRC8	1	methylation	down-regulates activity	0.259	Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 at R388 in vitro and in vivo R388 methylation suppresses the H3K18 deacetylase activity of SIRT7 without modulating its subcellular localization.	SIGNOR-275888
P46060	O75592	1	relocalization	down-regulates quantity by destabilization	0.315	SUMOylated RanGAP1 Inhibits MYCBP2 Activity and Mediates Its Transport to the Nucleus. Surprisingly, we did not find MYCBP2-dependent ubiquitylation of SUMOylated RanGAP1 but instead a strong inhibition of the ubiquitin ligase activity of MYCBP2 in the presence of SUMOylated RanGAP1, as determined by the presence of ubiquitylated proteins. this effect was specific for SUMOylated RanGAP1, because the unmodified form of RanGAP1 did not affect MYCBP2-dependent protein ubiquitylation. , SUMOylated RanGAP1 inhibited the ubiquitin ligase activity of MYCBP2, and it is tempting to speculate that SUMOylated RanGAP1 inhibits the ubiquitin ligase activity of MYCBP2 to ensure MYCBP2 silencing during its transport to the nucleus	SIGNOR-261203
P30305	Q9UNH5	0	dephosphorylation	down-regulates activity	0.56	Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).\|Together, these data indicate that Cdc14A dephosphorylates Cdc25B, inhibiting its catalytic activity.	SIGNOR-276968
Q9Y5Q3	P49840	0	phosphorylation	down-regulates	0.2	We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.	SIGNOR-159432
P41221	Q13467	2	binding	up-regulates	0.832	These results identify hfz5 as a receptor for wnt-5a.	SIGNOR-46897
Q7Z6J0	Q12852	2	binding	up-regulates	0.376	One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks	SIGNOR-108577
P06493	Q08050	1	phosphorylation	up-regulates	0.762	A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity	SIGNOR-187880
P02818	P15036	0	transcriptional regulation	up-regulates quantity by expression	0.2	Ets2 is expressed at high levels during the differentiation and matrix mineralization phases of MC3T3-E1 culture. In addition, several extracellular matrix (ECM) associated gene products are targets of Ets2. Some of these matrix associated genes include: bone sialoprotein, osteonectin, osteocalcin and osteopontin	SIGNOR-259875
P23246	P11387	2	binding	up-regulates	0.372	We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i	SIGNOR-60563
Q96GX5	P31749	0	phosphorylation	up-regulates activity	0.2	Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation.	SIGNOR-277515
P00533	P35222	1	phosphorylation	up-regulates activity	0.773	EGFR and TRKA effect on WNT3a mediated Topflash induction was abolished by U0126 or expression of dominant negative LRP6-5A mutant (XREF_FIG), demonstrating that both EGFR and TRKA signal via ERK and LRP6 pathway to upregulate WNT and beta-catenin signaling.\|FGFR2, FGFR3, EGFR and TRKA Phosphorylate beta-catenin at Tyr142.	SIGNOR-278309
P28335	P63096	2	binding	up-regulates activity	0.293	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256734
Q9UNH7	P11717	2	binding	down-regulates quantity	0.364	Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.	SIGNOR-269443
Q9UJD0	A6NNM3	2	binding	down-regulates activity	0.265	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264374
Q05655	O15162	1	phosphorylation	up-regulates	0.424	Following the induction of apoptosis, however, phosphorylation of serine residues decreased and it increased on threonine, consistent with the predicted pkc phosphorylation site at thr-161. Transfection of cho cells with scramblase and pkc_, but not scramblase or pkc_ alone, increased scramblase activity	SIGNOR-76904
P18089	P19086	2	binding	up-regulates activity	0.437	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257109
Q8IYW5	Q14669	0	ubiquitination	down-regulates activity	0.465	Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1.	SIGNOR-266783
Q13976	P11831	1	phosphorylation	up-regulates	0.275	Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. \| Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.	SIGNOR-188185
P11940	Q13064	0	ubiquitination	down-regulates activity	0.2	MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA\|Altogether, it is thus clear that the ubiquitination of PABPC1 or PABPC4 by MKRN3 negatively regulates the formation of translation initiation complex (TIC), attenuates their binding to poly (A)-tail contained mRNAs, and leads to the shortened poly (A) tail-length of GNRH1 mRNA.	SIGNOR-278764
Q01973	P12931	1	phosphorylation	up-regulates	0.318	Ror1 binds to and phosphorylates c-src / ror1 kinase-dependent c-src activation	SIGNOR-196751
Q96T88	P48730	0	phosphorylation	up-regulates	0.245	We further show that uhrf1 physically interacts with _-trcp1 in a manner dependent on phosphorylation of serine 108 (s108(uhrf1)) within the dsg degron. Furthermore, we demonstrate that s108(uhrf1) phosphorylation is catalyzed by casein kinase 1 delta (ck1_) and is important for the recognition of uhrf1 by scf(_-trcp).	SIGNOR-200349
Q9HCI7	P04637	1	ubiquitination	down-regulates activity	0.37	Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization. MSL2 ubiquitination of p53 is required for p53 cytoplasmic localization.	SIGNOR-271774
P0DTD1-PRO_0000449624	Q9UHD2	2	binding	down-regulates activity	0.2	We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F).	SIGNOR-262510
O15409	Q13224	1	transcriptional regulation	up-regulates quantity by expression	0.318	By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.	SIGNOR-266834
P28482	P23469	0	dephosphorylation	down-regulates activity	0.39	The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling\|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop	SIGNOR-248448

Q16566

Q9UNW9

1

phosphorylation

up-regulates quantity

0.255

CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. CaMKIV Phosphorylates Nova-2 and Regulates Its Nuclear Localization. Conversely, Nova-2 with single or double mutations to alanine (2A and 1A2A) was predominantly nuclear, like the WT (Figures 5H and and5I).5I). In contrast, glutamate mutations at site 3 had no effect on Nova-2 localization (Figures 5H and and5I)5I) or on Nova-2 binding to RNA (Figure S5E). These results showed that active CaMKIV reduces Nova-2 nuclear localization by phosphorylating sites 1 and 2 (S25, T27).

SIGNOR-273521

P29966

P17252

0

phosphorylation

down-regulates activity

0.73

Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin

SIGNOR-249650

P24941

P38936

2

phosphorylation

down-regulates quantity by destabilization

0.954

Cdk2 destabilizes p21 via the cy2 cyclin-binding motif and p21 phosphorylation at ser-130.

SIGNOR-149416

P03372

P27986

2

binding

up-regulates

0.628

Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k.

SIGNOR-140470

P06241

Q9Y210

1

phosphorylation

up-regulates activity

0.505

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

SIGNOR-279717

P15374

P62979

1

cleavage

up-regulates quantity

0.802

Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.

SIGNOR-270828

P61073

Q05655

0

phosphorylation

down-regulates activity

0.2

Therefore, internalization of CXCR4 in response to PMA appears to be mediated by activation of protein kinase C | However, mutation of the dileucine motif or the serines at positions 324, 325, 338, and 339 profoundly decreased internalization.

SIGNOR-260898

P09471

P25103

2

binding

up-regulates activity

0.2

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257249

Q14449

P49840

0

phosphorylation

down-regulates activity

0.264

Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.

SIGNOR-264871

P12931

Q13642

1

phosphorylation

up-regulates activity

0.26

However, overexpression of Src promoted most of the Flag-FHL1-WT to translocate to the nucleus, whereas the Flag-FHL1-Y149-272F mutant (phosphorylation deficient mutant) remained in the cytoplasm (XREF_FIG).|We found that Src phosphorylates FHL1 at Y149 and Y272, demonstrating that FHL1 is a bona fide novel substrate of Src.

SIGNOR-278213

Q96GD4

Q99661

1

phosphorylation

up-regulates

0.731

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

SIGNOR-155890

P78527

O75030

1

phosphorylation

up-regulates activity

0.2

These results suggest that DNA-PK can target MITF-S325 for phosphorylation. In melanocytes and melanoma cells, MITF is rapidly phosphorylated by DNA-PK and interacts with NBS1–RAD50 but not MRE11, destabilizing the MRN complex.

SIGNOR-277899

Q9ULT8

P07900

1

ubiquitination

down-regulates quantity

0.2

We demonstrate that Hectd1 is a functional ubiquitin ligase and that one of its substrates is Hsp90, a chaperone protein with both intra- and extracellular clients. Identification of Hsp90 in both proteomic screens suggested that members of the Hsp90 superfamily may be substrates of Hectd1. Myc-Hectd1ANK and HA-Hsp90bd (the fragment identified in the yeast two-hybrid screen) bind in an in vitro binding assay (Fig. 3 D) and when coexpressed in HEK293T cells. Hectd1 is required for K63-linked Ubn of Hsp90. Together, these results demonstrate that Hectd1-dependent Ubn of Hsp90 targets it away from the membrane and the secretory pathway.

SIGNOR-261199

Q92830

P84243

1

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269603

Q9NPD5

P53567

0

transcriptional regulation

up-regulates quantity by expression

0.2

Taken together, these findings suggest that the LPS-induced down-regulation of Oatp4 is likely due to reduction in the binding of HNF1alpha, C/EBP, HNF3, and RXR:RAR to the Oatp4 promoter.

SIGNOR-268986

O15530

Q00005

2

binding

down-regulates activity

0.331

Here, we show that PPP2R2B, encoding the B55² regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55²-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation.

SIGNOR-243511

P43405

P15498

2

phosphorylation

up-regulates

0.92

Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k.

SIGNOR-107046

P01019-PRO_0000032457

P12821

2

binding

up-regulates activity

0.2

Ang I is subsequently converted into the major RAS effector peptide Ang II or Ang (1–8), through activity of the zinc-dependent protease ACE, which hydrolyzes two amino acids from the carboxy terminus of Ang I

SIGNOR-260231

Q00535

Q13794

1

phosphorylation

down-regulates

0.356

We show that noxa is phosphorylated on a serine residue (s(13)) in the presence of glucose. Phosphorylation promotes its cytosolic sequestration and suppresses its apoptotic function. We identify cdk5 as the noxa kinase

SIGNOR-170357

Q05397

P63000

1

phosphorylation

up-regulates activity

0.574

Both Src and FAK phosphorylate Rac1 at tyrosine 64.|Our investigations of direct interactions between Rac1, Src, and FAK were motivated by our previous insights into FAK augmentation of Rac1 activation during cell spreading, and the Cerione lab 's work on the interactions between Src and Cdc42 , .

SIGNOR-279652

Q99523

Q13153

0

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-273718

Q92914

Q9UI33

2

binding

down-regulates activity

0.2

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253438

Q6STE5

P15172

2

binding

up-regulates activity

0.538

We show that the muscle determination factor MyoD and the SWI/SNF subunit BAF60c interact on the regulatory elements of MyoD-target genes in myoblasts, prior to activation of transcription. BAF60c facilitates MyoD binding to target genes and marks the chromatin for signal-dependent recruitment of the SWI/SNF core to muscle genes.

SIGNOR-238289

Q13586

P28482

0

phosphorylation

up-regulates

0.351

The netrin-2-mediated nfatc3 activation was coincident with robust interactions between cdo and stim1 in myoblasts and the erk-mediated stim1 phosphorylation at serine 575

SIGNOR-192788

P78527

P31749

1

phosphorylation

up-regulates activity

0.754

DNA-PK phosphorylates HM Ser473 of PKB. However, we also noted similar patterns in T loop Thr308 phosphorylation after _-IR []his function is apparently restricted to the PKBalpha isoform

SIGNOR-252431

P06493

P53350

2

binding

up-regulates activity

0.611

Moreover, CDK1 phosphorylates RSF1 at Ser1375, and this phosphorylation is necessary for PLK1 recruitment. Subsequently, PLK1 phosphorylates RSF1 at Ser1359, stabilizing PLK1 deposition.

SIGNOR-273589

Q04637

P17252

0

phosphorylation

up-regulates activity

0.258

Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186.

SIGNOR-276327

O14640

Q53G59

2

binding

down-regulates quantity by destabilization

0.621

KLHL12 recruits Dsh to Cullin-3 for protein degradation. In vitro ubiquitination of Dsh3 by KLHL12–Cullin-3–Roc1. The E3 ligase complex was obtained by transfection of HEK293T cells . We show that the BTB-containing protein KLHL12 negatively regulates Dsh function by recruiting a pool of Dsh to the Cullin-3 ligase scaffold, thereby promoting its ubiquitination and degradation.

SIGNOR-271558

Q05655

P04040

1

phosphorylation

up-regulates activity

0.266

Endothelin-1 stimulates catalase activity through the PKCδ-mediated phosphorylation of serine 167.

SIGNOR-260904

Q9H0K1

O75581

1

phosphorylation

up-regulates activity

0.2

Mechanistically, SIK2, phosphorylated by CK1α, directly phosphorylated LRP6 in a SIK2 kinase activity-dependent manner, leading to Wnt/β-catenin signaling pathway activation.

SIGNOR-275399

Q9H2X6

P06276

1

phosphorylation

down-regulates quantity

0.2

As shown in XREF_FIG, HIPK2 overexpression strongly reduced Myc-Che-1 levels, whereas it produced little effect on Che-1 T144A expression.|Notably, we found that HIPK2 phosphorylates a specific residue of Che-1, which is required for its interaction with Pin1 and for its degradation through the proteasome pathway.

SIGNOR-279190

P08246

P05546

1

cleavage

down-regulates activity

0.451

Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC.

SIGNOR-256510

Q96SW2

Q9H3D4

1

polyubiquitination

down-regulates quantity by destabilization

0.2

CRBN functions as a substrate receptor of the E3 ubiquitin ligase CRL4, whose substrate specificity is modulated by thalidomide and its analogs.When thalidomide binds to CRBN, substrate specificity of CRL4CRBN is altered and CRBN neomorphically binds to ∆Np63, TAp63 and other neosubstrates and ubiquitinates them for proteasomal degradation.

SIGNOR-272214

Q8NHW3

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.257

We also demonstrate that gsk-3 triggers mafa sequential phosphorylation on residues s61, t57, t53, and s49 /we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity./ Taken together, these results suggest that, in contrast to what can be expected from ubiquitination/degradation, gsk-3-mediated mafa phosphorylation increases its transactivating ability, thereby controlling its biological activity.

SIGNOR-159462

Q05195

P17480

1

transcriptional regulation

down-regulates quantity by repression

0.36

MAD1 and c-MYC regulate UBF and rDNA transcription during granulocyte differentiation|MAD1 repressed and c-MYC activated rDNA transcription in nuclear run-on assays. Repression of rDNA transcription by MAD1 was associated with its ability to interact directly with the promoter of upstream binding factor (UBF), an rDNA regulatory factor. Conversely, c-MYC activated transcription from the UBF promoter.

SIGNOR-269646

Q9NP62

Q14012

0

phosphorylation

up-regulates activity

0.388

We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.

SIGNOR-262680

P28336

P19086

2

binding

up-regulates activity

0.25

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257315

Q71DI3

Q9Y4C1

0

demethylation

up-regulates activity

0.2

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

SIGNOR-276844

O14654

Q9UNE7

0

polyubiquitination

down-regulates quantity by destabilization

0.2

IRS4 was phosphorylated at Ser859 by CK1γ2 in vitro and in vivo, which promoted the polyubiquitination and degradation of IRS4 through the ubiquitin/lysosome pathway by the carboxyl terminus of Hsc70-interacting protein(CHIP).

SIGNOR-277616

P12931

P78352

1

phosphorylation

up-regulates

0.565

These results indicate that psd-95 phosphorylation by src facilitates the integration of pyk2 to psd-95 signal complex, the activation of pyk2/src, as well as the subsequent tyrosine phosphorylation of nr2a, which ultimately results in the upregulation of nmda receptor function and synaptic transmission.

SIGNOR-205120

Q15276

Q15139

0

phosphorylation

up-regulates activity

0.382

PKD phosphorylates Rabaptin-5 at Ser407, and this controls alphavbeta3 and alpha5beta1 integrin and EGFR recycling.

SIGNOR-278192

Q5VWQ8

P15976

2

binding

up-regulates activity

0.2

DAB2IP suppresses transcription of stem cell factor receptor CD117, by interacting with GATA-1 on a silencer element on its gene

SIGNOR-254770

P50542

O43933

2

binding

up-regulates activity

0.548

Pex1, Pex6, and Pex26 are involved in Pex5 export from peroxisomes., we found that Pex1 and Pex6 bind to Pex5 (Fig. (Fig.6). Therefore, it is conceivable that Pex1 and Pex6 pull out Pex5 from peroxisome membranes in an ATP-dependent manner.

SIGNOR-253618

Q13315

Q9Y6K9

1

phosphorylation

down-regulates activity

0.739

Atm phosphorylates serine-85 of nemo to promote its ubiquitin-dependent nuclear export.

SIGNOR-144813

Q8N752

Q8NEG4

2

binding

up-regulates quantity

0.2

We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.

SIGNOR-273759

Q13185

P17612

0

phosphorylation

up-regulates

0.2

We demonstrate that p-ser 83-hp1gamma has an exclusively euchromatic localization, interacts with ku70 (a regulatory protein involved in multiple nuclear procesess), has impaired silencing activity and serves as a marker for transcription elongation.

SIGNOR-145109

Q09472

P31749

0

phosphorylation

up-regulates

0.697

We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity

SIGNOR-148983

Q9NR28

P53779

0

phosphorylation

down-regulates

0.341

Here we demonstrate that jnk3 can phosphorylate smac. Phosphorylation of smac by jnk3 attenuates its interaction with xiap. These results suggest that jnk3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between smac and xiap.

SIGNOR-157280

P51812

O15297

0

dephosphorylation

down-regulates activity

0.361

RSK2 (p90 ribosomal S6 kinase 2) is activated via the ERK (extracellular-signal-regulated kinase) pathway by phosphorylation on four sites: Ser227 in the activation loop of the N-terminal kinase domain, Ser369 in the linker, Ser386 in the hydrophobic motif and Thr577 in the C-terminal kinase domain of RSK2. In the present study, we demonstrate that RSK2 is associated in vivo with PP2Cdelta (protein phosphatase 2Cdelta). In epidermal growth factorstimulated cells, RSK2 is partially dephosphorylated on all four sites in an Mn2+-dependent manner, leading to reduced protein kinase activity

SIGNOR-248322

P01189

P40763

0

transcriptional regulation

up-regulates quantity by expression

0.638

We show that phospho-STAT3 activates POMC promoter in response to leptin signaling through a mechanism that requires an SP1-binding site in the POMC promoter.

SIGNOR-263497

Q7Z6Z7

P43405

0

phosphorylation

up-regulates activity

0.2

Collectively, these data suggest that TNF induced tyrosine phosphorylation of Mule by Syk contributes to its E3 ligase activity.

SIGNOR-280150

Q14814

P23409

1

transcriptional regulation

up-regulates quantity by expression

0.573

Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis.

SIGNOR-238715

P23771

Q969H0

0

ubiquitination

down-regulates quantity by destabilization

0.403

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

SIGNOR-276635

P49840

Q13554

0

phosphorylation

down-regulates

0.291

Inhibitory phosphorylation of gsk-3 by camkii couples depolarization to neuronal survival.

SIGNOR-167962

P04179

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.45

BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2

SIGNOR-254652

P42224

O14543

1

transcriptional regulation

up-regulates quantity by expression

0.677

Expression of SOCS1 and SOCS3 is regulated primarily by activation of STAT1 and STAT3, respectively, although their expression can be mediated through other signaling cascades, including the mitogen activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) pathways.

SIGNOR-249565

Q16633

P14859

2

binding

up-regulates

0.622

Obf1 enhances transcriptional potential of oct1.

SIGNOR-100968

O75582

Q92934

1

phosphorylation

down-regulates activity

0.344

Phosphorylation of Bad at Ser112 in response to growth factors or cytokines is generally linked to cell survival. Knockdown of MSK1 suppressed Bad phosphorylation after calcium ionophore A23187 treatment in neuronal cells

SIGNOR-262990

P11142

O75061

0

relocalization

up-regulates activity

0.883

Hsc70, recruited by the J-domain protein auxilin, mediates clathrin uncoating and release of a free vesicle, primed to fuse with a target membrane.

SIGNOR-260719

P29353

P29317

2

binding

up-regulates

0.616

We also show that the interaction of epha2 with grb2 is indirect and mediated by shc and that this complex is necessary for epha2-mediated activation of erk kinases.

SIGNOR-94804

P28482

Q96RK0

1

phosphorylation

down-regulates

0.372

Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3))[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3

SIGNOR-169875

P08575

P23458

1

dephosphorylation

up-regulates

0.454

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

SIGNOR-87154

P13674

Q01581

1

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-279853

Q8N122

P27361

0

phosphorylation

up-regulates activity

0.469

We found three proline-directed residues within raptor, ser(8), ser(696), and ser(863), which are directly phosphorylated by erk1/2. Expression of phosphorylation-deficient alleles of raptor revealed that phosphorylation of these sites by erk1/2 normally promotes mtorc1 activity and signaling to downstream substrates, such as 4e-bp1.

SIGNOR-169530

P17252

Q16760

1

phosphorylation

down-regulates activity

0.366

The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain.

SIGNOR-249265

P25101

P19086

2

binding

up-regulates activity

0.25

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257320

Q13905

P46108

2

binding

up-regulates

0.901

The endogenous c3g could be coprecipitated with crk from cell lysates of cells expressing high levels of c-crk or v-crk, suggesting high binding affinity and a possible interaction in vivo.

SIGNOR-33732

Q13547

Q96KB5

0

phosphorylation

up-regulates activity

0.245

TOPK overexpression promotes HDAC1 and HDAC2 phosphorylation and Histone 3 and Histone 4 acetylation in BV2 cells.|The results of in vitro studies further confirmed the effect of TOPK on HDAC activity by showing that TOPK overexpression significantly up-regulated p-HDAC1 and p-HDAC2, resulting in an increase in the acetylation of histones H3 and H4 in BV2 cells.

SIGNOR-279086

P63000

Q9BRR9

0

gtpase-activating protein

down-regulates activity

0.606

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-260464

O15357

Q9ULV8

2

binding

down-regulates

0.2

This association between ship2 and cbl could sequester cbl from the egfr, thereby regulating the kinetics of egfr-cbl association and subsequent internalization and degradation of the receptor.

SIGNOR-133388

P00519

P37231

1

phosphorylation

up-regulates quantity

0.341

We show that the tyrosine kinase Abelson murine leukemia viral oncogene (cAbl) is an adipogenic key regulator. c-Abl promotes adipogenesis by phosphorylation and subsequent stabilization of PPARγ.

SIGNOR-262297

Q92835

P16885

1

dephosphorylation

down-regulates activity

0.312

An adaptor protein Dok-3 mediates the suppressive function of LYN. The Dok-3 phosphorylated by LYN upon BCR stimulation forms a complex with GRB2, which allows it to enter into the signalosome and associate with activation of SHIP protein. This translocation facilitates the efficient inhibition of PLCc2 and SYK from activation, subsequently resulting in the suppression of downstream Ca2+ signaling.

SIGNOR-268455

P53350

Q96FF9

1

phosphorylation

down-regulates activity

0.705

Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.

SIGNOR-276122

O14920

Q9NQC7

1

phosphorylation

down-regulates activity

0.548

Thus, serine 418 is phosphorylated in vivo.Cyld phosphorylation may serve as a mechanism to inactivate its traf2 deubiquitination activity.

SIGNOR-204716

Q00535

P00352

1

phosphorylation

up-regulates quantity

0.2

Cdk5 Phosphorylates ALDH1A1 at S75 and S274.|These results demonstrate that Cdk5 increases ALDH1A1 levels in neurotoxin exposed neuronal cells both at transcriptional level and by direct phosphorylation at S75 and S274 sites.

SIGNOR-279399

Q96LA8

Q9NRC8

1

methylation

down-regulates activity

0.259

Protein arginine methyltransferase 6 (PRMT6) directly interacts with and methylates SIRT7 at R388 in vitro and in vivo R388 methylation suppresses the H3K18 deacetylase activity of SIRT7 without modulating its subcellular localization.

SIGNOR-275888

P46060

O75592

1

relocalization

down-regulates quantity by destabilization

0.315

SUMOylated RanGAP1 Inhibits MYCBP2 Activity and Mediates Its Transport to the Nucleus. Surprisingly, we did not find MYCBP2-dependent ubiquitylation of SUMOylated RanGAP1 but instead a strong inhibition of the ubiquitin ligase activity of MYCBP2 in the presence of SUMOylated RanGAP1, as determined by the presence of ubiquitylated proteins. this effect was specific for SUMOylated RanGAP1, because the unmodified form of RanGAP1 did not affect MYCBP2-dependent protein ubiquitylation. , SUMOylated RanGAP1 inhibited the ubiquitin ligase activity of MYCBP2, and it is tempting to speculate that SUMOylated RanGAP1 inhibits the ubiquitin ligase activity of MYCBP2 to ensure MYCBP2 silencing during its transport to the nucleus

SIGNOR-261203

P30305

Q9UNH5

0

dephosphorylation

down-regulates activity

0.56

Cdc14A inhibits Cdc25A and Cdc25B activity, the latter through direct binding and dephosphorylation ( ).|Together, these data indicate that Cdc14A dephosphorylates Cdc25B, inhibiting its catalytic activity.

SIGNOR-276968

Q9Y5Q3

P49840

0

phosphorylation

down-regulates

0.2

We showed that c-maf and mafb, like mafa, are indeed phosphorylated by gsk-3/ we demonstrated that phosphorylation by gsk-3 is conserved among the large maf proteins. It couples ubiquitination/degradation and transcriptional activation and modulates maf biological activity.

SIGNOR-159432

P41221

Q13467

2

binding

up-regulates

0.832

These results identify hfz5 as a receptor for wnt-5a.

SIGNOR-46897

Q7Z6J0

Q12852

2

binding

up-regulates

0.376

One explanation as provided by our model is that mlk3 and dlk interact indirectly via posh with mutual activation when both are wild-type the multidomain protein posh binds to the constitutively active form of rac1, which is known to regulate the activity of mlks, while jip1 binds to mlks and additional components of the jnk pathway and appears to be capable of activating mlks

SIGNOR-108577

P06493

Q08050

1

phosphorylation

up-regulates

0.762

A conserved phosphorylation site within the forkhead domain of foxm1b is required for its activation by cyclin-cdk1further analysis reveals that the leu-641 residue within an lxl motif is required for the recruitment of the cyclin-cdk complex, and the thr-596 residue is a critical cdk1 phosphorylation site within the activation domain of foxm1b. Cdk-dependent phosphorylation stimulates the foxm1b transcriptional activity

SIGNOR-187880

P02818

P15036

0

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-259875

P23246

P11387

2

binding

up-regulates

0.372

We show that the psf/p54 dimer has pronounced stimulatory effect on dna catalysis by topoisomerase i

SIGNOR-60563

Q96GX5

P31749

0

phosphorylation

up-regulates activity

0.2

Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation.

SIGNOR-277515

P00533

P35222

1

phosphorylation

up-regulates activity

0.773

EGFR and TRKA effect on WNT3a mediated Topflash induction was abolished by U0126 or expression of dominant negative LRP6-5A mutant (XREF_FIG), demonstrating that both EGFR and TRKA signal via ERK and LRP6 pathway to upregulate WNT and beta-catenin signaling.|FGFR2, FGFR3, EGFR and TRKA Phosphorylate beta-catenin at Tyr142.

SIGNOR-278309

P28335

P63096

2

binding

up-regulates activity

0.293

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-256734

Q9UNH7

P11717

2

binding

down-regulates quantity

0.364

Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.

SIGNOR-269443

Q9UJD0

A6NNM3

2

binding

down-regulates activity

0.265

SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.

SIGNOR-264374

Q05655

O15162

1

phosphorylation

up-regulates

0.424

Following the induction of apoptosis, however, phosphorylation of serine residues decreased and it increased on threonine, consistent with the predicted pkc phosphorylation site at thr-161. Transfection of cho cells with scramblase and pkc_, but not scramblase or pkc_ alone, increased scramblase activity

SIGNOR-76904

P18089

P19086

2

binding

up-regulates activity

0.437

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257109

Q8IYW5

Q14669

0

ubiquitination

down-regulates activity

0.465

Here, we show that TRIP12 and UBR5, two HECT domain ubiquitin E3 ligases, control accumulation of RNF168, a rate-limiting component of a pathway that ubiquitylates histones after DNA breakage. We find that RNF168 can be saturated by increasing amounts of DSBs. Depletion of TRIP12 and UBR5 allows accumulation of RNF168 to supraphysiological levels, followed by massive spreading of ubiquitin conjugates and hyperaccumulation of ubiquitin-regulated genome caretakers such as 53BP1 and BRCA1.

SIGNOR-266783

Q13976

P11831

1

phosphorylation

up-regulates

0.275

Myotonic dystrophy protein kinase (DMPK), a muscle- and neuron-restricted kinase, enhanced SRF-mediated promoter activity of the skeletal and cardiac alpha-actin genes in C2C12 myoblasts as well as in nonmyogenic cells. | Threonine 159 in the MADS box alphaI coil was a specific phosphorylation target in vitro as well as in vivo of both DMPK and protein kinase C-alpha.

SIGNOR-188185

P11940

Q13064

0

ubiquitination

down-regulates activity

0.2

MKRN3-mediated ubiquitination was found to attenuate the binding of PABPs to the poly(A) tails of mRNA|Altogether, it is thus clear that the ubiquitination of PABPC1 or PABPC4 by MKRN3 negatively regulates the formation of translation initiation complex (TIC), attenuates their binding to poly (A)-tail contained mRNAs, and leads to the shortened poly (A) tail-length of GNRH1 mRNA.

SIGNOR-278764

Q01973

P12931

1

phosphorylation

up-regulates

0.318

Ror1 binds to and phosphorylates c-src / ror1 kinase-dependent c-src activation

SIGNOR-196751

Q96T88

P48730

0

phosphorylation

up-regulates

0.245

We further show that uhrf1 physically interacts with _-trcp1 in a manner dependent on phosphorylation of serine 108 (s108(uhrf1)) within the dsg degron. Furthermore, we demonstrate that s108(uhrf1) phosphorylation is catalyzed by casein kinase 1 delta (ck1_) and is important for the recognition of uhrf1 by scf(_-trcp).

SIGNOR-200349

Q9HCI7

P04637

1

ubiquitination

down-regulates activity

0.37

Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization. MSL2 ubiquitination of p53 is required for p53 cytoplasmic localization.

SIGNOR-271774

P0DTD1-PRO_0000449624

Q9UHD2

2

binding

down-regulates activity

0.2

We use unbiased screening to identify SARS-CoV-2 proteins that antagonize type I interferon (IFN-I) response. We found three proteins that antagonize IFN-I production via distinct mechanisms: nonstructural protein 6 (nsp6) binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation, nsp13 binds and blocks TBK1 phosphorylation, and open reading frame 6 (ORF6) binds importin Karyopherin α 2 (KPNA2) to inhibit IRF3 nuclear translocation. the results indicate that (1) nsp6 binds to TBK1 without affecting TBK1 phosphorylation, but the nsp6/TBK1 interaction decreases IRF3 phosphorylation, which leads to reduced IFN-β production; and (2) nsp13 binds and inhibits TBK1 phosphorylation, resulting in decreased IRF3 activation and IFN-β production (Figure 2F).

SIGNOR-262510

O15409

Q13224

1

transcriptional regulation

up-regulates quantity by expression

0.318

By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.

SIGNOR-266834

P28482

P23469

0

dephosphorylation

down-regulates activity

0.39

The effect of PTP epsilon on ERKs is at least in part indirect because phosphorylation of the threonine residue in the ERK activation loop is reduced in the presence of PTP epsilon. Nonetheless, PTP epsilon is present in a molecular complex with ERK, providing PTP epsilon with opportunity to act on ERK proteins also directly. We conclude that PTP epsilon is a physiological inhibitor of ERK signaling|These enzymes are joined by the large family of dual-specificity phosphatases, which are structurally similar to tyrosine phosphatases but which can dephosphorylate both residues of the activation loop

SIGNOR-248448