GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q8TB45	Q15418	phosphorylation	down-regulates	0.492	We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1	SIGNOR-176883
P63096	Q9Y4H4	binding	down-regulates activity	0.492	GPSM3 acts through its two GoLoco motifs to exert GDP dissociation inhibitor activity over Galpha(i) subunits\|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET.	SIGNOR-264864
P46734	Q16584	phosphorylation	up-regulates activity	0.492	Immunoprecipitated mlk-3 catalyzed the phosphorylation of sek1 in vitro, and co-transfected mlk-3 induced phosphorylation of sek1 and mkk3 at sites required for activation, suggesting direct regulation of these protein kinases.	SIGNOR-45788
P50148	O15552	binding	up-regulates activity	0.492	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-257188
Q9H9S0	P27361	phosphorylation	down-regulates	0.492	We found that activation of ERK1 signaling inhibited transactivation activity of Nanog.\|We showed the direct phosphorylation of Nanog by ERK1 and clearly showed that Ser52 is the major phosphorylation site and Ser65 is weakly phosphorylated by ERK1.	SIGNOR-278487
P04035	Q12772	transcriptional regulation	up-regulates quantity by expression	0.492	The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription	SIGNOR-265161
P13349	P23759	transcriptional regulation	up-regulates quantity by expression	0.492	Together, these experiments indicate that Pax7 enforces satellite cell commitment by recruiting a HMT complex to Myf5, resulting in transcriptional activation.	SIGNOR-255641
Q9NVN3	P38405	binding	up-regulates activity	0.492	In the olfactory sensory neurons located in the nasal epithelium, OR activation by odorants or other stimuli can switch on a specific olfactory G-protein (GNAL), which in turn stimulatesand ADCY3 and Ric8b leads to cyclic adenosine monophosphate (cAMP) generation from adenosine triphosphate (ATP)	SIGNOR-278071
Q04721	P21741	binding	up-regulates	0.491	We showed that mk binds to the notch2 receptor in hacat keratinocytes. We further found that mk activates notch2	SIGNOR-161427
P55011	Q9H4A3	phosphorylation	up-regulates activity	0.491	Combining these biochemical studies with the live cell imaging data, these results collectively suggest that the entire CTD is necessary for WNK1 to drive optimal SPAK/OSR1 activation and downstream NKCC1/KCC phosphorylation via PS.	SIGNOR-277859
Q15326	Q9UKY1	binding	down-regulates activity	0.491	Corepressor BS69 interacts with ZHX1, a member of the ZHX family having zinc-fingers and homeoboxes. Although BS69 was originally found as a corepressor interacting with ZHX1, BS69 was also found to function as a transcriptional activator in HEK293 cells, in which the activation required the MYND domain of BS69. Co-transfection of BS69 with a mutant form of ZHX1, which cannot interact with BS69, led to increase the transcriptional activation of BS69, suggesting that transcriptional activation mediated by BS69 is suppressed by ZHX1.	SIGNOR-263898
Q12947	Q00403	binding	up-regulates activity	0.491	The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. FREAC-2 dependent activation of transcription by TFIIB.	SIGNOR-220317
P20339	P53611	lipidation	up-regulates activity	0.491	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265573
P50148	P34981	binding	up-regulates activity	0.491	TRH receptors are textbook calcium-mobilizing receptors: they are coupled to Gq and G11, which activate phospholipase Cβ (PLCβ).	SIGNOR-267202
O43524	P53350	phosphorylation	down-regulates activity	0.491	Furthermore, PLK1 can directly phosphorylate FOXO3 in an in vitro kinase assay.\|PLK1 induces translocation of FOXO3 from the nucleus to the cytoplasm and suppresses FOXO3 activity, measured by the decrease in the pro-apoptotic Bim protein levels and in the cell cycle inhibitor protein p27.	SIGNOR-279095
Q03113	Q9HBW0	binding	up-regulates	0.491	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. lpa2 also can couple to the gi/o, g12/13, and gqfamilies.	SIGNOR-135834
P63092	P35408	binding	up-regulates activity	0.491	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 ‚â• -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 ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256760
P46531	Q9NYJ7	binding	up-regulates activity	0.491	Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.	SIGNOR-209738
Q9Y210	Q13976	phosphorylation	down-regulates activity	0.491	PKG phosphorylated TRPC6, and both T70 and S322 were targeted. Both sites were functionally relevant, as 8Br-cGMP strongly suppressed current in wild-type TRPC6 channels, but not in those with phospho-silencing mutations (T70A, S322A or S322Q).	SIGNOR-276271
Q9P212	P62834	binding	up-regulates quantity	0.491	The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε.	SIGNOR-278142
O75531	Q8IV63	phosphorylation	down-regulates activity	0.491	Although VRK3 has been regarded as a genuine pseudokinase from structural and biochemical studies, recent reports suggest that VRK3 acts as an active kinase as well as a signaling scaffold in cells. Here, we demonstrate that VRK3 phosphorylates the nuclear envelope protein barrier-to-autointegration factor (BAF) on Ser4.\|Ectopic expression of VRK3 induces the translocation of BAF from the nucleus to the cytoplasm. I	SIGNOR-264564
Q01726	Q96G30	binding	down-regulates activity	0.491	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252365
Q9Y2I7	P31749	phosphorylation	up-regulates	0.491	Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme.	SIGNOR-252474
Q08211	Q99836	binding	up-regulates activity	0.491	We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing.	SIGNOR-260955
P84022	Q03112	binding	down-regulates	0.491	Evi-1 interacts with smad3, an intracellular mediator of tgf-beta signalling, thereby suppressing the transcriptional activity of smad3.	SIGNOR-59132
P36888	Q12913	dephosphorylation	down-regulates activity	0.49	Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro.\|The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation.	SIGNOR-277092
P23443	Q6ZVD8	dephosphorylation	down-regulates activity	0.49	We show that PHLPP preferentially dephosphorylates the hydrophobic motif T389 site in S6K1 in vitro	SIGNOR-248247
Q07812	Q9BXH1	relocalization	up-regulates	0.49	Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.	SIGNOR-185671
P30622	P06493	phosphorylation	up-regulates activity	0.49	Cdc2 phosphorylates T287\|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. \|These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression.	SIGNOR-275470
P00533	Q12913	dephosphorylation	up-regulates quantity by stabilization	0.49	We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex\|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173	SIGNOR-248697
P60953	Q3KRB8	gtpase-activating protein	down-regulates activity	0.49	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-260468
P41182	Q86XK2	binding	down-regulates	0.49	Fbxo11 targets bcl6 for degradation	SIGNOR-177652
P12931	P16234	phosphorylation	up-regulates activity	0.49	The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells.	SIGNOR-247984
Q13351	Q92793	acetylation	up-regulates activity	0.49	EKLF residues acetylated by CREB binding protein (CBP) in vitro map to Lys-288 in its transactivation domain and Lys-302 in its zinc finger domain.	SIGNOR-251826
P16949	Q16566	phosphorylation	down-regulates	0.49	Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr.	SIGNOR-34743
Q92574	P28482	phosphorylation	down-regulates	0.49	Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin.	SIGNOR-157162
P19419	P45984	phosphorylation	up-regulates activity	0.49	However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity.	SIGNOR-247062
Q53H47	O14757	phosphorylation	down-regulates activity	0.49	We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination.	SIGNOR-273610
O95837	P30556	binding	up-regulates activity	0.49	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-257133
O95239	P06493	phosphorylation	up-regulates activity	0.489	Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization.	SIGNOR-265994
P05067	P07339	cleavage	down-regulates quantity by destabilization	0.489	The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. \| two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.	SIGNOR-261767
Q92574	P06493	phosphorylation	down-regulates	0.489	Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex	SIGNOR-118584
Q16539	P06241	phosphorylation	up-regulates	0.489	T cell src family kinases and zap70 activate p38 by phosphorylating tyr323.	SIGNOR-134293
Q53ET0	P54646	phosphorylation	down-regulates	0.489	Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2	SIGNOR-142211
Q16543	P19784	phosphorylation	up-regulates activity	0.489	Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. \| In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site.	SIGNOR-250982
P32245	Q8TCY5	binding	down-regulates activity	0.489	We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.	SIGNOR-252362
O15392	Q8IWT3	ubiquitination	down-regulates quantity	0.489	CUL9 promotes the ubiquitylation and degradation of survivin and is inhibited by CUL7.\|Together, these results demonstrate the specificity of survivin ubiquitylation by CUL9 E3 ligase complex.	SIGNOR-278808
P41182	P28482	phosphorylation	down-regulates	0.489	Here we show that antigen receptor activation leads to bcl-6 phosphorylation by mitogen-activated protein kinase (mapk). Phosphorylation, in turn, targets bcl-6 for rapid degradation by the ubiquitin/proteasome pathway.	SIGNOR-58481
P22415	P78347	binding	up-regulates activity	0.489	TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription	SIGNOR-268538
P01135	P78536	cleavage	up-regulates activity	0.489	ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF	SIGNOR-259841
Q16678	P35869	transcriptional regulation	up-regulates quantity by expression	0.489	The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 .	SIGNOR-253642
O14920	Q96Q05	binding	up-regulates activity	0.489	We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates.	SIGNOR-269673
P30411	P34947	phosphorylation	down-regulates activity	0.489	Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.	SIGNOR-251208
P42574	O15392	binding	down-regulates	0.489	Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21.	SIGNOR-72882
P10398	P12931	phosphorylation	up-regulates activity	0.489	A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation	SIGNOR-236459
P01137	P35555	binding	up-regulates quantity	0.489	We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling.	SIGNOR-251888
Q96P20	Q9BZY9	ubiquitination	down-regulates quantity by destabilization	0.489	Taken together, these data indicated that TRIM31 directly induced the K48-linked ubiquitination of NLRP3 through its E3 ligase activity.\|Taken together, these results indicated that TRIM31 could promote proteasomal degradation of NLRP3.	SIGNOR-278603
P51679	P13500	binding	up-regulates activity	0.489	CCR2 and CCR4 are two cell surface receptors that bind CCL2	SIGNOR-237555
Q16539	P54829	binding	up-regulates	0.489	First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a.	SIGNOR-194829
Q14511	Q06124	dephosphorylation	down-regulates activity	0.488	In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.\|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity.	SIGNOR-277083
P08754	P18825	binding	up-regulates activity	0.488	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-256842
Q13315	O15297	dephosphorylation	down-regulates	0.488	The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity.	SIGNOR-185135
P15498	P50570	binding	up-regulates quantity by stabilization	0.488	Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability.	SIGNOR-259080
Q15796	P24941	phosphorylation	down-regulates activity	0.488	Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2.\|Moreover, CDK2 is the predominant cyclin-dependent kinase that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2.	SIGNOR-279678
Q9BZS1	P26358	transcriptional regulation	down-regulates quantity by repression	0.488	Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35)	SIGNOR-269053
Q9Y2K2	Q15831	phosphorylation	up-regulates	0.488	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122835
P10451	Q13950	transcriptional regulation	up-regulates quantity	0.488	Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.	SIGNOR-245336
P23560	P16220	transcriptional regulation	up-regulates quantity	0.488	Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF.	SIGNOR-265062
P38936	Q15831	phosphorylation	down-regulates activity	0.488	Mass spectrometry analysis of the phosphorylated CDKN1A identified Thr80 as the residue phosphorylated by LKB1 in vitro (Figure 4A and S5A).\|UVB induced phosphorylation of LKB1 T366 mediates CDKN1A degradation.	SIGNOR-278253
P36873	P51955	phosphorylation	down-regulates	0.488	Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity.	SIGNOR-78603
Q8N5S9	P0DP24	binding	up-regulates	0.488	The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases	SIGNOR-266328
P84022	P49841	phosphorylation	down-regulates quantity by destabilization	0.488	Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation.	SIGNOR-160318
Q8WUP2	Q86UX7	binding	up-regulates activity	0.488	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton.	SIGNOR-266104
Q9H7Z6	Q03164	binding	up-regulates	0.488	Mll1 and mof can form a stable complex in vivo / given that an interaction of dmof with msl1 through its zinc finger is essential for correct targeting of mof to the male x chromosome	SIGNOR-138245
Q15910	Q8NG27	ubiquitination	down-regulates quantity by destabilization	0.488	Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2	SIGNOR-255664
P42224	P42226	binding	down-regulates activity	0.488	STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site	SIGNOR-249552
P22681	Q13882	phosphorylation	down-regulates activity	0.488	Herein we report that PTK6 phosphorylates and down-regulates E3 ubiquitin ligase c-Cbl.	SIGNOR-279348
Q96IV0	Q04323	binding	up-regulates activity	0.488	PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome.	SIGNOR-261060
O60500	P19544	transcriptional regulation	up-regulates quantity by expression	0.487	The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner	SIGNOR-252299
P15559	Q16236	transcriptional regulation	up-regulates quantity by expression	0.487	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256275
Q9UEW8	Q04759	phosphorylation	up-regulates activity	0.487	Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK.	SIGNOR-276007
Q969S3	Q99683	phosphorylation	up-regulates	0.487	Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis.	SIGNOR-175113
Q9Y6H5	P49841	phosphorylation	down-regulates	0.487	Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1	SIGNOR-140609
Q01094	O96017	phosphorylation	up-regulates quantity by stabilization	0.487	We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage	SIGNOR-100898
P12830	O60315	transcriptional regulation	down-regulates quantity by repression	0.487	SIP 1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadh promoter.SIP1 induction resulted in the loss of cell-cell adhesion, in activation of invasion and in at random, multidirectional migration instead of unidirectional coherent migration (required in neurulation).	SIGNOR-268950
P48736	P63211	binding	up-regulates	0.487	Therefore, we conclude that in vivo, g beta gamma activates pi3k gamma by a mechanism assigning specific roles for both pi3k gamma subunits, i.e., membrane recruitment is mediated via the noncatalytic p101 subunit, and direct stimulation of g beta gamma with p110 gamma contributes to activation of pi3k gamma.	SIGNOR-96831
Q14643	P06241	phosphorylation	up-regulates	0.487	We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm).	SIGNOR-121795
P16220	Q13627	phosphorylation	up-regulates activity	0.487	Regarding to the functional role of Dyrk1A, active Dyrk1A phosphorylates the transcription factor cAMP response element -binding protein (CREB), which subsequently leads to the stimulation of cAMP response element-mediated gene transcription during neuronal differentiation ( ).	SIGNOR-279989
P29590	P78317	polyubiquitination	down-regulates quantity by destabilization	0.487	Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.	SIGNOR-272884
P24844	O43293	phosphorylation	up-regulates	0.487	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188789
Q5RD31	Q16236	transcriptional regulation	up-regulates quantity by expression	0.487	NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.NFE2L2-mediated upregulation of NQO1 is implicated in promoting resistance to ferroptosis inducers, such as erastin and sorafenib, in HCC cells	SIGNOR-279860
Q9NZV8	P78411	transcriptional regulation	down-regulates quantity by repression	0.487	Irx5 Directly Represses the Kcnd2 Promoter	SIGNOR-266045
Q96ST3	O14901	binding	up-regulates activity	0.487	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222344
P14618	P30304	dephosphorylation	up-regulates activity	0.487	Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2 dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.\|Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent \u03b2-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.	SIGNOR-276967
P30679	P34981	binding	up-regulates activity	0.487	Ga16 is phosphorylated in vivo by PMA and by TRH receptor stimulation	SIGNOR-278132
O43395	Q13107	deubiquitination	down-regulates activity	0.487	Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site.	SIGNOR-271975
P78504	Q8NES3	binding	down-regulates	0.486	Although jagged1-induced signaling was suppressed by lfng and mfng	SIGNOR-131560
Q9Y6D9	P12270	binding	up-regulates	0.486	Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20).	SIGNOR-181918
Q68G74	Q5JUK2	transcriptional regulation	up-regulates quantity by expression	0.486	Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.	SIGNOR-266076
P54725	Q05086	polyubiquitination	down-regulates quantity by destabilization	0.486	Here we report the identification of HHR23A, one of the human homologues of the yeast DNA repair protein Rad23, as an E6-independent target of E6AP. E6AP-mediated ubiquitination and degradation of HHR23A and HHR23B.	SIGNOR-272550

Q8TB45

Q15418

0

phosphorylation

down-regulates

0.492

We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1

SIGNOR-176883

P63096

Q9Y4H4

0

binding

down-regulates activity

0.492

GPSM3 acts through its two GoLoco motifs to exert GDP dissociation inhibitor activity over Galpha(i) subunits|interactions between GPSM3 and Galphai1 or Gbeta1 (20) was assayed by BRET.

SIGNOR-264864

P46734

Q16584

0

phosphorylation

up-regulates activity

0.492

Immunoprecipitated mlk-3 catalyzed the phosphorylation of sek1 in vitro, and co-transfected mlk-3 induced phosphorylation of sek1 and mkk3 at sites required for activation, suggesting direct regulation of these protein kinases.

SIGNOR-45788

P50148

O15552

0

binding

up-regulates activity

0.492

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-257188

Q9H9S0

P27361

0

phosphorylation

down-regulates

0.492

We found that activation of ERK1 signaling inhibited transactivation activity of Nanog.|We showed the direct phosphorylation of Nanog by ERK1 and clearly showed that Ser52 is the major phosphorylation site and Ser65 is weakly phosphorylated by ERK1.

SIGNOR-278487

P04035

Q12772

0

transcriptional regulation

up-regulates quantity by expression

0.492

The processed SREBP2, designated nuclear SREBP2 (nSREBP2), then enters the nucleus as a homodimer, binds to the sterol regulatory element (SRE) sequence in the promoters of target genes, including HMGCR and SQLE (encoding squalene monooxygenase), and upregulates their transcription

SIGNOR-265161

P13349

P23759

0

transcriptional regulation

up-regulates quantity by expression

0.492

Together, these experiments indicate that Pax7 enforces satellite cell commitment by recruiting a HMT complex to Myf5, resulting in transcriptional activation.

SIGNOR-255641

Q9NVN3

P38405

0

binding

up-regulates activity

0.492

In the olfactory sensory neurons located in the nasal epithelium, OR activation by odorants or other stimuli can switch on a specific olfactory G-protein (GNAL), which in turn stimulatesand ADCY3 and Ric8b leads to cyclic adenosine monophosphate (cAMP) generation from adenosine triphosphate (ATP)

SIGNOR-278071

Q04721

P21741

0

binding

up-regulates

0.491

We showed that mk binds to the notch2 receptor in hacat keratinocytes. We further found that mk activates notch2

SIGNOR-161427

P55011

Q9H4A3

0

phosphorylation

up-regulates activity

0.491

Combining these biochemical studies with the live cell imaging data, these results collectively suggest that the entire CTD is necessary for WNK1 to drive optimal SPAK/OSR1 activation and downstream NKCC1/KCC phosphorylation via PS.

SIGNOR-277859

Q15326

Q9UKY1

0

binding

down-regulates activity

0.491

Corepressor BS69 interacts with ZHX1, a member of the ZHX family having zinc-fingers and homeoboxes. Although BS69 was originally found as a corepressor interacting with ZHX1, BS69 was also found to function as a transcriptional activator in HEK293 cells, in which the activation required the MYND domain of BS69. Co-transfection of BS69 with a mutant form of ZHX1, which cannot interact with BS69, led to increase the transcriptional activation of BS69, suggesting that transcriptional activation mediated by BS69 is suppressed by ZHX1.

SIGNOR-263898

Q12947

Q00403

0

binding

up-regulates activity

0.491

The human forkhead protein FREAC-2 contains two functionally redundant activation domains and interacts with TBP and TFIIB. FREAC-2 dependent activation of transcription by TFIIB.

SIGNOR-220317

P20339

P53611

0

lipidation

up-regulates activity

0.491

Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional

SIGNOR-265573

P50148

P34981

0

binding

up-regulates activity

0.491

TRH receptors are textbook calcium-mobilizing receptors: they are coupled to Gq and G11, which activate phospholipase Cβ (PLCβ).

SIGNOR-267202

O43524

P53350

0

phosphorylation

down-regulates activity

0.491

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

SIGNOR-279095

Q03113

Q9HBW0

0

binding

up-regulates

0.491

Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13. lpa2 also can couple to the gi/o, g12/13, and gqfamilies.

SIGNOR-135834

P63092

P35408

0

binding

up-regulates activity

0.491

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 ‚â• -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 ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256760

P46531

Q9NYJ7

0

binding

up-regulates activity

0.491

Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.

SIGNOR-209738

Q9Y210

Q13976

0

phosphorylation

down-regulates activity

0.491

PKG phosphorylated TRPC6, and both T70 and S322 were targeted. Both sites were functionally relevant, as 8Br-cGMP strongly suppressed current in wild-type TRPC6 channels, but not in those with phospho-silencing mutations (T70A, S322A or S322Q).

SIGNOR-276271

Q9P212

P62834

0

binding

up-regulates quantity

0.491

The SUR1 subunit of KATP channels recruits Epac2 to the plasma membrane where a signaling complex comprised of Epac2, Rap1 and PLC-ε is formed. Rap1 is activated by Epac2, and the activated form of Rap1 binds to and activates PLC-ε.

SIGNOR-278142

O75531

Q8IV63

0

phosphorylation

down-regulates activity

0.491

Although VRK3 has been regarded as a genuine pseudokinase from structural and biochemical studies, recent reports suggest that VRK3 acts as an active kinase as well as a signaling scaffold in cells. Here, we demonstrate that VRK3 phosphorylates the nuclear envelope protein barrier-to-autointegration factor (BAF) on Ser4.|Ectopic expression of VRK3 induces the translocation of BAF from the nucleus to the cytoplasm. I

SIGNOR-264564

Q01726

Q96G30

0

binding

down-regulates activity

0.491

We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.

SIGNOR-252365

Q9Y2I7

P31749

0

phosphorylation

up-regulates

0.491

Here we report that serine318 on the fyve domain-containing ptdins3p 5-kinase (pikfyve) is a novel substrate for pkb, and show that phosphorylation stimulates the ptdins3p 5-kinase activity of the enzyme.

SIGNOR-252474

Q08211

Q99836

0

binding

up-regulates activity

0.491

We further showed that both DHX9 and DHX36 are localized within the cytosol and are directly bound to the Toll-interleukin receptor domain of MyD88 via their helicase-associated domain 2 and DUF domains. This study demonstrates that DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of pDCs and suggests a much broader role for DHX helicases in viral sensing.

SIGNOR-260955

P84022

Q03112

0

binding

down-regulates

0.491

Evi-1 interacts with smad3, an intracellular mediator of tgf-beta signalling, thereby suppressing the transcriptional activity of smad3.

SIGNOR-59132

P36888

Q12913

0

dephosphorylation

down-regulates activity

0.49

Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro.|The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation.

SIGNOR-277092

P23443

Q6ZVD8

0

dephosphorylation

down-regulates activity

0.49

We show that PHLPP preferentially dephosphorylates the hydrophobic motif T389 site in S6K1 in vitro

SIGNOR-248247

Q07812

Q9BXH1

0

relocalization

up-regulates

0.49

Puma promotes bax translocation by both by directly interacting with bax and by competitive binding to bcl-x(l) in uv-induced apoptosis.

SIGNOR-185671

P30622

P06493

0

phosphorylation

up-regulates activity

0.49

Cdc2 phosphorylates T287|CLIP-170, the founding member of microtubule “plus ends tracking” proteins, is involved in many critical microtubule-related functions, including recruitment of dynactin to the microtubule plus ends and formation of kinetochore-microtubule attachments during metaphase. |These results demonstrate that Cdc2-mediated phosphorylation of CLIP-170 is essential for the normal function of this protein during cell cycle progression.

SIGNOR-275470

P00533

Q12913

0

dephosphorylation

up-regulates quantity by stabilization

0.49

We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex|By employing commercially available antibodies, which are supposed to recognize specific tyrosine phosphorylation sites of EGFR, we found that depletion of endogenous DEP-1 nonselectively increased receptor phosphorylation, affecting all three sites we analyzed (tyrosines 1045, 1068, and 1173

SIGNOR-248697

P60953

Q3KRB8

0

gtpase-activating protein

down-regulates activity

0.49

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-260468

P41182

Q86XK2

0

binding

down-regulates

0.49

Fbxo11 targets bcl6 for degradation

SIGNOR-177652

P12931

P16234

0

phosphorylation

up-regulates activity

0.49

The increased Src activity is mainly due to the phosphorylation of Tyr-419, rather than the dephosphorylation of Tyr-530 of Src protein. PDGFR, not FAK or EGFR, appears to be the upstream protein tyrosine kinase responsible for the detachment-induced Src activation in the lung tumor cells.

SIGNOR-247984

Q13351

Q92793

0

acetylation

up-regulates activity

0.49

EKLF residues acetylated by CREB binding protein (CBP) in vitro map to Lys-288 in its transactivation domain and Lys-302 in its zinc finger domain.

SIGNOR-251826

P16949

Q16566

0

phosphorylation

down-regulates

0.49

Serine 16 of oncoprotein 18 is a major cytosolic target for the ca2+/calmodulin-dependent kinase-gr.

SIGNOR-34743

Q92574

P28482

0

phosphorylation

down-regulates

0.49

Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin.

SIGNOR-157162

P19419

P45984

0

phosphorylation

up-regulates activity

0.49

However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity.

SIGNOR-247062

Q53H47

O14757

0

phosphorylation

down-regulates activity

0.49

We previously found that Chk1 phosphorylation of Metnase on S495 enhanced its DNA DSB repair activity but decreased its ability to re-start stalled replication forks. Here we show that phosphorylated Metnase feeds back to increase the half-life of Chk1. Chk1 half-life is regulated by DDB1 targeting it to Cul4A for ubiquitination and destruction. Metnase decreases Chk1 interaction with DDB1, and decreases Chk1 ubiquitination.

SIGNOR-273610

O95837

P30556

0

binding

up-regulates activity

0.49

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-257133

O95239

P06493

0

phosphorylation

up-regulates activity

0.489

Identification of Cdk phosphorylation of Kif4A at T1161 in early mitosis. We show that Cdk phosphorylation of Kif4A licenses its chromosome localization.

SIGNOR-265994

P05067

P07339

0

cleavage

down-regulates quantity by destabilization

0.489

The precise cathepsin D cleavage sites within these recombinant betaAPP substrates were identified using this technique. Both recombinant substrates were cleaved at the following sites: Leu49-Val50, Asp68-Ala69, Phe93-Phe94. | two additional cleavage sites near the amino terminus of betaA4, Glu-3-Val-2 and Glu3-Phe4, were observed, indicating that cathepsin D cleavage of betaAPP is influenced by the structural integrity of the substrate. Taken together, these results indicate that in vitro, cathepsin D is unlikely to function as gamma-secretase; however, the ability of this enzyme to efficiently cleave betaAPP substrates at nonamyloidogenic sites within the molecule may reflect a role in betaAPP catabolism.

SIGNOR-261767

Q92574

P06493

0

phosphorylation

down-regulates

0.489

Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin b.Cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (thr417) is in the hamartin-tuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70s6 kinase by the hamartin-tuberin complex

SIGNOR-118584

Q16539

P06241

0

phosphorylation

up-regulates

0.489

T cell src family kinases and zap70 activate p38 by phosphorylating tyr323.

SIGNOR-134293

Q53ET0

P54646

0

phosphorylation

down-regulates

0.489

Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2

SIGNOR-142211

Q16543

P19784

0

phosphorylation

up-regulates activity

0.489

Phosphorylation of serine 13 is required for the proper function of the Hsp90 co-chaperone, Cdc37. | In this report, we demonstrate that mammalian Cdc37 is phosphorylated on Ser13 in situ in rabbit reticulocyte lysate and in cultured K562 cells and that casein kinase II is capable of quantitatively phosphorylating recombinant Cdc37 at this site.

SIGNOR-250982

P32245

Q8TCY5

0

binding

down-regulates activity

0.489

We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). MRAP and MRAP2 can reduce the surface expression of MC4R and also the signaling of this receptor. we observed a significant decrease in the cell-surface expression of MC4R and MC5R in the presence of MRAP and MRAP2. It is interesting that MRAP and MRAP2 have opposite effects in the modulation of different MCR family members.

SIGNOR-252362

O15392

Q8IWT3

0

ubiquitination

down-regulates quantity

0.489

CUL9 promotes the ubiquitylation and degradation of survivin and is inhibited by CUL7.|Together, these results demonstrate the specificity of survivin ubiquitylation by CUL9 E3 ligase complex.

SIGNOR-278808

P41182

P28482

0

phosphorylation

down-regulates

0.489

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

SIGNOR-58481

P22415

P78347

0

binding

up-regulates activity

0.489

TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription

SIGNOR-268538

P01135

P78536

0

cleavage

up-regulates activity

0.489

ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF

SIGNOR-259841

Q16678

P35869

0

transcriptional regulation

up-regulates quantity by expression

0.489

The formation of the AHR/ARNT dimerization complex converts the AHR into a high affinity DNA-binding form that recognizes specific DNA recognition sites termed DREs. In this manner, the agonist activated AHR upregulates a battery of target genes, including those involved in the metabolism of chemical carcinogens, such as CYP1A1 and CYP1B1 .

SIGNOR-253642

O14920

Q96Q05

0

binding

up-regulates activity

0.489

We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates.

SIGNOR-269673

P30411

P34947

0

phosphorylation

down-regulates activity

0.489

Ligand-induced phosphorylation is found at Ser339 and Ser346/Ser348 that could be executed by several G protein-coupled receptor kinases. 32P labeling of peptide 3 containing pS346/pS348 was enhanced 1.5–3-fold as compared with mock-transfected cells in the order GRK6 < GRK5 < GRK2 < GRK4α < GRK3. several endogenous GRKs may phosphorylate the B2R and that the various GRKs, even without apparent effect on total GPCR phosphorylation levels, may induce distinct phosphorylation patterns with possible functional consequences for receptor desensitization and sequestration.

SIGNOR-251208

P42574

O15392

0

binding

down-regulates

0.489

Use of a dominant-negative survivin mutant or antisense survivin complementary dna disrupts a supramolecular assembly of survivin, caspase-3 and the cyclin-dependent-kinase inhibitor p21waf1/cip1 within centrosomes, and results in caspase-dependent cleavage of p21.

SIGNOR-72882

P10398

P12931

0

phosphorylation

up-regulates activity

0.489

A-raf behaves like raf-1, being weakly activated by oncogenic ras more strongly activated by oncogenic src, and these signals synergize to give maximal activation

SIGNOR-236459

P01137

P35555

0

binding

up-regulates quantity

0.489

We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling.

SIGNOR-251888

Q96P20

Q9BZY9

0

ubiquitination

down-regulates quantity by destabilization

0.489

Taken together, these data indicated that TRIM31 directly induced the K48-linked ubiquitination of NLRP3 through its E3 ligase activity.|Taken together, these results indicated that TRIM31 could promote proteasomal degradation of NLRP3.

SIGNOR-278603

P51679

P13500

0

binding

up-regulates activity

0.489

CCR2 and CCR4 are two cell surface receptors that bind CCL2

SIGNOR-237555

Q16539

P54829

0

binding

up-regulates

0.489

First [] step prevents upstream activating kinases from promiscuously binding and activating p38a. Second, by blocking access to the mapk insert pocket, through the stepcat interaction, step can prevent the binding of allosteric signaling molecules that induce autoactivation of p38a.

SIGNOR-194829

Q14511

Q06124

0

dephosphorylation

down-regulates activity

0.488

In this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L.|These results show that both SH2 domains of SHP-2 are necessary for the interaction with Cas-L.\nIn this study we demonstrated that SHP-2 inhibits tyrosine phosphorylation of Cas-L, and negatively regulates the cell migration induced by Cas-L. Furthermore, our data raise the possibility that Cas-L is a direct substrate for SHP-2, although SHP-2 may inhibit Cas-L phosphorylation indirectly by regulating kinase activity.

SIGNOR-277083

P08754

P18825

0

binding

up-regulates activity

0.488

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-256842

Q13315

O15297

0

dephosphorylation

down-regulates

0.488

The negative regulator wip1 plays an important role in inhibiting atm, resulting in a pulse of atm activity.

SIGNOR-185135

P15498

P50570

0

binding

up-regulates quantity by stabilization

0.488

Disruption of the Dyn2-Vav1 interaction targets Vav1 to the lysosome for degradation via an interaction with the cytoplasmic chaperone Hsc70, resulting in a dramatic reduction of Vav1 protein stability.

SIGNOR-259080

Q15796

P24941

0

phosphorylation

down-regulates activity

0.488

Moreover, CDK2 is the predominant CDK that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2.|Moreover, CDK2 is the predominant cyclin-dependent kinase that phosphorylates Smad2 on T8 in myeloma cells, leading to inhibition of Smad2-Smad4 association that precludes transcriptional regulation by Smad2.

SIGNOR-279678

Q9BZS1

P26358

0

transcriptional regulation

down-regulates quantity by repression

0.488

Our results showed that arsenic induced the high expression of DNMT1 and Foxp3 gene promoter methylation level, thereby inhibiting the expression levels of Foxp3, followed by decreasing Tregs and reducing related anti-inflammatory cytokines, such as interleukin 10 (IL-10) and interleukin 10 (IL-35)

SIGNOR-269053

Q9Y2K2

Q15831

0

phosphorylation

up-regulates

0.488

Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold

SIGNOR-122835

P10451

Q13950

0

transcriptional regulation

up-regulates quantity

0.488

Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.

SIGNOR-245336

P23560

P16220

0

transcriptional regulation

up-regulates quantity

0.488

Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF.

SIGNOR-265062

P38936

Q15831

0

phosphorylation

down-regulates activity

0.488

Mass spectrometry analysis of the phosphorylated CDKN1A identified Thr80 as the residue phosphorylated by LKB1 in vitro (Figure 4A and S5A).|UVB induced phosphorylation of LKB1 T366 mediates CDKN1A degradation.

SIGNOR-278253

P36873

P51955

0

phosphorylation

down-regulates

0.488

Pp1 is a substrate for nek2 and phosphorylation of pp1gamma(1) on two c-terminal sites reduces its phosphatase activity.

SIGNOR-78603

Q8N5S9

P0DP24

0

binding

up-regulates

0.488

The binding of Ca2+/CaM to CaM-KK is absolutely required for its activation and efficient phosphorylation of target protein kinases

SIGNOR-266328

P84022

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.488

Mechanistically, axin facilitates gsk3-beta-mediated phosphorylation of smad3 at thr66, which triggers smad3 ubiquitination and degradation.

SIGNOR-160318

Q8WUP2

Q86UX7

0

binding

up-regulates activity

0.488

Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton.

SIGNOR-266104

Q9H7Z6

Q03164

0

binding

up-regulates

0.488

Mll1 and mof can form a stable complex in vivo / given that an interaction of dmof with msl1 through its zinc finger is essential for correct targeting of mof to the male x chromosome

SIGNOR-138245

Q15910

Q8NG27

0

ubiquitination

down-regulates quantity by destabilization

0.488

Biochemical and genetic evidence demonstrates that the MYOD-induced E3 ubiquitin ligase Praja1 (PJA1) is involved in regulating EZH2 levels upon p38α activation. EZH2 premature degradation in proliferating myoblasts is prevented by low levels of PJA1, its cytoplasmic localization and the lower activity towards unphosphorylated EZH2

SIGNOR-255664

P42224

P42226

0

binding

down-regulates activity

0.488

STAT6 mediates suppression of STAT1 and NF-kB-dependent transcription by distinct mechanisms. Both processes are dependent upon the STAT6 transactivation domain and may involve sequestration of necessary but different transcriptional coactivator proteins. These two suppressive mechanisms are controlled differentially by the nature of the STAT6 DNA-binding site

SIGNOR-249552

P22681

Q13882

0

phosphorylation

down-regulates activity

0.488

Herein we report that PTK6 phosphorylates and down-regulates E3 ubiquitin ligase c-Cbl.

SIGNOR-279348

Q96IV0

Q04323

0

binding

up-regulates activity

0.488

PNGase is directed to polyubiquitinated MGPs via VCP and the adaptor protein SAKS1, allowing PNGase to deglycosylate MGPs, which can then be degraded by the proteasome. PNGase itself is reported to bind to the S4 component of the 19 S proteasome.

SIGNOR-261060

O60500

P19544

0

transcriptional regulation

up-regulates quantity by expression

0.487

The Wilms tumor suppressor gene (WT1) is a zinc-finger-containing transcription factor that is coexpressed with NPHS1 in differentiated podocytes; gel shift binding assays demonstrate that a recombinant WT1 protein can bind and activate the 186-bp NPHS1 fragment in a sequence-specific manner

SIGNOR-252299

P15559

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.487

In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).

SIGNOR-256275

Q9UEW8

Q04759

0

phosphorylation

up-regulates activity

0.487

Recombinant SPAK was phosphorylated on Ser-311 in its kinase domain by PKCtheta, but not by PKCalpha. This synergistic activity, as well as the receptor-induced SPAK activation, required the PKCtheta-interacting region of SPAK, and Ser-311 mutation greatly reduced these activities of SPAK.

SIGNOR-276007

Q969S3

Q99683

0

phosphorylation

up-regulates

0.487

Ask1 directly phosphorylated zpr9 at ser(314) and thr(318), suggesting that zpr9 can act as an ask1 substrate. Ask1-mediated phosphorylation of zpr9 at ser(314) and thr(318) was also responsible for zpr9-induced apoptosis.

SIGNOR-175113

Q9Y6H5

P49841

0

phosphorylation

down-regulates

0.487

Synphilin-1 s556a mutant, which is less phosphorylated by gsk3beta, formed more inclusion bodies than wild type synphilin-1. Mutation analysis showed that ser556 is a major gsk3beta phosphorylation site in synphilin-1

SIGNOR-140609

Q01094

O96017

0

phosphorylation

up-regulates quantity by stabilization

0.487

We report that checkpoint kinase 2 (chk2) regulates e2f-1 activity in response to the dna-damaging agent etoposide. A chk2 consensus phosphorylation site in e2f-1 is phosphorylated in response to dna damage

SIGNOR-100898

P12830

O60315

0

transcriptional regulation

down-regulates quantity by repression

0.487

SIP 1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadh promoter.SIP1 induction resulted in the loss of cell-cell adhesion, in activation of invasion and in at random, multidirectional migration instead of unidirectional coherent migration (required in neurulation).

SIGNOR-268950

P48736

P63211

0

binding

up-regulates

0.487

Therefore, we conclude that in vivo, g beta gamma activates pi3k gamma by a mechanism assigning specific roles for both pi3k gamma subunits, i.e., membrane recruitment is mediated via the noncatalytic p101 subunit, and direct stimulation of g beta gamma with p110 gamma contributes to activation of pi3k gamma.

SIGNOR-96831

Q14643

P06241

0

phosphorylation

up-regulates

0.487

We have identified tyrosine 353 (tyr353) in the ip3-binding domain of type 1 ip3r (ip3r1) as a phosphorylation site for fyntyrosine phosphorylation of ip3r1 increased ip3 binding at low ip3 concentrations (<10 nm).

SIGNOR-121795

P16220

Q13627

0

phosphorylation

up-regulates activity

0.487

Regarding to the functional role of Dyrk1A, active Dyrk1A phosphorylates the transcription factor cAMP response element -binding protein (CREB), which subsequently leads to the stimulation of cAMP response element-mediated gene transcription during neuronal differentiation ( ).

SIGNOR-279989

P29590

P78317

0

polyubiquitination

down-regulates quantity by destabilization

0.487

Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.

SIGNOR-272884

P24844

O43293

0

phosphorylation

up-regulates

0.487

More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.

SIGNOR-188789

Q5RD31

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.487

NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification.NFE2L2-mediated upregulation of NQO1 is implicated in promoting resistance to ferroptosis inducers, such as erastin and sorafenib, in HCC cells

SIGNOR-279860

Q9NZV8

P78411

0

transcriptional regulation

down-regulates quantity by repression

0.487

Irx5 Directly Represses the Kcnd2 Promoter

SIGNOR-266045

Q96ST3

O14901

0

binding

up-regulates activity

0.487

detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.

SIGNOR-222344

P14618

P30304

0

dephosphorylation

up-regulates activity

0.487

Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2 dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.|Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2-dependent \u03b2-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop.

SIGNOR-276967

P30679

P34981

0

binding

up-regulates activity

0.487

Ga16 is phosphorylated in vivo by PMA and by TRH receptor stimulation

SIGNOR-278132

O43395

Q13107

0

deubiquitination

down-regulates activity

0.487

Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site.

SIGNOR-271975

P78504

Q8NES3

0

binding

down-regulates

0.486

Although jagged1-induced signaling was suppressed by lfng and mfng

SIGNOR-131560

Q9Y6D9

P12270

0

binding

up-regulates

0.486

Tpr directly binds to mad1 and mad2. / depletion of tpr decreases the levels of mad1 at kinetochores during prometaphase, correlating with the inability of mad1 to activate mad2, which is required for inhibiting apc(cdc20).

SIGNOR-181918

Q68G74

Q5JUK2

0

transcriptional regulation

up-regulates quantity by expression

0.486

Cotransfection of a mouse Sohlh1 expression vector with E box-containing promoter regions of mouse Lhx8, Zp1, and Zp3 fused to luciferase resulted in significant transactivation . Mutation of the E box sequences abolished SOHLH1-dependent stimulation. Thus, Lhx8, Zp1, and Zp3 are likely direct downstream target genes of SOHLH1 through the E box elements in their promoters.

SIGNOR-266076

P54725

Q05086

0

polyubiquitination

down-regulates quantity by destabilization

0.486

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

SIGNOR-272550