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
Q14209	Q14186	2	binding	up-regulates activity	0.738	The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3.	SIGNOR-240550
Q16620	P23560	2	binding	up-regulates	0.817	Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb	SIGNOR-31597
P53671	Q13464	0	phosphorylation	up-regulates	0.632	Specific activation of lim kinase 2 via phosphorylation of threonine 505 by rock, a rho-dependent protein kinase	SIGNOR-82755
P36956	Q9H5J4	1	transcriptional regulation	up-regulates quantity by expression	0.45	These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c.	SIGNOR-267943
Q92915	P68400	0	phosphorylation	up-regulates activity	0.269	Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275738
P08069	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.66	We could prove that Mdm2 physically associates with IGF-1R and that Mdm2 causes IGF-1R ubiquitination in an in vitro assay.	SIGNOR-278571
Q96FI4	Q12899	0	ubiquitination	down-regulates quantity	0.247	Mule and TRIM26 ubiquitylate NEIL1 in vitro within C-terminal lysine residues.\|Similar to these previous results, we again demonstrate that a knockdown of Mule or TRIM26 causes an elevation in the protein stability of NEIL1 in comparison to non-targeting siRNA, unirradiated control (Figure and ; compare lanes 1 and 2).	SIGNOR-278647
P17612	Q93034	1	phosphorylation	up-regulates activity	0.322	Elimination of the S730 but not the T325 PKA phosphorylation site of VACM-1 resulted in a complete inhibition of the VACM-1 activity, thus suggesting a direct effect of PKA on the VACM-1 receptor.	SIGNOR-250352
O14649	P17612	0	phosphorylation	up-regulates activity	0.2	Mutation of the ser393 to alanine, which can neither be phosphorylated nor mimic a phosphorylated residue, resulted in the channel failing to pass current all of our findings support the conclusion that camp-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both k2p3.1 and k2p9.1.	SIGNOR-172430
P01189-PRO_0000024969	P16519	0	cleavage	up-regulates quantity	0.2	POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide	SIGNOR-268725
Q9Y618	P51843	2	binding	up-regulates activity	0.393	The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes.	SIGNOR-271785
Q8IVT5	P15056	2	binding	up-regulates activity	0.63	In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.	SIGNOR-273878
Q14012	Q92974	1	phosphorylation	up-regulates activity	0.389	In this study, we found that CaMKI phosphorylated GEF-H1 at Thr103, which is located close to the C1 domain.	SIGNOR-279359
Q14703	Q70SY1	1	cleavage	up-regulates	0.561	Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei	SIGNOR-151309
P00519	Q9Y6Q9	1	phosphorylation	up-regulates	0.348	Tyrosine phosphorylation of the nuclear receptor coactivator aib1/src-3 is enhanced by abl kinase and is required for its activity in cancer cellstyrosine kinase directly phosphorylates aib1/src-3 at y1357 and modulates the association of aib1 with c-abl, eralpha, the transcriptional cofactor p300,	SIGNOR-180571
Q86UR1	P12931	0	phosphorylation	up-regulates	0.408	Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation.	SIGNOR-168545
P01588	Q16665	0	transcriptional regulation	up-regulates quantity by expression	0.643	Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor that regulates hypoxia-inducible genes including the human erythropoietin (EPO) gene.	SIGNOR-253695
P15173	P15173	2	transcriptional regulation	up-regulates	0.2	Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle	SIGNOR-151694
P10398	P36507	1	phosphorylation	up-regulates	0.754	Active raf phosphorylates mek.	SIGNOR-175142
P26367	O00330	2	binding	down-regulates activity	0.2	In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3.	SIGNOR-254903
Q99501	P51955	0	phosphorylation	up-regulates activity	0.2	Nek2A mediates G2/M phosphorylation of GAS2L1. GAS2L1 and its Ser352 phosphorylation are required for proper spindle organization and chromosome segregation.	SIGNOR-273683
O00255	P31269	1	methylation	up-regulates quantity by expression	0.477	Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus.	SIGNOR-255894
Q04760	P12931	0	phosphorylation	up-regulates activity	0.2	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276189
P60953	O15068	0	guanine nucleotide exchange factor	up-regulates activity	0.751	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-260560
P32245	P42127	2	binding	down-regulates activity	0.5	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268708
P30153	Q5FBB7	2	binding	up-regulates	0.2	Identification of subunits of protein phosphatase 2a (pp2a) as sgo1 binding proteins / pp2a is required for proper chromosome segregation and centromeric localization of sgo1 in hela cells	SIGNOR-145486
P00352	Q00535	0	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
O00585	P32248	2	binding	up-regulates	0.786	The regulated expression of the chemokine secondary lymphoid tissue chemokine (slc/ccl21) and its corresponding receptor, ccr7.	SIGNOR-117566
P49683	O95837	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-257198
Q8NHY2	Q13315	0	phosphorylation	down-regulates	0.2	Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism	SIGNOR-149082
P16220	P48729	0	phosphorylation	up-regulates	0.312	Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement.	SIGNOR-64258
P05067	O60260	0	ubiquitination	down-regulates quantity	0.2	Similarly, in transgenic AD mice models, lentiviral parkin expression ubiquitinates Abeta to reduce its intracellular levels while preventing plaque deposition, and this is associated with induction of beclin dependent autophagy .\|Thus, parkin reduces Abeta levels by enhancing both UPS- and autophagy dependent clearance of Abeta.	SIGNOR-278709
P12931	Q9BXK1	1	phosphorylation	up-regulates activity	0.245	We further confirmed that the Tyr-10 residue of KLF16 is phosphorylated in uterine cells (Fig. 7c). Additional experiments using both pharmacological and dominant negative inhibitors of Src further supported a role for this tyrosine kinase in modulating the activity of KLF16 (Fig. 7, d and f).	SIGNOR-276398
P13688	P12931	0	phosphorylation	up-regulates activity	0.426	Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515	SIGNOR-246471
A8MT69	Q8IYD8	2	binding	up-regulates	0.2	We also provide biochemical evidence that mhf1 and mhf2 assemble into a heterodimer that binds dna and enhances the dna branch migration activity of fancm. These findings reveal critical roles of the mhf1-mhf2 dimer in dna damage repair and genome maintenance through fancm.	SIGNOR-164729
Q6PCD5	Q06609	1	ubiquitination	up-regulates activity	0.401	Rad51 directly interacts with the N-terminal of RFWD3 and is ubiquitinated by RFWD3.	SIGNOR-278543
P50542	Q13501	2	binding	up-regulates activity	0.372	Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.	SIGNOR-262793
P49840	P51812	0	phosphorylation	down-regulates activity	0.265	P90-rsk and akt may promote rapid phosphorylation/inactivation of glycogen synthase kinase 3 in chemoattractant-stimulated neutrophils. These reactions were monitored with a phosphospecific antibody that only recognized the alpha- or beta-isoforms of GSK-3 when these proteins were phosphorylated on serine residues 21 and 9, respectively.	SIGNOR-110827
P15173	P50461	2	binding	up-regulates activity	0.519	we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.	SIGNOR-241113
Q8N4C8	Q12809	2	binding	up-regulates	0.284	Herg, a human homologue of the ether-a-go-go gene of the fruitfly drosophila melanogaster, encodes aproteinthat produces the rapidly activating cardiac delayed rectifier (i[kr]). / our results show that mink physically associates with herg and that the interaction leads to increased ikr current density.	SIGNOR-49869
O75197	O14904	2	binding	up-regulates	0.658	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-132073
Q01726	O95837	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-257085
P06241	Q13224	1	phosphorylation	up-regulates activity	0.768	We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases	SIGNOR-247176
P61586	P15498	0	guanine nucleotide exchange factor	up-regulates activity	0.75	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-260580
Q9H1B7	Q12947	0	transcriptional regulation	up-regulates quantity by expression	0.253	FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation.	SIGNOR-267152
P42336	P16520	2	binding	up-regulates	0.4	Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein.	SIGNOR-120264
P06493	O43521	1	phosphorylation	up-regulates activity	0.404	Furthermore, active recombinant Cdk1/cyclin B1 phosphorylates BimEL and BimL in vitro and Serine 44 on BimL has been identified as a Cdk1 phosphorylation site. Collectively, these results suggest that Cdk1/cyclin B1-dependent hyper-phosphorylation of Bim during prolonged mitotic arrest is an important cell death signal.	SIGNOR-267985
P49840	P49840	2	phosphorylation	up-regulates	0.2	Gsk3a is activated by phosphorylation at tyr-279.	SIGNOR-180035
P08754	Q9GZQ6	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-256851
P60484	Q14653	1	dephosphorylation	up-regulates activity	0.256	PTEN can dephosphorylate IRF-3 S97 residue and facilitate its nuclear import for the IFN signaling pathway (7).\|PTEN expression directly increases activated IRF-3 nuclear import and subsequent interferon (IFN) synthesis.	SIGNOR-277025
P27361	Q8IZP0	1	phosphorylation	up-regulates	0.454	We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1.	SIGNOR-172881
P06213	P53004	1	phosphorylation	up-regulates activity	0.479	Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).\|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK	SIGNOR-275514
Q9UP38	O14640	2	binding	up-regulates activity	0.688	When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.	SIGNOR-253512
Q12965	O43426	2	binding	up-regulates activity	0.427	We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta.	SIGNOR-265423
Q14289	P29350	0	dephosphorylation	down-regulates	0.359	Raftk binds constitutively to the protein tyrosine phosphatase shptp1.SHPTP1 Plays a negative role in pyk2/raftk signaling by dephosphorylating raftk on tyr-402, thereby inhibiting the interaction of the sh2 domain of c-src with raftk	SIGNOR-71414
P24941	P10644	1	phosphorylation	up-regulates	0.343	In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue.	SIGNOR-145577
P68104	P05771	0	phosphorylation	up-regulates activity	0.2	PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein.	SIGNOR-263167
P08575	P07948	1	dephosphorylation	down-regulates activity	0.666	CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.\| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)	SIGNOR-248354
Q9NX45	P10721	1	transcriptional regulation	up-regulates quantity by expression	0.325	Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.	SIGNOR-266206
P35125	P63000	0	relocalization	up-regulates	0.338	In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin.	SIGNOR-98938
Q8N140	Q4FZB7	0	transcriptional regulation	up-regulates quantity by expression	0.2	Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene.	SIGNOR-266640
Q15139	Q8WUI4	1	phosphorylation	down-regulates	0.478	We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf.	SIGNOR-179430
O95633	O14793	2	binding	down-regulates	0.674	Fstl3 inhibits myostatin via its n-terminal domain.	SIGNOR-199063
P30989	P63096	2	binding	up-regulates activity	0.267	Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways	SIGNOR-278059
P54840	Q9UQK1	2	binding	up-regulates	0.753	In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)	SIGNOR-271731
P25098	P08069	1	phosphorylation	down-regulates quantity by destabilization	0.2	GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation	SIGNOR-276413
Q06124	Q14451	1	dephosphorylation	up-regulates activity	0.435	Dephosphorylation of Grb7 was blocked by the SHP inhibitor NSC-87877 (Zhan et al., 2009), supporting the specificity of SHP-2 in dephosphorylating Grb7.\|Nuclear SHP-2 mediates the formation of an EGF induced complex of Grb7, HuR, and CRM1.\|Using the \u03ba\u2013opioid receptor (OR [KOR]) as a model, we demonstrate that EGF activates nuclear SHP-2 (Src homology region 2\u2013containing tyrosine phosphatase), which dephosphorylates Grb7 in the nucleus.	SIGNOR-277169
P14780	P20742	2	cleavage	down-regulates quantity by destabilization	0.349	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.\|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261785
P63092	P47871	2	binding	up-regulates activity	0.512	Glucagon signals through its receptor on the cell surface (Fig.1). The binding of glucagon to the extracellular loops of the glucagon receptor results in conformational changes of the latter, leading to subsequent activation of the coupled G proteins. At least two classes of G proteins are known to be associated with and involved in the signal transduction of the glucagon receptor, namely Gsα and Gq. The activation of Gsα leads to activation of adenylate cyclase, increase in intracellular cAMP levels, and subsequent activation of protein kinase A (PKA).	SIGNOR-267715
O60313	Q96TA2	0	cleavage	up-regulates activity	0.455	YME1L cleaves OPA1 at S2 and S3 site to transform into L-OPA1 to induce fusion when cells are faced with increased oxidative phosphorylation, whereas OMA1 cleaves OPA1 at an S1 site to transform into S-OPA1, resulting in the fragmented response to cellular stress, mitochondrial dysfunction, or deletion of YME1L	SIGNOR-274140
P09917	Q9UQM7	0	phosphorylation	up-regulates activity	0.2	Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export\|We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques\|Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca2+/calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO.	SIGNOR-264408
Q9BQS8	Q9GZQ8	2	binding	up-regulates activity	0.517	The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures.	SIGNOR-260597
P30679	Q15077	2	binding	up-regulates activity	0.401	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-257277
Q9Y566	P35637	0	post transcriptional regulation	up-regulates quantity	0.2	These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.\|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition.	SIGNOR-262104
P22681	P06239	1	polyubiquitination	down-regulates quantity by destabilization	0.711	Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain.	SIGNOR-272614
Q13315	P27707	1	phosphorylation	up-regulates activity	0.399	Here we report that ATM phosphorylation of dCK on Serine 74 is essential to activate the G2/M checkpoint in response to DNA damage.\|Together, these results indicate that the dCK-Cdk1 interaction is enhanced in response to DNA damage and that ATM mediated dCK Serine 74 phosphorylation is required for the interaction.	SIGNOR-278221
P15311	Q9P289	0	phosphorylation	up-regulates	0.2	Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. Mst4 phosphorylates the regulatory t567 residue of ezrin.	SIGNOR-185563
P43699	P07202	1	transcriptional regulation	up-regulates quantity by expression	0.379	TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8.	SIGNOR-267278
P60510	Q04206	1	dephosphorylation	up-regulates activity	0.361	Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation	SIGNOR-248549
Q9H1H9	Q68DK2	2	binding	up-regulates activity	0.415	We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B.	SIGNOR-265539
P38398	Q92878	2	binding	up-regulates	0.789	Brca1 interacts in vitro and in vivo with hrad50. Brca1 is important for the cellular responses to dna damage that are mediated by the hrad50-hmre11-p95 complex.	SIGNOR-69701
Q99933	O75807	1	null	down-regulates activity	0.444	Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.\|BAG-1 negatively modulates GADD34-bound PP1 activity, and the expression of BAG-1 isoforms can also mask GADD34-mediated inhibition of colony formation and suppression of transcription. Our findings suggest that BAG-1 may function to suppress the GADD34-mediated cellular stress response and support a role for BAG-1 in the survival of cells undergoing stress.	SIGNOR-254117
Q7KZI7	P17612	0	phosphorylation	down-regulates activity	0.2	Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409.	SIGNOR-276870
P50148	P35368	2	binding	up-regulates activity	0.614	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-257079
P29371	P63092	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 ‚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-256794
Q9NYJ8	O43318	2	binding	up-regulates activity	0.936	Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages	SIGNOR-120268
Q6IN85	P60510	2	binding	up-regulates	0.2	Our data demonstrate that pp4r4 forms a novel cytosolic complex with pp4c, independent from the complexes containing pp4r1, pp4r2.PP4R3, and alpha4, and that the regulatory subunits of pp4c have evolved different modes of interaction with the catalytic subunit.	SIGNOR-180244
P49841	P16220	1	phosphorylation	up-regulates activity	0.691	GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant	SIGNOR-251233
Q9Y385	Q13490	0	ubiquitination	down-regulates quantity by destabilization	0.37	We also found that ubiquitin-ligase (E3), c-IAP1 preferentially interacts with phosphorylated Ube2j1. Moreover, we noticed that phosphorylated Ube2j1 is rapidly degraded by the proteasome during ER stress cell recovery. Taken together, these data suggest that Ube2j1 and its phosphorylation is important for transient ER stress cell recovery and the phosphorylated Ube2j1 is degraded by the proteasome.	SIGNOR-263092
P16298	P0DP23	2	binding	up-regulates	0.696	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-114101
P00533	P61925	1	phosphorylation	up-regulates	0.307	The difference in inhibitory potency between pki_ and pki_ has been attributed to the absence of a tyrosine residue (tyr7) in pki_ that is present in the nh2-terminal region of pki_. This suggests that the absence of a single amino acid residue can result in variations in how the catalytic subunit of camp-dependent protein kinase interacts with pki which ultimately can result in alterations in pki inhibitory potency.	SIGNOR-22455
C9JLW8	Q13363	2	binding	down-regulates activity	0.2	CtBP is recruited to promoter elements of target genes by interacting with the DNA-binding transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby competitively inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.	SIGNOR-264776
P11488	Q99835	2	binding	up-regulates	0.262	Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.	SIGNOR-148496
P51817	P98161	1	phosphorylation	up-regulates	0.257	The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd.	SIGNOR-158852
P46783	Q9UHC7	0	ubiquitination	up-regulates activity	0.2	We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1.Our data show that MKRN1 associates with polysomes and ubiquitylates RPS10, indicating a role in translational control. We hypothesize that ribosomes encountering the MKRN1-PABPC1 complex are stalled, possibly via ubiquitylation of RPS10 on K107 and other MKRN1 substrates.	SIGNOR-272216
P12830	O60716	2	binding	up-regulates quantity by stabilization	0.947	P120 regulates E-cadherin turnover at the cell membrane. Because direct binding of p120 to E-cadherin is required, it is possible that p120 binding blocks the interaction of an unknown binding partner (or event) that targets E-cadherin for degradation	SIGNOR-252123
P48730	P17252	0	phosphorylation	up-regulates activity	0.2	In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity.	SIGNOR-277452
O15294	P49841	0	phosphorylation	up-regulates activity	0.518	But OGT activity is modulated by GSK3beta (XREF_FIG) and GSK3beta activity is known to oscillate through Ser9 phoshorylation.\|Here, we found that OGT is phosphorylated at serines 3 or 4 by GSK3beta and that O GlcNAcylation of OGT also occurs on the same or neighboring serine residues, suggesting interacting phosphorylation and O GlcNAcylation events on OGT itself.	SIGNOR-279528
Q9UER7	Q86Z02	0	phosphorylation	down-regulates activity	0.611	HIPK1 phosphorylates Daxx on Ser 669, and phosphorylation of this site is important in modulating the ability of Daxx to function as a transcriptional repressor. \| Therefore, phosphorylation at Ser 669 by HIPK1 diminishes the ability of Daxx to repress transcription.	SIGNOR-260842
P78563	Q05513	0	phosphorylation	up-regulates activity	0.2	Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.	SIGNOR-277391

Q14209

Q14186

2

binding

up-regulates activity

0.738

The transcriptionally active forms of E2F are heterodimers composed of one polypeptide encoded by the E2F gene family and one polypeptide encoded by the DP gene family.In transfected cells, DP-1 did not accumulate in the nucleus unless it was coexpressed with the heterodimeric partners E2F-1, E2F-2, or E2F-3.

SIGNOR-240550

Q16620

P23560

2

binding

up-regulates

0.817

Its interactions with trkb can be distinguished from those of brain-derived neurotrophic factor (bdnf) with trkb

SIGNOR-31597

P53671

Q13464

0

phosphorylation

up-regulates

0.632

Specific activation of lim kinase 2 via phosphorylation of threonine 505 by rock, a rho-dependent protein kinase

SIGNOR-82755

P36956

Q9H5J4

1

transcriptional regulation

up-regulates quantity by expression

0.45

These data demonstrated that Elovl-6 is regulated directly and primarily by SREBP-1c.

SIGNOR-267943

Q92915

P68400

0

phosphorylation

up-regulates activity

0.269

Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.

SIGNOR-275738

P08069

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.66

We could prove that Mdm2 physically associates with IGF-1R and that Mdm2 causes IGF-1R ubiquitination in an in vitro assay.

SIGNOR-278571

Q96FI4

Q12899

0

ubiquitination

down-regulates quantity

0.247

Mule and TRIM26 ubiquitylate NEIL1 in vitro within C-terminal lysine residues.|Similar to these previous results, we again demonstrate that a knockdown of Mule or TRIM26 causes an elevation in the protein stability of NEIL1 in comparison to non-targeting siRNA, unirradiated control (Figure and ; compare lanes 1 and 2).

SIGNOR-278647

P17612

Q93034

1

phosphorylation

up-regulates activity

0.322

Elimination of the S730 but not the T325 PKA phosphorylation site of VACM-1 resulted in a complete inhibition of the VACM-1 activity, thus suggesting a direct effect of PKA on the VACM-1 receptor.

SIGNOR-250352

O14649

P17612

0

phosphorylation

up-regulates activity

0.2

Mutation of the ser393 to alanine, which can neither be phosphorylated nor mimic a phosphorylated residue, resulted in the channel failing to pass current all of our findings support the conclusion that camp-dependent protein kinase is responsible for the phosphorylation of the terminal serine in both k2p3.1 and k2p9.1.

SIGNOR-172430

P01189-PRO_0000024969

P16519

0

cleavage

up-regulates quantity

0.2

POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide

SIGNOR-268725

Q9Y618

P51843

2

binding

up-regulates activity

0.393

The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes.

SIGNOR-271785

Q8IVT5

P15056

2

binding

up-regulates activity

0.63

In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.

SIGNOR-273878

Q14012

Q92974

1

phosphorylation

up-regulates activity

0.389

In this study, we found that CaMKI phosphorylated GEF-H1 at Thr103, which is located close to the C1 domain.

SIGNOR-279359

Q14703

Q70SY1

1

cleavage

up-regulates

0.561

Bbf2h7 is cleaved by s1p in response to er stress / cleaved fragments of the bbf2h7 n-terminal portion containing the bzip domain translocate into nuclei

SIGNOR-151309

P00519

Q9Y6Q9

1

phosphorylation

up-regulates

0.348

Tyrosine phosphorylation of the nuclear receptor coactivator aib1/src-3 is enhanced by abl kinase and is required for its activity in cancer cellstyrosine kinase directly phosphorylates aib1/src-3 at y1357 and modulates the association of aib1 with c-abl, eralpha, the transcriptional cofactor p300,

SIGNOR-180571

Q86UR1

P12931

0

phosphorylation

up-regulates

0.408

Here, we show that the interaction of noxa1 and tks proteins is dependent on src activity. Interestingly, the abolishment of src-mediated phosphorylation of tyr110 on noxa1 and of tyr508 on tks4 blocks their binding and decreases nox1-dependent ros generation.

SIGNOR-168545

P01588

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.643

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix transcription factor that regulates hypoxia-inducible genes including the human erythropoietin (EPO) gene.

SIGNOR-253695

P15173

2

transcriptional regulation

up-regulates

0.2

Upon the expression of myogenin, myogenin, mef2d, and brg1 localize to the myogenin promoter to maintain myogenin expression./ Swi/snf chromatin-remodeling activity is required for myogenin expression in differentiated skeletal muscle

SIGNOR-151694

P10398

P36507

1

phosphorylation

up-regulates

0.754

Active raf phosphorylates mek.

SIGNOR-175142

P26367

O00330

2

binding

down-regulates activity

0.2

In the heterologous cell line BHK-21, Pdx1 inhibited by 60 to 80% the activation of the alpha-cell specific element G1 conferred by Pax-6 and/or Cdx-2/3. Although Pdx1 could bind three AT-rich motifs within G1, two of which are binding sites for Pax-6 and Cdx-2/3, the affinity of Pdx1 for G1 was much lower as compared to Pax-6. In addition, Pdx1 inhibited Pax-6 mediated activation through G3, to which Pdx1 was unable to bind. Moreover, a mutation impairing DNA binding of Pdx1 had no effect on its inhibition on Cdx-2/3. Since Pdx1 interacts directly with Pax-6 and Cdx-2/3 forming heterodimers, we suggest that Pdx1 inhibits glucagon gene transcription through protein to protein interactions with Pax-6 and Cdx-2/3.

SIGNOR-254903

Q99501

P51955

0

phosphorylation

up-regulates activity

0.2

Nek2A mediates G2/M phosphorylation of GAS2L1. GAS2L1 and its Ser352 phosphorylation are required for proper spindle organization and chromosome segregation.

SIGNOR-273683

O00255

P31269

1

methylation

up-regulates quantity by expression

0.477

Men1 excision causes reduction of Hoxa9 expression, colony formation by hematopoietic progenitors, and the peripheral white blood cell count. Menin directly activates Hoxa9 expression, at least in part, by binding to the Hoxa9 locus, facilitating methylation of H3K4, and recruiting the methylated H3K4 binding protein chd1 to the locus.

SIGNOR-255894

Q04760

P12931

0

phosphorylation

up-regulates activity

0.2

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).

SIGNOR-276189

P60953

O15068

0

guanine nucleotide exchange factor

up-regulates activity

0.751

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-260560

P32245

P42127

2

binding

down-regulates activity

0.5

The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins

SIGNOR-268708

P30153

Q5FBB7

2

binding

up-regulates

0.2

Identification of subunits of protein phosphatase 2a (pp2a) as sgo1 binding proteins / pp2a is required for proper chromosome segregation and centromeric localization of sgo1 in hela cells

SIGNOR-145486

P00352

Q00535

0

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

O00585

P32248

2

binding

up-regulates

0.786

The regulated expression of the chemokine secondary lymphoid tissue chemokine (slc/ccl21) and its corresponding receptor, ccr7.

SIGNOR-117566

P49683

O95837

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-257198

Q8NHY2

Q13315

0

phosphorylation

down-regulates

0.2

Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism

SIGNOR-149082

P16220

P48729

0

phosphorylation

up-regulates

0.312

Ser108, ser111 and ser114, located in a region matching the consensus sequence for the casein kinase ii target, were required.These results strongly suggest that the casein kinase ii target region is involved in cell cycle-regulated phosphorylation of the creb protein and also in transcriptional enhancement.

SIGNOR-64258

P05067

O60260

0

ubiquitination

down-regulates quantity

0.2

Similarly, in transgenic AD mice models, lentiviral parkin expression ubiquitinates Abeta to reduce its intracellular levels while preventing plaque deposition, and this is associated with induction of beclin dependent autophagy .|Thus, parkin reduces Abeta levels by enhancing both UPS- and autophagy dependent clearance of Abeta.

SIGNOR-278709

P12931

Q9BXK1

1

phosphorylation

up-regulates activity

0.245

We further confirmed that the Tyr-10 residue of KLF16 is phosphorylated in uterine cells (Fig. 7c). Additional experiments using both pharmacological and dominant negative inhibitors of Src further supported a role for this tyrosine kinase in modulating the activity of KLF16 (Fig. 7, d and f).

SIGNOR-276398

P13688

P12931

0

phosphorylation

up-regulates activity

0.426

Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515

SIGNOR-246471

A8MT69

Q8IYD8

2

binding

up-regulates

0.2

We also provide biochemical evidence that mhf1 and mhf2 assemble into a heterodimer that binds dna and enhances the dna branch migration activity of fancm. These findings reveal critical roles of the mhf1-mhf2 dimer in dna damage repair and genome maintenance through fancm.

SIGNOR-164729

Q6PCD5

Q06609

1

ubiquitination

up-regulates activity

0.401

Rad51 directly interacts with the N-terminal of RFWD3 and is ubiquitinated by RFWD3.

SIGNOR-278543

P50542

Q13501

2

binding

up-regulates activity

0.372

Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.

SIGNOR-262793

P49840

P51812

0

phosphorylation

down-regulates activity

0.265

P90-rsk and akt may promote rapid phosphorylation/inactivation of glycogen synthase kinase 3 in chemoattractant-stimulated neutrophils. These reactions were monitored with a phosphospecific antibody that only recognized the alpha- or beta-isoforms of GSK-3 when these proteins were phosphorylated on serine residues 21 and 9, respectively.

SIGNOR-110827

P15173

P50461

2

binding

up-regulates activity

0.519

we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.

SIGNOR-241113

Q8N4C8

Q12809

2

binding

up-regulates

0.284

Herg, a human homologue of the ether-a-go-go gene of the fruitfly drosophila melanogaster, encodes aproteinthat produces the rapidly activating cardiac delayed rectifier (i[kr]). / our results show that mink physically associates with herg and that the interaction leads to increased ikr current density.

SIGNOR-49869

O75197

O14904

2

binding

up-regulates

0.658

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-132073

Q01726

O95837

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-257085

P06241

Q13224

1

phosphorylation

up-regulates activity

0.768

We have investigated the tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B by exogenous Src Phosphorylation-site specific antibodies identified NR2B Tyr1472 as a phosphorylation site for intrinsic PSD tyrosine kinases

SIGNOR-247176

P61586

P15498

0

guanine nucleotide exchange factor

up-regulates activity

0.75

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-260580

Q9H1B7

Q12947

0

transcriptional regulation

up-regulates quantity by expression

0.253

FOXF2 directly bound the promoter of E3 ligase interferon regulatory factor 2-binding protein-like (IRF2BPL) and induced its transcriptional expression. IRF2BPL in turn interacted with β-catenin, increasing its ubiquitination and degradation.

SIGNOR-267152

P42336

P16520

2

binding

up-regulates

0.4

Expression of the g__ sequestrant, _-transducin, inhibits both ras activation and membrane translocation of _-arrestin1, suggesting that g__ dimers from g_i2 and g_q activate different effectors to coordinately regulate the pi 3-kinase/akt pathway. , these data indicate that _-thrombin stimulates rapid pi 3-kinase activity and akt phosphorylation by the g__ dimers released from a ptx-sensitive g protein.

SIGNOR-120264

P06493

O43521

1

phosphorylation

up-regulates activity

0.404

Furthermore, active recombinant Cdk1/cyclin B1 phosphorylates BimEL and BimL in vitro and Serine 44 on BimL has been identified as a Cdk1 phosphorylation site. Collectively, these results suggest that Cdk1/cyclin B1-dependent hyper-phosphorylation of Bim during prolonged mitotic arrest is an important cell death signal.

SIGNOR-267985

P49840

2

phosphorylation

up-regulates

0.2

Gsk3a is activated by phosphorylation at tyr-279.

SIGNOR-180035

P08754

Q9GZQ6

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-256851

P60484

Q14653

1

dephosphorylation

up-regulates activity

0.256

PTEN can dephosphorylate IRF-3 S97 residue and facilitate its nuclear import for the IFN signaling pathway (7).|PTEN expression directly increases activated IRF-3 nuclear import and subsequent interferon (IFN) synthesis.

SIGNOR-277025

P27361

Q8IZP0

1

phosphorylation

up-regulates

0.454

We show that erk colocalizes with the wrc at lamellipodial leading edges and directly phosphorylates two wrc components: wave2 and abi1.

SIGNOR-172881

P06213

P53004

1

phosphorylation

up-regulates activity

0.479

Human BVR (hBVR) also reduces the hemeoxygenase activity product biliverdin to bilirubin and is directly activated by insulin receptor kinase (IRK).|in addition to Y198 in the YMKM motif, 2 other tyrosines, Y228 in the YLSF motif and Y291 in the C-terminus of the protein, are directly phosphorylated by IRK

SIGNOR-275514

Q9UP38

O14640

2

binding

up-regulates activity

0.688

When canonical wnts bind to their respective fzd receptors, heterotrimeric g-proteins and dsh get activated and lead to the recruitment of axin to the fzd co-receptor lrp.

SIGNOR-253512

Q12965

O43426

2

binding

up-regulates activity

0.427

We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta.

SIGNOR-265423

Q14289

P29350

0

dephosphorylation

down-regulates

0.359

Raftk binds constitutively to the protein tyrosine phosphatase shptp1.SHPTP1 Plays a negative role in pyk2/raftk signaling by dephosphorylating raftk on tyr-402, thereby inhibiting the interaction of the sh2 domain of c-src with raftk

SIGNOR-71414

P24941

P10644

1

phosphorylation

up-regulates

0.343

In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue.

SIGNOR-145577

P68104

P05771

0

phosphorylation

up-regulates activity

0.2

PKCβI phosphorylates eEF1A at Ser53.our proteomics exploration of cPKC signaling in the nuclei of C2C12 cells demonstrated that the up-regulation of eEF1A intranuclear content, evoked by insulin, is associated with an increase in the phosphorylation of the Ser53 residue of the protein.

SIGNOR-263167

P08575

P07948

1

dephosphorylation

down-regulates activity

0.666

CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)

SIGNOR-248354

Q9NX45

P10721

1

transcriptional regulation

up-regulates quantity by expression

0.325

Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.

SIGNOR-266206

P35125

P63000

0

relocalization

up-regulates

0.338

In quiescent cells, tre17 is localized to intracellular filamentous and punctate structures in the cytoplasm, folded in an inactive conformation. Upon growth factor addition, cdc42 and rac1 become activated and recruit tre17 to the plasma membrane. Stable membrane localization of tre17 also requires polymerized actin. This recruitment process leads to a conformational change in tre17, such that the n-terminal portion of the molecule further stimulates the accumulation of cortical actin.

SIGNOR-98938

Q8N140

Q4FZB7

0

transcriptional regulation

up-regulates quantity by expression

0.2

Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. The novel inhibitor of differentiation Eid3 is an FRG1/Suv4-20h1 target involved in the myogenic defects caused by FRG1 over-expression. Eid3 is down-regulated upon muscle differentiation and behaves as a myogenic inhibitor gene.

SIGNOR-266640

Q15139

Q8WUI4

1

phosphorylation

down-regulates

0.478

We show for the first time that vegf stimulated phosphorylation of hdac7 at the sites of ser178, ser344, and ser479we found that phospholipase cgamma/protein kinase c/protein kinase d1 (pkd1)-dependent signal pathway mediated hdac7 phosphorylation and cytoplasmic accumulation by vegf.

SIGNOR-179430

O95633

O14793

2

binding

down-regulates

0.674

Fstl3 inhibits myostatin via its n-terminal domain.

SIGNOR-199063

P30989

P63096

2

binding

up-regulates activity

0.267

Altogether, these results reveal for the first time the ability of hNTS1 to directly activate the Gαq-, Gαi1-, GαoA-, and Gα13-mediated signaling pathways

SIGNOR-278059

P54840

Q9UQK1

2

binding

up-regulates

0.753

In the liver, PTG and PPP1R3B(GL)are expressed at roughly equivalent levels [55], and they jointly promote hepatic glycogen mobilization and storage. PTG overexpression significantly increased glycogen content, mainly due to its ability to promote the redistribution of PP1 and glycogen synthase to glycogen granules, significantly increasing GS activity and glycogen synthesis (Figure 2)

SIGNOR-271731

P25098

P08069

1

phosphorylation

down-regulates quantity by destabilization

0.2

GRK2 and GRK6 coimmunoprecipitate with IGF-1R and increase IGF-1R serine phosphorylation, promoting β-arrestin1 association. Using immunoprecipitation, confocal microscopy, and FRET analysis, we demonstrated β-arrestin/IGF-1R association to be transient for GRK2 and stable for GRK6. Using bioinformatic studies we identified serines 1248 and 1291 as the major serine phosphorylation sites of the IGF-1R. Targeted mutation of S1248 recapitulates GRK2 modulation, whereas S1291 mutation resembles GRK6 effects on IGF-1R signaling/degradation

SIGNOR-276413

Q06124

Q14451

1

dephosphorylation

up-regulates activity

0.435

Dephosphorylation of Grb7 was blocked by the SHP inhibitor NSC-87877 (Zhan et al., 2009), supporting the specificity of SHP-2 in dephosphorylating Grb7.|Nuclear SHP-2 mediates the formation of an EGF induced complex of Grb7, HuR, and CRM1.|Using the \u03ba\u2013opioid receptor (OR [KOR]) as a model, we demonstrate that EGF activates nuclear SHP-2 (Src homology region 2\u2013containing tyrosine phosphatase), which dephosphorylates Grb7 in the nucleus.

SIGNOR-277169

P14780

P20742

2

cleavage

down-regulates quantity by destabilization

0.349

The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.

SIGNOR-261785

P63092

P47871

2

binding

up-regulates activity

0.512

Glucagon signals through its receptor on the cell surface (Fig.1). The binding of glucagon to the extracellular loops of the glucagon receptor results in conformational changes of the latter, leading to subsequent activation of the coupled G proteins. At least two classes of G proteins are known to be associated with and involved in the signal transduction of the glucagon receptor, namely Gsα and Gq. The activation of Gsα leads to activation of adenylate cyclase, increase in intracellular cAMP levels, and subsequent activation of protein kinase A (PKA).

SIGNOR-267715

O60313

Q96TA2

0

cleavage

up-regulates activity

0.455

YME1L cleaves OPA1 at S2 and S3 site to transform into L-OPA1 to induce fusion when cells are faced with increased oxidative phosphorylation, whereas OMA1 cleaves OPA1 at an S1 site to transform into S-OPA1, resulting in the fragmented response to cellular stress, mitochondrial dysfunction, or deletion of YME1L

SIGNOR-274140

P09917

Q9UQM7

0

phosphorylation

up-regulates activity

0.2

Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export|We report here that 5-LO is constitutively phosphorylated on Ser-271 in transfected NIH 3T3 cells. This residue is nested in a classical nuclear export sequence, and phosphorylated Ser-271 5-LO was exclusively found in the nucleus by immunofluorescence and by fractionation techniques|Nuclear export of 5-LO can also be induced by KN-93, an inhibitor of Ca2+/calmodulin-dependent kinase II, and the effects of SB 203,580 plus KN-93 are additive. Finally, HeLa cells, which lack nuclear 5-LO, also lack constitutive phosphorylation of Ser-271. Taken together, these results indicate that the phosphorylation of Ser-271 serves to inhibit the nuclear export of 5-LO.

SIGNOR-264408

Q9BQS8

Q9GZQ8

2

binding

up-regulates activity

0.517

The preferential binding to LC3A and -B was confirmed in vivo by co-immunoprecipitation experiments of Myc-tagged FYCO1 and GFP fusions of human ATG8 family pro-teins expressed in HEK293 cells (Fig. 2B). GFP-LC3A and GFP-LC3B were efficiently co-precipitated with Myc-FYCO1,whereas GFP-LC3C, GFP-GABARAP, GFP-GABARAPL1 and-L2 were not. The effects we see on late steps of basal autophagy on mutation of the FYCO1 LIR motif correlate with a role of FYCO1 in regulating kinesin-mediated transport of LC3-positive autophagic structures.

SIGNOR-260597

P30679

Q15077

2

binding

up-regulates activity

0.401

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-257277

Q9Y566

P35637

0

post transcriptional regulation

up-regulates quantity

0.2

These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.|As seen in Figure 7 (top panel), both PSD-95 Q1-Q2 and Shank1a GQ probes pulled down endogenous FUS, whereas their M2 mutants did not, indicating that the GQ structure is sufficient for recognition.

SIGNOR-262104

P22681

P06239

1

polyubiquitination

down-regulates quantity by destabilization

0.711

Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain.

SIGNOR-272614

Q13315

P27707

1

phosphorylation

up-regulates activity

0.399

Here we report that ATM phosphorylation of dCK on Serine 74 is essential to activate the G2/M checkpoint in response to DNA damage.|Together, these results indicate that the dCK-Cdk1 interaction is enhanced in response to DNA damage and that ATM mediated dCK Serine 74 phosphorylation is required for the interaction.

SIGNOR-278221

P15311

Q9P289

0

phosphorylation

up-regulates

0.2

Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. Mst4 phosphorylates the regulatory t567 residue of ezrin.

SIGNOR-185563

P43699

P07202

1

transcriptional regulation

up-regulates quantity by expression

0.379

TSH regulates TPO expression through the cAMP pathway and acts with thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8.

SIGNOR-267278

P60510

Q04206

1

dephosphorylation

up-regulates activity

0.361

Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation

SIGNOR-248549

Q9H1H9

Q68DK2

2

binding

up-regulates activity

0.415

We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B.

SIGNOR-265539

P38398

Q92878

2

binding

up-regulates

0.789

Brca1 interacts in vitro and in vivo with hrad50. Brca1 is important for the cellular responses to dna damage that are mediated by the hrad50-hmre11-p95 complex.

SIGNOR-69701

Q99933

O75807

1

null

down-regulates activity

0.444

Human BAG-1 proteins bind to the cellular stress response protein GADD34 and interfere with GADD34 functions.|BAG-1 negatively modulates GADD34-bound PP1 activity, and the expression of BAG-1 isoforms can also mask GADD34-mediated inhibition of colony formation and suppression of transcription. Our findings suggest that BAG-1 may function to suppress the GADD34-mediated cellular stress response and support a role for BAG-1 in the survival of cells undergoing stress.

SIGNOR-254117

Q7KZI7

P17612

0

phosphorylation

down-regulates activity

0.2

Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409.

SIGNOR-276870

P50148

P35368

2

binding

up-regulates activity

0.614

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-257079

P29371

P63092

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 ‚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-256794

Q9NYJ8

O43318

2

binding

up-regulates activity

0.936

Our results indicate that two distinct TAK1 complexes are present in cells. One comprises TAK1 complexed with TAB1 and TAB2, and the other TAK1 complexed with TAB1 and TAB3. Both complexes are activated in response to tumour necrosis factor-alpha or interleukin-1 in human epithelial KB cells or bacterial lipopolysaccharide in RAW264.7 macrophages

SIGNOR-120268

Q6IN85

P60510

2

binding

up-regulates

0.2

Our data demonstrate that pp4r4 forms a novel cytosolic complex with pp4c, independent from the complexes containing pp4r1, pp4r2.PP4R3, and alpha4, and that the regulatory subunits of pp4c have evolved different modes of interaction with the catalytic subunit.

SIGNOR-180244

P49841

P16220

1

phosphorylation

up-regulates activity

0.691

GSK-3 can phosphorylate CREB at S129 Transactivation of CREB is significantly reduced (p ≤ 0.05) by 86% for the S129A mutant

SIGNOR-251233

Q9Y385

Q13490

0

ubiquitination

down-regulates quantity by destabilization

0.37

We also found that ubiquitin-ligase (E3), c-IAP1 preferentially interacts with phosphorylated Ube2j1. Moreover, we noticed that phosphorylated Ube2j1 is rapidly degraded by the proteasome during ER stress cell recovery. Taken together, these data suggest that Ube2j1 and its phosphorylation is important for transient ER stress cell recovery and the phosphorylated Ube2j1 is degraded by the proteasome.

SIGNOR-263092

P16298

P0DP23

2

binding

up-regulates

0.696

Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.

SIGNOR-114101

P00533

P61925

1

phosphorylation

up-regulates

0.307

The difference in inhibitory potency between pki_ and pki_ has been attributed to the absence of a tyrosine residue (tyr7) in pki_ that is present in the nh2-terminal region of pki_. This suggests that the absence of a single amino acid residue can result in variations in how the catalytic subunit of camp-dependent protein kinase interacts with pki which ultimately can result in alterations in pki inhibitory potency.

SIGNOR-22455

C9JLW8

Q13363

2

binding

down-regulates activity

0.2

CtBP is recruited to promoter elements of target genes by interacting with the DNA-binding transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby competitively inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications.

SIGNOR-264776

P11488

Q99835

2

binding

up-regulates

0.262

Consistent with its predicted topology, smo couples to a specific family of inhibitory g protein (gis) to regulate hh signaling.

SIGNOR-148496

P51817

P98161

1

phosphorylation

up-regulates

0.257

The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd.

SIGNOR-158852

P46783

Q9UHC7

0

ubiquitination

up-regulates activity

0.2

We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1.Our data show that MKRN1 associates with polysomes and ubiquitylates RPS10, indicating a role in translational control. We hypothesize that ribosomes encountering the MKRN1-PABPC1 complex are stalled, possibly via ubiquitylation of RPS10 on K107 and other MKRN1 substrates.

SIGNOR-272216

P12830

O60716

2

binding

up-regulates quantity by stabilization

0.947

P120 regulates E-cadherin turnover at the cell membrane. Because direct binding of p120 to E-cadherin is required, it is possible that p120 binding blocks the interaction of an unknown binding partner (or event) that targets E-cadherin for degradation

SIGNOR-252123

P48730

P17252

0

phosphorylation

up-regulates activity

0.2

In the present study we analyzed the CK1δ kinase domain for phosphorylation sites targeted by PKCα. Several phosphorylation sites were identified in vitro by initially using GST-CK1δ wild type and phosphorylation-site mutant protein fragments originating from the CK1δ kinase domain. Residues S53, T176, and S181 could finally be confirmed as targets for PKCα. Determination of kinetic parameters of full-length wild type and mutant GST-CK1δ-mediated substrate phosphorylation revealed that integrity of residue T176 is crucial for maintaining CK1δ kinase activity.

SIGNOR-277452

O15294

P49841

0

phosphorylation

up-regulates activity

0.518

But OGT activity is modulated by GSK3beta (XREF_FIG) and GSK3beta activity is known to oscillate through Ser9 phoshorylation.|Here, we found that OGT is phosphorylated at serines 3 or 4 by GSK3beta and that O GlcNAcylation of OGT also occurs on the same or neighboring serine residues, suggesting interacting phosphorylation and O GlcNAcylation events on OGT itself.

SIGNOR-279528

Q9UER7

Q86Z02

0

phosphorylation

down-regulates activity

0.611

HIPK1 phosphorylates Daxx on Ser 669, and phosphorylation of this site is important in modulating the ability of Daxx to function as a transcriptional repressor. | Therefore, phosphorylation at Ser 669 by HIPK1 diminishes the ability of Daxx to repress transcription.

SIGNOR-260842

P78563

Q05513

0

phosphorylation

up-regulates activity

0.2

Here, we identified ADAR2 as a direct substrate of PKCζ in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCζ/ADAR2 axis regulates miR-200 secretion through RNA editing.

SIGNOR-277391