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
P23443	O60346	0	dephosphorylation	down-regulates activity	0.572	Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP.	SIGNOR-237454
P49589	P18848	0	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269416
Q00653	P62877	0	ubiquitination	up-regulates	0.281	Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase.	SIGNOR-120342
P31314	P62714	2	binding	down-regulates activity	0.301	HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade.	SIGNOR-240722
Q15633	Q9UBS0	0	phosphorylation	up-regulates activity	0.333	We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.	SIGNOR-274066
Q8WW43	P49810	2	binding	up-regulates	0.909	By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.	SIGNOR-93310
P00533	P17252	0	phosphorylation	down-regulates activity	0.609	Biochemical and morphological analyses indicate that threonine-phosphorylated EGFR molecules undergo normal internalization, but instead of sorting to lysosomal degradation, they recycle back to the cell surfaceThe inhibitory effects of pkc are mediated by a single threonine residue (threonine 654) of egfr	SIGNOR-77421
O95997	Q14674	2	binding	down-regulates activity	0.945	Prior to anaphase, separase is kept inactive by its inhibitor securin	SIGNOR-275538
P08754	P35372	2	binding	up-regulates activity	0.513	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-256854
P61011	Q07955	2	binding	up-regulates activity	0.299	We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65).	SIGNOR-261161
P48730	Q16665	1	phosphorylation	down-regulates	0.324	In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha	SIGNOR-167476
P49795	P28482	0	phosphorylation	up-regulates	0.474	Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation.	SIGNOR-129883
Q9ULK5	P35790	0	phosphorylation	down-regulates activity	0.2	CKI\u03b5-dependent phosphorylation increases Stbm turnover at junctions, and thus promotes complex sorting, while phosphorylation of Dsh decreases its turnover.\|Interestingly, CKI\u03b5 has been implicated in phosphorylation of both Stbm and Dsh.	SIGNOR-278925
Q6UB99	P51153	1	transcriptional regulation	up-regulates quantity by expression	0.2	Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.	SIGNOR-266738
Q9UNH5	P48200	1	dephosphorylation	up-regulates activity	0.348	IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis.	SIGNOR-248829
O75474	P49841	2	binding	down-regulates activity	0.695	The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation.	SIGNOR-244030
Q16204	Q969H0	2	binding	down-regulates	0.367	Fbxw7 interacts with and targets ccdc6 for ubiquitin-mediated proteasomal degradation	SIGNOR-199279
Q92985	P03206	2	binding	down-regulates activity	0.2	We have shown that Epstein-Barr virus (EBV) IE protein Zta (BZLF1) physically interacts with IRF7, inhibiting its ability to activate the IFN-α, IFN-β, and Tap2 promoters	SIGNOR-266643
O95388	P35222	0	transcriptional regulation	up-regulates quantity	0.2	This study identifies WISP-1 as a beta-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and beta-catenin expression.	SIGNOR-256270
Q5FBB7	O43683	0	phosphorylation	up-regulates quantity by stabilization	0.2	Bub1 phosphorylates Sgo1 in the vicinity of its APC/C degrons in vitro.\|On the other hand, Bub1 targets PP2A to centromeres, which in turn maintains Sgo1 at centromeres by counteracting Plk1 mediated chromosome removal of Sgo1.	SIGNOR-278915
Q12778	Q13153	0	phosphorylation	down-regulates activity	0.358	Pak1 efficiently phosphorylated GST-FKHR.	SIGNOR-279242
P21127	Q9Y2W1	1	phosphorylation	up-regulates activity	0.206	In addition, genetic knockout of CLK1 or chemical inhibition in mice ameliorated diet-induced obesity and insulin resistance at 22\u00b0C. Through proteomics, we uncovered thyroid hormone receptor-associated protein 3 (THRAP3) as an interacting partner of CLK1, further confirmed by co-immunoprecipitation assays.\|We further demonstrated that CLK1 phosphorylates THRAP3 at Ser243, which is required for its regulatory interaction with phosphorylated peroxisome proliferator-activated receptor gamma (PPAR\u03b3), resulting in impaired adipose tissue browning and insulin sensitivity.	SIGNOR-280209
P68400	Q16666	1	phosphorylation	up-regulates activity	0.321	Here we examine the functionality of the interferon-induced factor 16 (IFI 16) CcN motif, demonstrating its ability to target a heterologous protein to the nucleus, and to be phosphorylated specifically by the CcN-motif-phosphorylating protein kinase CK2 (CK2). \| Specific phosphorylation of IFI 16 Ser132 in HeLa cell extracts and by purified CK2 in vitro	SIGNOR-250902
O15379	O15105	2	binding	up-regulates	0.342	We show here that smad7 can form a complex with endogenous histone deacetylase proteins hdac-1 and hdac-3 in nih 3t3 mouse fibroblast cells	SIGNOR-199967
Q02156	P28329	1	phosphorylation	up-regulates	0.312	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation	SIGNOR-129312
Q9HBA0	O00141	0	phosphorylation	up-regulates activity	0.361	Recently, we identified that TRPV4 is also one of SGK1 substrate proteins (Fig. . , and the phosphorylation on serine 824 by SGK1 regulates the binding affinity to actin or tubulin [31].\|Therefore, we propose the hypothesis that the SGK1 phosphorylation may enhance TRPV4 channel density in the plasma membrane through the dissociation from STIM1, similar with the regulation mechanism of GLUT4 or AQP2 by insulin or vasopressin, respectively , ].	SIGNOR-279386
P27361	Q9HAV4	1	phosphorylation	down-regulates activity	0.312	Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.	SIGNOR-262985
P37231	Q14469	0	transcriptional regulation	down-regulates quantity by repression	0.248	CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo	SIGNOR-253584
P30679	P32239	2	binding	up-regulates activity	0.509	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-257412
P30304	Q13535	0	phosphorylation	down-regulates activity	0.643	ATR and CHK1 mediated loss of CDC25A activity suspends CDKs, such as CDK2, in an inactive phosphorylated state, blocking initiation of DNA replication origins.\|In the presence of replication stalling, activated CHK1 and ATR phosphorylates CDC25A and promotes its degradation.	SIGNOR-280183
O15234	O95271	0	ADP-ribosylation	down-regulates quantity by destabilization	0.2	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.	SIGNOR-263383
P38435	P04070	1	carboxylation	up-regulates activity	0.572	Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z	SIGNOR-265925
P50148	P34995	2	binding	up-regulates activity	0.449	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-257083
P58753	Q9NR96	2	binding	up-regulates activity	0.439	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266748
Q13535	P50549	1	phosphorylation	up-regulates quantity by stabilization	0.2	Collectively, the results described above indicate that ATR phosphorylates ETV1 and stabilizes it from proteolytic degradation.	SIGNOR-279355
P20265	P20265	2	binding	up-regulates activity	0.2	These experiments lead to the conclusion that the full-length Brn-2 protein can interact with full-length Brn-2. Assay of homodimerization properties of Brn-2 protein on the b2s1 dimer recognition sequence also demonstrated cooperativity, indicating that protein-protein contacts would be important for synergistic interactions between the Brn-2 subunits.	SIGNOR-221824
P61978	Q05655	0	phosphorylation	down-regulates	0.344	Ser302 is a major k protein site phosphorylated by pkcdelta in vitrothe ability of pkc_ to inducibly bind and phosphorylate k protein may serve not only to alter the activity of k protein itself, but k protein may also provide an avenue for pkc_ to engage in a cross-talk with other k protein molecular partners in response to specific changes in the extracellular environment	SIGNOR-67515
P05771	P04004	1	phosphorylation	up-regulates quantity by stabilization	0.303	Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.	SIGNOR-248963
Q7Z5H3	P63000	1	gtpase-activating protein	down-regulates activity	0.529	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-260477
Q13627	P55211	1	phosphorylation	down-regulates activity	0.388	Depletion of DYRK1A from human cells by short interfering RNA inhibits the basal phosphorylation of caspase 9 at an inhibitory site, Thr125. DYRK1A-dependent phosphorylation of Thr125 is also blocked by harmine, confirming the use of this beta-carboline alkaloid as a potent inhibitor of DYRK1A in cells.\|When co-expressed in cells, DYRK1A interacts with caspase 9, strongly induces Thr125 phosphorylation and inhibits caspase 9 auto-processing.	SIGNOR-279326
Q8TB45	P23443	0	phosphorylation	down-regulates	0.66	Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation.	SIGNOR-176866
Q9UI46	Q92949	0	transcriptional regulation	up-regulates quantity by expression	0.368	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266932
P15173	Q96NX9	0	transcriptional regulation	down-regulates quantity by repression	0.367	We confirmed Dach2 is a Mgn transcriptional repressor that mediates HDAC-dependent regulation by (i) overexpressing Dach2 in myotubes harboring the 133-bp Mgn promoter and (ii) rescuing TSA-mediated Mgn repression by Dach2 knockdown.	SIGNOR-261579
P45983	P28562	0	dephosphorylation	down-regulates	0.789	Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2.	SIGNOR-46079
Q9Y243	Q96ST2	1	phosphorylation	up-regulates activity	0.381	The data presented in this report confirmed the differential phosphorylation of IWS1 at Ser720/Thr721 by Akt3 and Akt1 and showed that its phosphorylation at this site is required for the recruitment of SetD2 to the Spt6-IWS1-Aly/REF complex.	SIGNOR-273496
Q6ZRV2	P49674	2	binding	up-regulates quantity	0.33	We identified members of the FAM83 family of proteins as partners of CK1 in cells. All eight members of the FAM83 family (FAM83A–H) interacted with the α and α-like isoforms of CK1; FAM83A, -B, -E, and -H also interacted with the δ and ε isoforms of CK1. The intrinsic catalytic activity of CK1 is not affected by or required for the association of CK1 with FAM83 proteins. Our findings imply that the DUF1669 domains of FAM83 proteins anchor CK1 α, α-like, δ, and ε isoforms in specific subcellular compartments and potentially mediate their association with substrates.	SIGNOR-273764
P04150	Q15788	1	transcriptional regulation	up-regulates quantity by expression	0.769	Transactivation of these templates depends on the association of the GR with co-activators such as SRC-1/NcoA1, GRIP-1/TIF-2/NcoA2 and p300/CBP.	SIGNOR-251682
P56545	Q9UNE7	0	ubiquitination	down-regulates quantity by destabilization	0.331	Our data showed that CHIP depletion resulted in up-regulation of the steady-state level of CtBP2 ( Fig. 1 B) and that CHIP ubiquitinated CtBP2 for proteasomal degradation ( Fig. 3 A).	SIGNOR-278722
P10636	O95155	0	ubiquitination	down-regulates quantity by destabilization	0.2	Ubiquitination and degradation of Tau by UBE4B and STUB1 in mammalian neuroblastoma cells.	SIGNOR-278682
P04637	P19525	0	phosphorylation	up-regulates	0.571	The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.	SIGNOR-68033
P09651	Q9UBS0	0	phosphorylation	up-regulates activity	0.416	Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export.	SIGNOR-279569
O15297	Q9H2X6	0	phosphorylation	down-regulates quantity by destabilization	0.419	HIPK2 phosphorylates WIP1 at Ser54 and Ser85, and phosphorylated WIP1 is subject to proteasomal degradation so that WIP1 is maintained at low levels.	SIGNOR-278230
P15514	P04626	1	phosphorylation	up-regulates	0.628	Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor	SIGNOR-31199
Q08345	P02452	2	binding	up-regulates activity	0.335	The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.\|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.	SIGNOR-272340
Q5TG30	P60953	1	gtpase-activating protein	down-regulates activity	0.41	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-260497
Q05655	Q96D96	1	phosphorylation	up-regulates activity	0.2	HVCN1S is phosphorylated more by PKC-δ than HVCN1L. PKC-δ in vitro kinase assay showing phosphorylation of HVCN1	SIGNOR-273827
O15151	Q93009	0	deubiquitination	up-regulates	0.757	Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins.	SIGNOR-139453
P63092	Q5NUL3	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 ‚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-256773
P02679	P45452	0	cleavage	down-regulates quantity by destabilization	0.2	Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII\| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.\|MMP-13 27YVATRDN g-chain\| 20ADSGEGD a-chain\| 124RNSVDXLNXN b-chain\| 442LRTGKEKV a-chain	SIGNOR-263614
O43524	Q96BR1	0	phosphorylation	down-regulates activity	0.435	Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)\|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.	SIGNOR-249135
P17612	P25098	1	phosphorylation	up-regulates activity	0.2	PKA directly phosphorylates GRK2 on serine 685. This modification increases G subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor.	SIGNOR-250334
P17844	Q13547	2	binding	up-regulates	0.393	Wt p68 co-immunoprecipitates efficiently with hdac1, the k53r p68 does not / sumoylation is important for the interaction of p68 with hdac1 and for transcriptional repression by p68	SIGNOR-153715
P00533	P07948	2	phosphorylation	up-regulates activity	0.586	EGFR phosphorylates p56 Lyn at Y32.\|In the presence of EGFR, p56 Lyn -mediated MCM7 phosphorylation was significantly augmented, suggesting that EGFR signaling potentiates p56 Lyn kinase activity for MCM7 phosphorylation.	SIGNOR-279369
Q12809	Q8N4C8	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
P04150	P48775	1	transcriptional regulation	down-regulates quantity by repression	0.337	Repression of GR-mediated expression of the tryptophan oxygenase gene by the SWI/SNF complex during liver development.	SIGNOR-268995
P19474	P49327	1	ubiquitination	down-regulates quantity by destabilization	0.2	FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels.	SIGNOR-267368
P68431	P51812	0	phosphorylation	down-regulates activity	0.2	Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.	SIGNOR-119229
P15927	Q13315	0	phosphorylation	up-regulates	0.809	Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro.	SIGNOR-121861
P04637	P51959	1	transcriptional regulation	up-regulates quantity by expression	0.791	Individual promoter and intron p53-binding motifs from the rat Cyclin G1 promoter region support transcriptional activation by p53 but do not show co-operative activation.	SIGNOR-268961
P40763	Q9UBE8	0	phosphorylation	up-regulates	0.347	Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna.	SIGNOR-155828
Q9H267	P18433	0	dephosphorylation	down-regulates activity	0.2	Here, we report that VPS33B, a host protein involved in vesicle trafficking, is dephosphorylated by PtpA leading to a block of phagosome maturation by M. tuberculosis.\|These data suggest that M. tuberculosis PtpA inhibits phagosome maturation.To assess the role of VPS33B in phagosome maturation, we attenuated the expression of endogenous VPS33B expression in THP-1 cells using a siRNA based approach.	SIGNOR-277015
Q9Y5I2	Q9Y5H3	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265704
P35222	P17252	0	phosphorylation	down-regulates	0.413	As shown in Fig. 1 B, PKCalpha readily phosphorylated Ser33 and Ser37 / Thr41 on full-length beta-catenin (beta-catenin 1 - 781) and CTD deletion mutant (beta-catenin 1-682).\|To examine the effect of the armadillo repeats 1-5 on PKCalpha mediated beta-catenin degradation, DNA constructs expressing beta-catenin 1 - 781 and beta-catenin deletion mutants (beta-catenin 1-422 and beta-catenin 1-138) were transfected into HEK293 cells, followed by treatment with increasing concentrations of A23187 and CGK062, which are known activators of PKCalpha.	SIGNOR-278492
P62714	O96017	1	dephosphorylation	up-regulates activity	0.309	Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells\|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation.	SIGNOR-248582
P23470	P23470	2	binding	down-regulates activity	0.2	The main regulatory mechanism of RPTP activity consists of the reversible transition from a homodimeric inactive form to a monomeric active form. PTPRG is constitutively expressed on monocyte plasma membrane as a homodimer with the WD involved in catalytic domain blockade.	SIGNOR-254737
Q9Y5H4	Q9Y5I2	2	binding	up-regulates activity	0.2	The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.	SIGNOR-265708
P42574	Q9UBF6	0	ubiquitination	down-regulates activity	0.2	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.	SIGNOR-271448
P12544	Q01105	1	cleavage	down-regulates	0.711	Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity.	SIGNOR-110462
P49758	P05106	2	binding	down-regulates	0.2	Numb binds to integrin-betas and localizes to clathrin-coated structures	SIGNOR-156762
Q96NR3	Q96QK1	2	binding	up-regulates quantity	0.2	Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus	SIGNOR-266653
P62993	Q92529	0	relocalization	up-regulates	0.819	In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation.	SIGNOR-146897
Q16539	Q16829	0	dephosphorylation	down-regulates	0.657	The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues	SIGNOR-166577
P31749	Q99490	1	phosphorylation	up-regulates	0.497	In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2.	SIGNOR-183543
P08100	P11488	2	binding	up-regulates activity	0.793	We report that his affected descendants carry a missense mutation in the gene encoding the a subunit of rod transducin — the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade.	SIGNOR-260007
Q9GZX6	Q969J5	2	binding	down-regulates	0.746	We identified a gene encoding a protein of 231 aa, showing 33 and 34% amino acid identity with the extracellular domains of the il-22 receptor and of the il-20r/cytokine receptor family 2-8,the recombinant protein was found to bind il-10-related t cell-derived inducible factor/il-22, and to inhibit the activity of this cytokine on hepatocytes and intestinal epithelial cells. We propose to name this natural cytokine antagonist il-22bp for il-22 binding protein. respectively, but lacking the transmembrane and cytoplasmic domains	SIGNOR-86110
P46459	Q00536	0	phosphorylation	down-regulates activity	0.439	Moreover, inhibition of Pctaire1 activity by transfecting its kinase-dead (KD) mutant into COS-7 cells enhances the self association of NSF.\|We demonstrate that the D2 domain of NSF, which is required for the oligomerization of NSF subunits, binds directly to and is phosphorylated by Pctaire1 on serine 569.	SIGNOR-279511
P42345	P53396	1	phosphorylation	up-regulates activity	0.332	Biochemical studies indicated that mTOR directly and specifically phosphorylated ACL on Ser 455 in vitro.	SIGNOR-278962
O14920	Q92905	1	phosphorylation	down-regulates activity	0.33	Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro.	SIGNOR-275519
P09471	P35346	2	binding	up-regulates activity	0.28	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-256969
P22681	P09619	1	polyubiquitination	down-regulates quantity by destabilization	0.629	Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as observed with PDGFRalpha.	SIGNOR-272549
Q05397	P08581	0	phosphorylation	up-regulates	0.497	Met-mediated fak phosphorylation could further activate fak. Indeed, we found that met phosphorylates fak at its known phosphorylation sites, including tyr-576 and tyr-577, both of which are located in the activating loop within the catalytic domain	SIGNOR-147199
P24941	Q15910	1	phosphorylation	up-regulates activity	0.547	Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1.	SIGNOR-255656
Q9NQB0	Q8WVD3	0	polyubiquitination	down-regulates quantity by destabilization	0.325	Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome.	SIGNOR-271593
P04798	P35869	0	transcriptional regulation	up-regulates quantity by expression	0.684	Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1.	SIGNOR-259909
P12956	Q16763	1	relocalization	up-regulates activity	0.347	As shown in Figure 4, we found that Ku70 (Figure 4b) and Ku80 (Figure 4c) co-immunoprecipitated with UBE2S.>Taken together, these results demonstrate that ETO enhances the UBE2S–Ku70 interaction, and UBE2S can be recruited to the same sites of DSBs with Ku70 upon ETO treatment.	SIGNOR-265079
Q13459	P63000	1	gtpase-activating protein	down-regulates activity	0.541	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-260510
O15169	O75581	0	relocalization	down-regulates activity	0.835	The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism.	SIGNOR-148668
P16885	P07948	0	phosphorylation	up-regulates activity	0.62	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249384
Q9HC98	O95235	1	phosphorylation	down-regulates activity	0.347	We show that Nek9, Nek6, and the kinesin Mklp2 form a signaling module, which is required for Mklp2 to localize to the central spindle in anaphase. Nek6 also phosphorylates Mklp2 at Ser244, inhibiting its bundling activity until anaphase onset.	SIGNOR-273891
O14647	Q13426	1	relocalization	up-regulates quantity	0.2	CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs.	SIGNOR-264528

P23443

O60346

0

dephosphorylation

down-regulates activity

0.572

Here we report the identification of ribosomal protein S6 kinase 1 (S6K1) as a novel substrate of PHLPP.

SIGNOR-237454

P49589

P18848

0

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269416

Q00653

P62877

0

ubiquitination

up-regulates

0.281

Mechanism of processing of the nf-kappa b2 p100 precursor: identification of the specific polyubiquitin chain-anchoring lysine residue and analysis of the role of nedd8-modification on the scf(beta-trcp) ubiquitin ligase.

SIGNOR-120342

P31314

P62714

2

binding

down-regulates activity

0.301

HOX11 also inhibited PP2A serine/threonine phosphatase activity concomitant with stimulation of the AKT/PKB signaling cascade.

SIGNOR-240722

Q15633

Q9UBS0

0

phosphorylation

up-regulates activity

0.333

We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells.

SIGNOR-274066

Q8WW43

P49810

2

binding

up-regulates

0.909

By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.

SIGNOR-93310

P00533

P17252

0

phosphorylation

down-regulates activity

0.609

Biochemical and morphological analyses indicate that threonine-phosphorylated EGFR molecules undergo normal internalization, but instead of sorting to lysosomal degradation, they recycle back to the cell surfaceThe inhibitory effects of pkc are mediated by a single threonine residue (threonine 654) of egfr

SIGNOR-77421

O95997

Q14674

2

binding

down-regulates activity

0.945

Prior to anaphase, separase is kept inactive by its inhibitor securin

SIGNOR-275538

P08754

P35372

2

binding

up-regulates activity

0.513

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-256854

P61011

Q07955

2

binding

up-regulates activity

0.299

We have now demonstrated that p54 interacts not only with SC35 and ASF/SF2 but also with U2AF. Pairwise interactions between p54 and other RS domain-containing spliceosomal proteins in comparison with SC35 and ASF/SF2 as detected by the yeast two-hybrid interaction assay. . It is conceivable that p54 can mediate 59 and 39 splice site interaction by interacting directly with U2AF65 associated with the 39 splice site and at the same time interact with other SR proteins, such as ASF/SF2 and SC35, which in turn interact with U1-70K. In this scenario, p54 is different from SC35 or ASF/SF2 in that it cannot directly interact with the 59 component (U1-70K) but can interact with the protein associated with the 39 splice site (U2AF65).

SIGNOR-261161

P48730

Q16665

1

phosphorylation

down-regulates

0.324

In this work, we investigate the phosphorylation of the n-terminal heterodimerization (pas) domain of hif-1alpha and identify ser247 as a major site of in vitro modification by casein kinase 1delta (ck1delta). Mutation of this site to alanine, surprisingly, enhanced the transcriptional activity of hif-1alpha

SIGNOR-167476

P49795

P28482

0

phosphorylation

up-regulates

0.474

Phosphorylation of gaip by erk2 were abrogated when serine at position 151 in the rgs domain was substituted by an alanine residue using site-directed mutagenesis. Furthermore, the lysosomal-autophagic pathway was not stimulated in s151a-gaip mutant-expressing cells when compared with wild-type gaip-expressing cells. These results demonstrate that the gtpase-activating protein activity of gaip is stimulated by erk2 phosphorylation.

SIGNOR-129883

Q9ULK5

P35790

0

phosphorylation

down-regulates activity

0.2

CKI\u03b5-dependent phosphorylation increases Stbm turnover at junctions, and thus promotes complex sorting, while phosphorylation of Dsh decreases its turnover.|Interestingly, CKI\u03b5 has been implicated in phosphorylation of both Stbm and Dsh.

SIGNOR-278925

Q6UB99

P51153

1

transcriptional regulation

up-regulates quantity by expression

0.2

Neurite growth-related genes such as Trkb, Bdnf, Gap43, Coronin 1B, and Rab13 are downregulated in ANKRD11-deficient neurons.

SIGNOR-266738

Q9UNH5

P48200

1

dephosphorylation

up-regulates activity

0.348

IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis.

SIGNOR-248829

O75474

P49841

2

binding

down-regulates activity

0.695

The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation.

SIGNOR-244030

Q16204

Q969H0

2

binding

down-regulates

0.367

Fbxw7 interacts with and targets ccdc6 for ubiquitin-mediated proteasomal degradation

SIGNOR-199279

Q92985

P03206

2

binding

down-regulates activity

0.2

We have shown that Epstein-Barr virus (EBV) IE protein Zta (BZLF1) physically interacts with IRF7, inhibiting its ability to activate the IFN-α, IFN-β, and Tap2 promoters

SIGNOR-266643

O95388

P35222

0

transcriptional regulation

up-regulates quantity

0.2

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

SIGNOR-256270

Q5FBB7

O43683

0

phosphorylation

up-regulates quantity by stabilization

0.2

Bub1 phosphorylates Sgo1 in the vicinity of its APC/C degrons in vitro.|On the other hand, Bub1 targets PP2A to centromeres, which in turn maintains Sgo1 at centromeres by counteracting Plk1 mediated chromosome removal of Sgo1.

SIGNOR-278915

Q12778

Q13153

0

phosphorylation

down-regulates activity

0.358

Pak1 efficiently phosphorylated GST-FKHR.

SIGNOR-279242

P21127

Q9Y2W1

1

phosphorylation

up-regulates activity

0.206

In addition, genetic knockout of CLK1 or chemical inhibition in mice ameliorated diet-induced obesity and insulin resistance at 22\u00b0C. Through proteomics, we uncovered thyroid hormone receptor-associated protein 3 (THRAP3) as an interacting partner of CLK1, further confirmed by co-immunoprecipitation assays.|We further demonstrated that CLK1 phosphorylates THRAP3 at Ser243, which is required for its regulatory interaction with phosphorylated peroxisome proliferator-activated receptor gamma (PPAR\u03b3), resulting in impaired adipose tissue browning and insulin sensitivity.

SIGNOR-280209

P68400

Q16666

1

phosphorylation

up-regulates activity

0.321

Here we examine the functionality of the interferon-induced factor 16 (IFI 16) CcN motif, demonstrating its ability to target a heterologous protein to the nucleus, and to be phosphorylated specifically by the CcN-motif-phosphorylating protein kinase CK2 (CK2). | Specific phosphorylation of IFI 16 Ser132 in HeLa cell extracts and by purified CK2 in vitro

SIGNOR-250902

O15379

O15105

2

binding

up-regulates

0.342

We show here that smad7 can form a complex with endogenous histone deacetylase proteins hdac-1 and hdac-3 in nih 3t3 mouse fibroblast cells

SIGNOR-199967

Q02156

P28329

1

phosphorylation

up-regulates

0.312

We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation

SIGNOR-129312

Q9HBA0

O00141

0

phosphorylation

up-regulates activity

0.361

Recently, we identified that TRPV4 is also one of SGK1 substrate proteins (Fig. . , and the phosphorylation on serine 824 by SGK1 regulates the binding affinity to actin or tubulin [31].|Therefore, we propose the hypothesis that the SGK1 phosphorylation may enhance TRPV4 channel density in the plasma membrane through the dissociation from STIM1, similar with the regulation mechanism of GLUT4 or AQP2 by insulin or vasopressin, respectively , ].

SIGNOR-279386

P27361

Q9HAV4

1

phosphorylation

down-regulates activity

0.312

Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading.

SIGNOR-262985

P37231

Q14469

0

transcriptional regulation

down-regulates quantity by repression

0.248

CREB inhibits hepatic PPAR-gamma expression in the fasted state by stimulating the expression of the Hairy Enhancer of Split (HES-1) gene, a transcriptional repressor that is shown here to be a mediator of fasting lipid metabolism in vivo

SIGNOR-253584

P30679

P32239

2

binding

up-regulates activity

0.509

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-257412

P30304

Q13535

0

phosphorylation

down-regulates activity

0.643

ATR and CHK1 mediated loss of CDC25A activity suspends CDKs, such as CDK2, in an inactive phosphorylated state, blocking initiation of DNA replication origins.|In the presence of replication stalling, activated CHK1 and ATR phosphorylates CDC25A and promotes its degradation.

SIGNOR-280183

O15234

O95271

0

ADP-ribosylation

down-regulates quantity by destabilization

0.2

Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.

SIGNOR-263383

P38435

P04070

1

carboxylation

up-regulates activity

0.572

Gamma-carboxylation is essential in the activation and proper functioning of multiple VK-dependent proteins (VKDP), the most well-known of which are involved in blood clotting, including coagulation factors (FII, FVII, FIX and FX) and natural anti-clotting agents (protein C, protein S (ProS; OMIM*176880) and protein Z

SIGNOR-265925

P50148

P34995

2

binding

up-regulates activity

0.449

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-257083

P58753

Q9NR96

2

binding

up-regulates activity

0.439

To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group

SIGNOR-266748

Q13535

P50549

1

phosphorylation

up-regulates quantity by stabilization

0.2

Collectively, the results described above indicate that ATR phosphorylates ETV1 and stabilizes it from proteolytic degradation.

SIGNOR-279355

P20265

2

binding

up-regulates activity

0.2

These experiments lead to the conclusion that the full-length Brn-2 protein can interact with full-length Brn-2. Assay of homodimerization properties of Brn-2 protein on the b2s1 dimer recognition sequence also demonstrated cooperativity, indicating that protein-protein contacts would be important for synergistic interactions between the Brn-2 subunits.

SIGNOR-221824

P61978

Q05655

0

phosphorylation

down-regulates

0.344

Ser302 is a major k protein site phosphorylated by pkcdelta in vitrothe ability of pkc_ to inducibly bind and phosphorylate k protein may serve not only to alter the activity of k protein itself, but k protein may also provide an avenue for pkc_ to engage in a cross-talk with other k protein molecular partners in response to specific changes in the extracellular environment

SIGNOR-67515

P05771

P04004

1

phosphorylation

up-regulates quantity by stabilization

0.303

Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.

SIGNOR-248963

Q7Z5H3

P63000

1

gtpase-activating protein

down-regulates activity

0.529

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-260477

Q13627

P55211

1

phosphorylation

down-regulates activity

0.388

Depletion of DYRK1A from human cells by short interfering RNA inhibits the basal phosphorylation of caspase 9 at an inhibitory site, Thr125. DYRK1A-dependent phosphorylation of Thr125 is also blocked by harmine, confirming the use of this beta-carboline alkaloid as a potent inhibitor of DYRK1A in cells.|When co-expressed in cells, DYRK1A interacts with caspase 9, strongly induces Thr125 phosphorylation and inhibits caspase 9 auto-processing.

SIGNOR-279326

Q8TB45

P23443

0

phosphorylation

down-regulates

0.66

Deptor is phosphorylated by s6k1 and rsk1 on the degron serine residues upon serum stimulation s6k1/rsk1 and _trcp are required for ubiquitination and degradation of endogenous deptor upon mitogen stimulation.

SIGNOR-176866

Q9UI46

Q92949

0

transcriptional regulation

up-regulates quantity by expression

0.368

FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).

SIGNOR-266932

P15173

Q96NX9

0

transcriptional regulation

down-regulates quantity by repression

0.367

We confirmed Dach2 is a Mgn transcriptional repressor that mediates HDAC-dependent regulation by (i) overexpressing Dach2 in myotubes harboring the 133-bp Mgn promoter and (ii) rescuing TSA-mediated Mgn repression by Dach2 knockdown.

SIGNOR-261579

P45983

P28562

0

dephosphorylation

down-regulates

0.789

Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2.

SIGNOR-46079

Q9Y243

Q96ST2

1

phosphorylation

up-regulates activity

0.381

The data presented in this report confirmed the differential phosphorylation of IWS1 at Ser720/Thr721 by Akt3 and Akt1 and showed that its phosphorylation at this site is required for the recruitment of SetD2 to the Spt6-IWS1-Aly/REF complex.

SIGNOR-273496

Q6ZRV2

P49674

2

binding

up-regulates quantity

0.33

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

SIGNOR-273764

P04150

Q15788

1

transcriptional regulation

up-regulates quantity by expression

0.769

Transactivation of these templates depends on the association of the GR with co-activators such as SRC-1/NcoA1, GRIP-1/TIF-2/NcoA2 and p300/CBP.

SIGNOR-251682

P56545

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.331

Our data showed that CHIP depletion resulted in up-regulation of the steady-state level of CtBP2 ( Fig. 1 B) and that CHIP ubiquitinated CtBP2 for proteasomal degradation ( Fig. 3 A).

SIGNOR-278722

P10636

O95155

0

ubiquitination

down-regulates quantity by destabilization

0.2

Ubiquitination and degradation of Tau by UBE4B and STUB1 in mammalian neuroblastoma cells.

SIGNOR-278682

P04637

P19525

0

phosphorylation

up-regulates

0.571

The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.

SIGNOR-68033

P09651

Q9UBS0

0

phosphorylation

up-regulates activity

0.416

Here, we show that S6K2 binds and phosphorylates hnRNPA1 on novel Ser4/6 sites, increasing its association with BCL-XL and XIAP mRNAs to promote their nuclear export.

SIGNOR-279569

O15297

Q9H2X6

0

phosphorylation

down-regulates quantity by destabilization

0.419

HIPK2 phosphorylates WIP1 at Ser54 and Ser85, and phosphorylated WIP1 is subject to proteasomal degradation so that WIP1 is maintained at low levels.

SIGNOR-278230

P15514

P04626

1

phosphorylation

up-regulates

0.628

Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor

SIGNOR-31199

Q08345

P02452

2

binding

up-regulates activity

0.335

The Discoidin Domain Receptors (DDRs) constitute a unique set of receptor tyrosine kinases that signal in response to collagen.|Consistent with this view128, we showed that ectopic expression of DDR1b or DDR2 in HT1080 cells elicited a potent growth inhibitory effect only when the cells were cultured on 2D or 3D COL1 matrices, in agreement with previous studies in melanoma48, breast cancer76,78, and lung cancer cells74,75.

SIGNOR-272340

Q5TG30

P60953

1

gtpase-activating protein

down-regulates activity

0.41

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-260497

Q05655

Q96D96

1

phosphorylation

up-regulates activity

0.2

HVCN1S is phosphorylated more by PKC-δ than HVCN1L. PKC-δ in vitro kinase assay showing phosphorylation of HVCN1

SIGNOR-273827

O15151

Q93009

0

deubiquitination

up-regulates

0.757

Subsequently, hausp was shown to deubiquitinate mdm2 and mdmx, thereby stabilizing these proteins.

SIGNOR-139453

P63092

Q5NUL3

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 ‚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-256773

P02679

P45452

0

cleavage

down-regulates quantity by destabilization

0.2

Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII| We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system.|MMP-13 27YVATRDN g-chain| 20ADSGEGD a-chain| 124RNSVDXLNXN b-chain| 442LRTGKEKV a-chain

SIGNOR-263614

O43524

Q96BR1

0

phosphorylation

down-regulates activity

0.435

Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a)|However, SGK and Akt display differences with respect to the efficacy with which they phosphorylate the three regulatory sites on FKHRL1. While both kinases can phosphorylate Thr-32, SGK displays a marked preference for Ser-315 whereas Akt favors Ser-253. These findings suggest that SGK and Akt may coordinately regulate the function of FKHRL1 by phosphorylating this transcription factor at distinct sites. The efficient phosphorylation of these three sites on FKHRL1 by SGK and Akt appears to be critical to the ability of growth factors to suppress FKHRL1-dependent transcription, thereby preventing FKHRL1 from inducing cell cycle arrest and apoptosis.

SIGNOR-249135

P17612

P25098

1

phosphorylation

up-regulates activity

0.2

PKA directly phosphorylates GRK2 on serine 685. This modification increases G subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor.

SIGNOR-250334

P17844

Q13547

2

binding

up-regulates

0.393

Wt p68 co-immunoprecipitates efficiently with hdac1, the k53r p68 does not / sumoylation is important for the interaction of p68 with hdac1 and for transcriptional repression by p68

SIGNOR-153715

P00533

P07948

2

phosphorylation

up-regulates activity

0.586

EGFR phosphorylates p56 Lyn at Y32.|In the presence of EGFR, p56 Lyn -mediated MCM7 phosphorylation was significantly augmented, suggesting that EGFR signaling potentiates p56 Lyn kinase activity for MCM7 phosphorylation.

SIGNOR-279369

Q12809

Q8N4C8

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

P04150

P48775

1

transcriptional regulation

down-regulates quantity by repression

0.337

Repression of GR-mediated expression of the tryptophan oxygenase gene by the SWI/SNF complex during liver development.

SIGNOR-268995

P19474

P49327

1

ubiquitination

down-regulates quantity by destabilization

0.2

FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels.

SIGNOR-267368

P68431

P51812

0

phosphorylation

down-regulates activity

0.2

Phosphorylation at ser-11 (h3s10ph) by rps6ka4 and rps6ka5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or uv irradiation and result in the activation of genes, such as c-fos and c-jun.

SIGNOR-119229

P15927

Q13315

0

phosphorylation

up-regulates

0.809

Replication protein a (rpa) is a single-stranded dna (ssdna) binding protein involved in various processes, including nucleotide excision repair and dna replication. The 32 kda subunit of rpa (rpa32) is phosphorylated in response to various dna-damaging agents, and two protein kinases, ataxia-telangiectasia mutated (atm) and the dna-dependent protein kinase (dna-pk) have been implicated in dna damage-induced phosphorylation of rpa32we show that both dna-pk and atm phosphorylate rpa32 on thr21 in vitro.

SIGNOR-121861

P04637

P51959

1

transcriptional regulation

up-regulates quantity by expression

0.791

Individual promoter and intron p53-binding motifs from the rat Cyclin G1 promoter region support transcriptional activation by p53 but do not show co-operative activation.

SIGNOR-268961

P40763

Q9UBE8

0

phosphorylation

up-regulates

0.347

Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna.

SIGNOR-155828

Q9H267

P18433

0

dephosphorylation

down-regulates activity

0.2

Here, we report that VPS33B, a host protein involved in vesicle trafficking, is dephosphorylated by PtpA leading to a block of phagosome maturation by M. tuberculosis.|These data suggest that M. tuberculosis PtpA inhibits phagosome maturation.To assess the role of VPS33B in phagosome maturation, we attenuated the expression of endogenous VPS33B expression in THP-1 cells using a siRNA based approach.

SIGNOR-277015

Q9Y5I2

Q9Y5H3

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265704

P35222

P17252

0

phosphorylation

down-regulates

0.413

As shown in Fig. 1 B, PKCalpha readily phosphorylated Ser33 and Ser37 / Thr41 on full-length beta-catenin (beta-catenin 1 - 781) and CTD deletion mutant (beta-catenin 1-682).|To examine the effect of the armadillo repeats 1-5 on PKCalpha mediated beta-catenin degradation, DNA constructs expressing beta-catenin 1 - 781 and beta-catenin deletion mutants (beta-catenin 1-422 and beta-catenin 1-138) were transfected into HEK293 cells, followed by treatment with increasing concentrations of A23187 and CGK062, which are known activators of PKCalpha.

SIGNOR-278492

P62714

O96017

1

dephosphorylation

up-regulates activity

0.309

Protein phosphatase 2A interacts with Chk2 and regulates phosphorylation at Thr-68 after cisplatin treatment of human ovarian cancer cells|In response to DNA damage, Chk2 is initially phosphorylated at Thr-68, which leads to its full activation.

SIGNOR-248582

P23470

2

binding

down-regulates activity

0.2

The main regulatory mechanism of RPTP activity consists of the reversible transition from a homodimeric inactive form to a monomeric active form. PTPRG is constitutively expressed on monocyte plasma membrane as a homodimer with the WD involved in catalytic domain blockade.

SIGNOR-254737

Q9Y5H4

Q9Y5I2

2

binding

up-regulates activity

0.2

The clustered protocadherins comprise the largest subfamily of the cadherin superfamily and are predominantly expressed in the nervous system. Pcdh-alpha proteins interact with beta1-integrin to promote cell adhesion. They also form oligomers with Pcdh-gamma proteins at the same membrane sites.

SIGNOR-265708

P42574

Q9UBF6

0

ubiquitination

down-regulates activity

0.2

SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.

SIGNOR-271448

P12544

Q01105

1

cleavage

down-regulates

0.711

Gzma cleaved the nucleosome assembly protein set after lys176 and disrupted its nucleosome assembly activity.

SIGNOR-110462

P49758

P05106

2

binding

down-regulates

0.2

Numb binds to integrin-betas and localizes to clathrin-coated structures

SIGNOR-156762

Q96NR3

Q96QK1

2

binding

up-regulates quantity

0.2

Using Western blotting, we validated our MS approach confirming the binding of Dgl4 (also known as PSD95) and VPS35 to the recombinant Ptchd1 C terminus. Endogenous DLG4 and VPS35 from membrane and soluble mouse brain fractions were recovered specifically on the GST fusion proteins containing the cytoplasmic but not the extracellular, negative control sequences of Ptchd1 (Fig. 5E). Binding of DLG4 was dependent on the PDZ-binding motif in Ptchd1, whereas VPS35 binding was not (Fig. 5E). These results demonstrate a biochemical interaction of Ptchd1 with postsynaptic trafficking proteins in the mouse brain. Together, these data suggest that loss of Ptchd1 results in severe alterations in synaptic function in the dentate gyrus

SIGNOR-266653

P62993

Q92529

0

relocalization

up-regulates

0.819

In addition to direct binding of grb2 to phosphotyrosine residues of receptor kinases, grb2 can also be recruited to the receptor by binding to shc when shc is tyrosine phosphorylated as a result of receptor stimulation.

SIGNOR-146897

Q16539

Q16829

0

dephosphorylation

down-regulates

0.657

The activity of mapks can be also regulated by a family of dusps, which dephosphorylates bot phosphotyrosine and phopsphothreonine residues

SIGNOR-166577

P31749

Q99490

1

phosphorylation

up-regulates

0.497

In addition, we have found that activated akt can bind and phosphorylate ggap2 at serine 629, which enhances gtp binding by ggap2.

SIGNOR-183543

P08100

P11488

2

binding

up-regulates activity

0.793

We report that his affected descendants carry a missense mutation in the gene encoding the a subunit of rod transducin — the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade.

SIGNOR-260007

Q9GZX6

Q969J5

2

binding

down-regulates

0.746

We identified a gene encoding a protein of 231 aa, showing 33 and 34% amino acid identity with the extracellular domains of the il-22 receptor and of the il-20r/cytokine receptor family 2-8,the recombinant protein was found to bind il-10-related t cell-derived inducible factor/il-22, and to inhibit the activity of this cytokine on hepatocytes and intestinal epithelial cells. We propose to name this natural cytokine antagonist il-22bp for il-22 binding protein. respectively, but lacking the transmembrane and cytoplasmic domains

SIGNOR-86110

P46459

Q00536

0

phosphorylation

down-regulates activity

0.439

Moreover, inhibition of Pctaire1 activity by transfecting its kinase-dead (KD) mutant into COS-7 cells enhances the self association of NSF.|We demonstrate that the D2 domain of NSF, which is required for the oligomerization of NSF subunits, binds directly to and is phosphorylated by Pctaire1 on serine 569.

SIGNOR-279511

P42345

P53396

1

phosphorylation

up-regulates activity

0.332

Biochemical studies indicated that mTOR directly and specifically phosphorylated ACL on Ser 455 in vitro.

SIGNOR-278962

O14920

Q92905

1

phosphorylation

down-regulates activity

0.33

Overexpression of IKKalpha or IKKbeta leads to enhanced phosphorylation of CSN5, the catalytic subunit for CSN deneddylase activity. Mutational analyses have revealed that phosphorylation at serine 201 and threonine 205 of CSN5 impairs CSN-mediated deneddylation activity in vitro.

SIGNOR-275519

P09471

P35346

2

binding

up-regulates activity

0.28

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-256969

P22681

P09619

1

polyubiquitination

down-regulates quantity by destabilization

0.629

Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as observed with PDGFRalpha.

SIGNOR-272549

Q05397

P08581

0

phosphorylation

up-regulates

0.497

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

SIGNOR-147199

P24941

Q15910

1

phosphorylation

up-regulates activity

0.547

Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ForkHead-associated domain of NIPP1.

SIGNOR-255656

Q9NQB0

Q8WVD3

0

polyubiquitination

down-regulates quantity by destabilization

0.325

Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome.

SIGNOR-271593

P04798

P35869

0

transcriptional regulation

up-regulates quantity by expression

0.684

Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1.

SIGNOR-259909

P12956

Q16763

1

relocalization

up-regulates activity

0.347

As shown in Figure 4, we found that Ku70 (Figure 4b) and Ku80 (Figure 4c) co-immunoprecipitated with UBE2S.>Taken together, these results demonstrate that ETO enhances the UBE2S–Ku70 interaction, and UBE2S can be recruited to the same sites of DSBs with Ku70 upon ETO treatment.

SIGNOR-265079

Q13459

P63000

1

gtpase-activating protein

down-regulates activity

0.541

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-260510

O15169

O75581

0

relocalization

down-regulates activity

0.835

The phosphorylation of lrp6 generates a docking site for axin and recruits it to the plasma membrane, where axin is inactivated and/or targeted for degradation by an unknown mechanism.

SIGNOR-148668

P16885

P07948

0

phosphorylation

up-regulates activity

0.62

The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.

SIGNOR-249384

Q9HC98

O95235

1

phosphorylation

down-regulates activity

0.347

We show that Nek9, Nek6, and the kinesin Mklp2 form a signaling module, which is required for Mklp2 to localize to the central spindle in anaphase. Nek6 also phosphorylates Mklp2 at Ser244, inhibiting its bundling activity until anaphase onset.

SIGNOR-273891

O14647

Q13426

1

relocalization

up-regulates quantity

0.2

CHD2 Promotes the Recruitment of Core NHEJ Factors. overexpression of ATPase-dead CHD2 (K515R; Figure S5F), but not wild-type CHD2, also reduced the recruitment of XRCC4 (Figure 5E). Together, these findings suggest that the chromatin remodeling activity of CHD2 promotes the efficient assembly of NHEJ complexes at DSBs.

SIGNOR-264528