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
P45985	Q7Z6J0	2	binding	up-regulates	0.31	We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2.	SIGNOR-96952
P35367	P38405	2	binding	up-regulates activity	0.2	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-256921
P09471	P47211	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-256966
Q9Y6K9	P78527	0	phosphorylation	down-regulates activity	0.296	Here, we show that DNA-dependent protein kinase (DNA-PK), an enzyme involved in DNA double-strand break (DSB) repair, triggers the phosphorylation of NEMO by genotoxic stress, thereby enabling shuttling of NEMO through the nucleus with subsequent NF-κB activation. We identified serine 43 of NEMO as a DNA-PK phosphorylation site and point mutation of this serine to alanine led to a complete block of NF-κB activation by ionizing radiation (IR).	SIGNOR-277508
O14777	P51955	0	phosphorylation	up-regulates	0.592	Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo.	SIGNOR-94322
P06241	P35613-2	1	phosphorylation	up-regulates activity	0.269	Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment.	SIGNOR-273999
P54257	O60282	2	binding	up-regulates activity	0.402	HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro	SIGNOR-264062
Q07817	O00198	2	binding	down-regulates	0.603	Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1.	SIGNOR-47797
O75553	P12931	0	phosphorylation	up-regulates activity	0.42	Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons.	SIGNOR-247080
Q9UKA9	P12931	1	post transcriptional regulation	down-regulates quantity by repression	0.285	Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). \|nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.	SIGNOR-261267
Q9BRK5	Q8IXL6	0	phosphorylation	up-regulates activity	0.2	Together, these results indicate that Fam20C kinase activity drives the sorting and secretion of the Cab45 dependent client LyzC.\|We show that Fam20C phosphorylates Cab45 on distinct residues and thereby decreases Cab45 retention in the TGN.	SIGNOR-279330
P34947	P37840	1	phosphorylation	down-regulates activity	0.636	Grk5 phosphorylated ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. Grk5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein.	SIGNOR-149372
P23258	Q8TDC3	0	phosphorylation	up-regulates	0.248	Sadb kinases associate and phosphorylate gamma-tubulin on ser 131 s131d gamma-tubulin expression amplifies centrosome duplication	SIGNOR-187405
Q15465	Q96QV1	2	binding	down-regulates activity	0.897	Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal.	SIGNOR-65078
P28221	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-257208
Q86TM6	P46527	1	ubiquitination	down-regulates quantity by destabilization	0.2	The E3 ligase activity of Hrd1 is required for p27 kip1 ubiquitination, because co-expression of Hrd1 containing an alanine point mutation at the critical cysteine within the RING E3 ligase region (Hrd1/CA) failed to enhance p27 kip1 ubiquitination (XREF_FIG).\|Therefore, our study identifies Hrd1 as an E3 ligase of p27 kip1 and establishes that Hrd1 mediated p27 kip1 degradation plays an important role in T-cell immunity.	SIGNOR-278786
Q08AM6	Q92562	2	binding	up-regulates quantity by stabilization	0.921	Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction.	SIGNOR-253534
P83916	P68431	2	binding	up-regulates activity	0.2	A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing.	SIGNOR-264493
P53350	Q9HAW4	1	phosphorylation	down-regulates	0.773	We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase	SIGNOR-148442
Q6UW88	P00533	2	binding	up-regulates	0.619	Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling.	SIGNOR-165779
Q9Y5X5	P09471	2	binding	up-regulates activity	0.272	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-256988
Q9H6Z9	P07550	1	hydroxylation	up-regulates quantity by stabilization	0.318	We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation.	SIGNOR-262007
P43405	Q9UHP3	1	phosphorylation	down-regulates quantity	0.385	Altogether, these data strengthen our results that SYK specifically phosphorylates USP25 and suggest that Y740 is the most probable phosphorylated tyrosine on USP25.We also assessed whether the SYK mediated phosphorylation of USP25 alters its protease activity.\|Preliminary data indicate that proteasome inhibition by MG132 treatment did not modify the SYK dependent decrease of USP25 levels in contrary to accumulation of USP25 protein by MG132 treatment in the absence of SYK overexpression.	SIGNOR-278458
P50458	P28360	2	binding	down-regulates activity	0.477	Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity	SIGNOR-241327
Q9UKA1	P48200	2	binding	down-regulates quantity by destabilization	0.746	We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus.	SIGNOR-271882
Q9Y6B2	O94952	2	binding	down-regulates quantity by destabilization	0.412	SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO)	SIGNOR-272429
P28336	Q03113	2	binding	up-regulates	0.282	These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways.	SIGNOR-107025
Q14393	O00712	0	transcriptional regulation	down-regulates quantity	0.2	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268882
Q8IUC6	O60603	2	binding	up-regulates activity	0.608	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-266746
P54646	Q8IYT8	0	phosphorylation	down-regulates	0.304	We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I	SIGNOR-173089
Q16539	Q92993	1	phosphorylation	up-regulates activity	0.321	We found that phosphorylation of Tip60-T158 was increased by p38\u03b1 isolated from Dox- or \u03b3-radiation-treated cells over that from untreated cells (Figure xref ), indicating that DNA damage induces the protein kinase activity of p38\u03b1 towards Tip60-T158.	SIGNOR-278958
P35222	Q5VWQ8	0	relocalization	down-regulates quantity	0.299	DAB2IP prevents β-catenin nuclear translocation.	SIGNOR-254755
P02708	O14904	2	binding	up-regulates	0.2	We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles.	SIGNOR-195972
Q14596	Q9GZQ8	2	binding	down-regulates	0.557	We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1.	SIGNOR-184252
O75496	O14965	0	phosphorylation	up-regulates activity	0.51	Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis.\|Thr25 of geminin is phosphorylated by Aurora-A.	SIGNOR-278509
P12931	P63244	1	phosphorylation	up-regulates	0.2	We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246	SIGNOR-94800
P36897	Q9H0M0	0	ubiquitination	down-regulates	0.533	Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7	SIGNOR-126581
P24752	P48163	1	acetylation	up-regulates activity	0.249	PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation.	SIGNOR-275571
P49790	Q92973	0	relocalization	up-regulates activity	0.499	TNPO1 only mediates the nuclear import of a subset of proteins.\|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import	SIGNOR-262100
Q8NG68	P68366	1	tyrosination	down-regulates	0.286	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176927
P61586	P12931	0	phosphorylation	down-regulates activity	0.668	When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.\|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity	SIGNOR-271701
Q15796	P28482	0	phosphorylation	up-regulates	0.722	We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity.	SIGNOR-91714
Q10571	Q9BQG0	2	binding	up-regulates activity	0.2	Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300.	SIGNOR-256021
P06239	P10747	1	phosphorylation	up-regulates	0.754	We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor	SIGNOR-45524
P50148	Q86VW2	2	binding	up-regulates activity	0.587	P63RhoGEF is autoinhibited by the Dbl homology (DH)-associated pleckstrin homology (PH) domain; activated Galpha(q) relieves this autoinhibition by interacting with a highly conserved C-terminal extension of the PH domain	SIGNOR-256493
Q86YJ5	P31994	1	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271541
P54646	Q8N122	1	phosphorylation	down-regulates activity	0.693	These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.\|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK	SIGNOR-163463
O43148	Q9BTL3	2	binding	up-regulates activity	0.2	Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM.	SIGNOR-268344
Q6PEY2	Q5SQI0	0	acetylation	up-regulates quantity by stabilization	0.267	Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.\|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules	SIGNOR-272248
P20333	Q9Y575	2	binding	down-regulates quantity by destabilization	0.397	While the ankyrin repeats of ASB3 interact with the C-terminal 37 amino acids of TNF-R2, the SOCS box of ASB3 is responsible for recruiting the E3 ubiquitin ligase adaptors Elongins-B/C, leading to TNF-R2 ubiquitination on multiple lysine residues within its C-terminal region. Downregulation of ASB3 expression by a small interfering RNA inhibited TNF-R2 degradation and potentiated TNF-R2-mediated cytotoxicity. The data presented here implicate ASB3 as a negative regulator of TNF-R2-mediated cellular responses to TNF-alpha by direct targeting of TNF-R2 for ubiquitination and proteasome-mediated degradation	SIGNOR-271546
Q13085	P17612	0	phosphorylation	down-regulates activity	0.2	TC1 = Ser-2Ser(P)-Met-3Ser(P)-Gly-Leu; TC2 = Arg-Met-1Ser(P)-Phe- Cyclic-AMP-dependent protein kinase phosphorylates sites 1 and 2 exclusively, whereas the AMP-activated protein kinase phosphorylates sites 1 and 3, plus at least one other minor site.[…]The results suggest that phosphorylation of site 3 is primarily responsible for the large decrease in Vmax produced by the AMP-activated protein kinase, while phosphorylation of site 1 may be primarily responsible for the increase in A0.5 for citrate and more modest depression of Vmax produced by cyclic-AMP-dependent protein kinase and ACK2	SIGNOR-267714
A1A4S6	P61586	1	gtpase-activating protein	down-regulates activity	0.668	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-260465
Q92985	Q9Y4K3	0	ubiquitination	up-regulates activity	0.732	We have shown that TRAF6 E3 ligase promotes IRF7 K63-linked ubiquitination that is required for EBV LMP1 activation of IRF7 [ xref ]; however, A20, a member with both E3 ligase and deubiquitinase activities in the OTU family, inhibits LMP1-stimulated IRF7 activity by acting as a deubiquitinase [ xref ].	SIGNOR-278788
P43119	P63092	2	binding	up-regulates activity	0.53	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-256806
Q9ULB1	P58417	2	binding	up-regulates	0.548	Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1	SIGNOR-62775
O43426	O96013	0	phosphorylation	up-regulates activity	0.2	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.	SIGNOR-263024
Q7Z6E9	Q8NAP3	1	ubiquitination	down-regulates quantity by destabilization	0.423	Thus, RBBP6 induces ZBTB38 protein degradation, and this depends on the activity of the proteasome.We next tested whether RBBP6 might directly ubiquitinate ZBTB38.\|We show that ZBTB38 is directly ubiquitinated by RBBP6 in human and mouse cells, in a process that is independent of p53 and MDM2, and leads to proteasomal degradation.	SIGNOR-278594
P60520	Q8IXH6	2	binding	up-regulates	0.602	Tp53inp2 binds to lc3 as well as to lc3-related proteins gabarap and gabarap-like2.	SIGNOR-182611
P09874	Q9P1Y6	0	ubiquitination	down-regulates quantity by destabilization	0.2	Furthermore, PHRF1 mediates PARP1 polyubiquitination for proteasomal degradation.	SIGNOR-278774
Q9Y4K3	O00635	0	polyubiquitination	down-regulates quantity by destabilization	0.43	As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6.	SIGNOR-272009
P56703	O75084	2	binding	up-regulates activity	0.743	These experiments suggest that activation of the Wnt/β-catenin pathway by Wnt3 is mediated in part through FZD7 in HCC cells.	SIGNOR-280437
P48729	P35222	1	phosphorylation	down-regulates	0.791	Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome	SIGNOR-165022
P45984	P50616	1	phosphorylation	down-regulates	0.34	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro.	SIGNOR-91067
P28336	P08949	2	binding	up-regulates	0.767	These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins.	SIGNOR-107022
Q9Y2X9	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.2	GSK-3beta phosphorylation-dependent degradation of ZNF281 by beta-TrCP2 suppresses colorectal cancer progression\|	SIGNOR-264890
P38405	P29274	2	binding	up-regulates activity	0.315	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-256909
Q15796	P29590	2	binding	up-regulates activity	0.549	Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome.	SIGNOR-128738
P15884	P30874	1	transcriptional regulation	up-regulates quantity by expression	0.358	Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain.	SIGNOR-261618
P42224	P14316	2	binding	up-regulates activity	0.547	We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2.	SIGNOR-254532
P49841	P98170	1	phosphorylation	up-regulates activity	0.394	We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAPT180A) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in Xenopus embryos.	SIGNOR-277390
P84022	P26367	2	binding	down-regulates activity	0.399	The paired domain of Pax6 interacts with the MH1 domain of Smad3. Smad3 prevents Pax6 paired domain from binding DNA	SIGNOR-251875
Q13627	P16220	1	phosphorylation	up-regulates activity	0.487	Regarding to the functional role of Dyrk1A, active Dyrk1A phosphorylates the transcription factor cAMP response element -binding protein (CREB), which subsequently leads to the stimulation of cAMP response element-mediated gene transcription during neuronal differentiation ( ).	SIGNOR-279989
P28324	Q9Y5U4	1	transcriptional regulation	up-regulates quantity by expression	0.2	Under these conditions, a significant reduction in INSIG2 expression was only observed when SAP1a siRNA was used. These observations provide supporting evidence that SAP1a may be one of the transactivators of the human INSIG2 promoter.	SIGNOR-261592
Q13315	P49959	2	phosphorylation	up-regulates	0.2	In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage.	SIGNOR-73366
P03956	O00755	0	transcriptional regulation	up-regulates quantity by expression	0.261	Because MMP1 is also another direct target of the canonical Wnt pathway (22), Wnt7a overexpression upregulated MMP1/10 to degrade the extracellular matrix and to facilitate UBC cell invasion.	SIGNOR-278868
P03372	Q92731	2	binding	up-regulates	0.527	It was recently shown that er? And er? Could form a heterodimer complex both in vitro and in vivo	SIGNOR-64427
P17612	P16220	1	phosphorylation	up-regulates activity	0.581	Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression.	SIGNOR-131307
P30291	Q13153	0	phosphorylation	down-regulates	0.299	Kinases targeted sequentially to the neck, cla4/pak and cdc5/polo, are responsible for stepwise phosphorylation and down-regulation of swe1.	SIGNOR-123528
P35398	Q99743	1	transcriptional regulation	up-regulates quantity by expression	0.665	Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267980
P61204	Q9Y6D6	0	guanine nucleotide exchange factor	up-regulates activity	0.366	Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) is an approximately 200-kDa brefeldin A-inhibited guanine nucleotide-exchange protein that preferentially activates ADP-ribosylation factor 1 (ARF1) and ARF3.	SIGNOR-272148
P18146	P10645	1	transcriptional regulation	up-regulates quantity by expression	0.2	Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.	SIGNOR-254265
Q92945	Q9UKA9	2	binding	up-regulates activity	0.463	Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). \|nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.	SIGNOR-261268
Q13546	Q13546	2	phosphorylation	up-regulates activity	0.2	These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1)	SIGNOR-276159
Q09472	P12755	2	binding	down-regulates	0.2	Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling.	SIGNOR-72664
Q96SB4	Q07955	1	phosphorylation	up-regulates	0.799	These results suggest that the formation of complexes between sf2/asf and srpks, which is influenced by the phosphorylation state of sf2/asf, may have regulatory roles in the assembly and localization of this splicing factor.	SIGNOR-66465
Q99638	Q92547	2	binding	up-regulates	0.826	The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner	SIGNOR-179382
P07948	Q13568	1	phosphorylation	down-regulates activity	0.329	Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity.	SIGNOR-277247
P63000	Q96N67	0	guanine nucleotide exchange factor	up-regulates activity	0.545	As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover.	SIGNOR-261887
P33981	O96017	2	phosphorylation	up-regulates	0.292	Ttk/hmps1 directly phosphorylates chk2 on thr-68 in vitro.ablation of ttk expression using small interfering rna results not only in reduced chk2 thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which ttk functions upstream from chk2 in response to dna damage	SIGNOR-132665
P48431	O95071	0	polyubiquitination	down-regulates quantity by destabilization	0.256	We identified UBR5 as a major ubiquitin E3 ligase that induces SOX2 degradation through ubiquitinating SOX2 at lysine 115.	SIGNOR-277446
P28482	Q9NZV8	1	phosphorylation	up-regulates activity	0.367	We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP.	SIGNOR-262935
P49841	Q9NP62	1	phosphorylation	down-regulates quantity by destabilization	0.2	We demonstrated that GSK-3beta mediates phosphorylation of GCM1 on Ser322, which is recognized by the F-box protein, FBW2, to promote GCM1 ubiquitination and degradation.	SIGNOR-278940
Q06124	P31260	1	dephosphorylation	up-regulates	0.373	We also identified hoxa10 as a substrate for shp2 in undifferentiated myeloid cells, an effect that diminished during myelopoiesis. However, a constitutively active form of shp2 dephosphorylated hoxa10 throughout ex vivo myelopoiesis and sustained repression of hoxa10 target genes involved in phagocyte effector functions.	SIGNOR-182475
Q8WZ73	Q6MZQ0	1	polyubiquitination	down-regulates quantity by destabilization	0.261	RFFL is an E3 ligase for PRR5L.	SIGNOR-271495
P38936	O15119	0	transcriptional regulation	down-regulates quantity by repression	0.304	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249602
Q14807	P06493	0	phosphorylation	up-regulates activity	0.344	Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes	SIGNOR-100964
P17252	Q9H3Q1	1	phosphorylation	down-regulates activity	0.2	Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes).	SIGNOR-263160
P13349	P23759	0	transcriptional regulation	up-regulates quantity by expression	0.492	Together, these experiments indicate that Pax7 enforces satellite cell commitment by recruiting a HMT complex to Myf5, resulting in transcriptional activation.	SIGNOR-255641
P04637	Q9H0A0	0	acetylation	up-regulates quantity by stabilization	0.337	NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.	SIGNOR-272406
O15247	Q7Z570	0	transcriptional regulation	down-regulates quantity by repression	0.2	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3).	SIGNOR-269465

P45985

Q7Z6J0

2

binding

up-regulates

0.31

We confirmed that posh binds activated rac1 and find that it also binds all mlk family members tested and interacts with mkk4/7 as well as jnk1 and jnk2.

SIGNOR-96952

P35367

P38405

2

binding

up-regulates activity

0.2

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

SIGNOR-256921

P09471

P47211

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-256966

Q9Y6K9

P78527

0

phosphorylation

down-regulates activity

0.296

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

SIGNOR-277508

O14777

P51955

0

phosphorylation

up-regulates

0.592

Phosphorylation of the mitotic regulator protein hec1 by nek2 kinase is essential for faithful chromosome segregation.Hec1 (highly expressed in cancer) plays essential roles in chromosome segregation by interacting through its coiled-coil domains with several proteins that modulate the g(2)/m phase.Nek2 phosphorylates hec1 on serine residue 165, both in vitro and in vivo.

SIGNOR-94322

P06241

P35613-2

1

phosphorylation

up-regulates activity

0.269

Our findings demonstrated that Fyn directly phosphorylates CD147 at Y140 and Y183. Moreover, the CD147-FF (Y140F/Y183F) mutation impaired the interaction between CD147 and GnT-V, leading to decreased CD147 glycosylation and membrane recruitment.

SIGNOR-273999

P54257

O60282

2

binding

up-regulates activity

0.402

HAP1 and GRIP1 are kinesin-1 adaptors that have been implicated individually in the transport of vesicular cargoes in the dendrites of neurons. We find that HAP1a and GRIP1 form a protein complex in the brain, and co-operate to activate the kinesin-1 subunit KIF5C in vitro

SIGNOR-264062

Q07817

O00198

2

binding

down-regulates

0.603

Hrk, physically interacts with the death-repressor proteins bcl2 and bcl2l1. Hrk activates cell death at least in part by interacting with and inhibiting the protection afforded by bcl2 and bcl2l1.

SIGNOR-47797

O75553

P12931

0

phosphorylation

up-regulates activity

0.42

Dab1 is rapidly phosphorylated when neurons isolated from embryonic brains are stimulated with Reelin, and several tyrosines have been implicated in this response. Mice with phenylalanine substitutions of all five tyrosines (Tyr(185), Tyr(198), Tyr(200), Tyr(220), and Tyr(232)) exhibit a reeler phenotype, implying that tyrosine phosphorylation is critical for Dab1 function. Here we report that, although Src can phosphorylate all five tyrosines in vitro, Tyr(198) and Tyr(220) represent the major sites of Reelin-induced Dab1 phosphorylation in embryonic neurons.

SIGNOR-247080

Q9UKA9

P12931

1

post transcriptional regulation

down-regulates quantity by repression

0.285

Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.

SIGNOR-261267

Q9BRK5

Q8IXL6

0

phosphorylation

up-regulates activity

0.2

Together, these results indicate that Fam20C kinase activity drives the sorting and secretion of the Cab45 dependent client LyzC.|We show that Fam20C phosphorylates Cab45 on distinct residues and thereby decreases Cab45 retention in the TGN.

SIGNOR-279330

P34947

P37840

1

phosphorylation

down-regulates activity

0.636

Grk5 phosphorylated ser-129 of alpha-synuclein at the plasma membrane and induced translocation of phosphorylated alpha-synuclein to the perikaryal area. Grk5-catalyzed phosphorylation also promoted the formation of soluble oligomers and aggregates of alpha-synuclein.

SIGNOR-149372

P23258

Q8TDC3

0

phosphorylation

up-regulates

0.248

Sadb kinases associate and phosphorylate gamma-tubulin on ser 131 s131d gamma-tubulin expression amplifies centrosome duplication

SIGNOR-187405

Q15465

Q96QV1

2

binding

down-regulates activity

0.897

Hip encodes a membrane glycoprotein that binds to all three mammalian hedgehog proteins with an affinity comparable to that of ptc-1. our findings support a model in which hip attenuates hedgehog signalling as a result of binding to hedgehog proteins: a negative regulatory feedback loop established in this way could thus modulate the responses to any hedgehog signal.

SIGNOR-65078

P28221

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-257208

Q86TM6

P46527

1

ubiquitination

down-regulates quantity by destabilization

0.2

The E3 ligase activity of Hrd1 is required for p27 kip1 ubiquitination, because co-expression of Hrd1 containing an alanine point mutation at the critical cysteine within the RING E3 ligase region (Hrd1/CA) failed to enhance p27 kip1 ubiquitination (XREF_FIG).|Therefore, our study identifies Hrd1 as an E3 ligase of p27 kip1 and establishes that Hrd1 mediated p27 kip1 degradation plays an important role in T-cell immunity.

SIGNOR-278786

Q08AM6

Q92562

2

binding

up-regulates quantity by stabilization

0.921

Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction.

SIGNOR-253534

P83916

P68431

2

binding

up-regulates activity

0.2

A core characteristic of heterochromatin is its association with heterochromatin protein 1 (HP1) proteins, a highly conserved family of chromosomal proteins that bind to di- and trimethylated H3K9 via a conserved N-terminal domain called the chromodomain (CD) HP1 proteins are a highly conserved family of eukaryotic proteins that bind to methylated histone H3 lysine 9 (H3K9) and are required for heterochromatic gene silencing.

SIGNOR-264493

P53350

Q9HAW4

1

phosphorylation

down-regulates

0.773

We show that claspin, an adaptor protein required for chk1 activation, becomes degraded at the onset of mitosis. Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbtrcp ubiquitin ligase. This interaction was phosphorylation dependent and required the activity of the plk1 kinase

SIGNOR-148442

Q6UW88

P00533

2

binding

up-regulates

0.619

Remarkably, three members of the epidermal growth factor (egf) family (ereg, areg, and epgn) showed increased expression that was associated with elevated epidermal activation of the egf receptor (egfr) and stat3, a downstream effector of egfr signaling.

SIGNOR-165779

Q9Y5X5

P09471

2

binding

up-regulates activity

0.272

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-256988

Q9H6Z9

P07550

1

hydroxylation

up-regulates quantity by stabilization

0.318

We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation.

SIGNOR-262007

P43405

Q9UHP3

1

phosphorylation

down-regulates quantity

0.385

Altogether, these data strengthen our results that SYK specifically phosphorylates USP25 and suggest that Y740 is the most probable phosphorylated tyrosine on USP25.We also assessed whether the SYK mediated phosphorylation of USP25 alters its protease activity.|Preliminary data indicate that proteasome inhibition by MG132 treatment did not modify the SYK dependent decrease of USP25 levels in contrary to accumulation of USP25 protein by MG132 treatment in the absence of SYK overexpression.

SIGNOR-278458

P50458

P28360

2

binding

down-regulates activity

0.477

Protein complex formation between Msx1 and Lhx2 homeoproteins is incompatible with DNA binding activity

SIGNOR-241327

Q9UKA1

P48200

2

binding

down-regulates quantity by destabilization

0.746

We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus.

SIGNOR-271882

Q9Y6B2

O94952

2

binding

down-regulates quantity by destabilization

0.412

SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO)

SIGNOR-272429

P28336

Q03113

2

binding

up-regulates

0.282

These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins. Studies with human small cell lung cancer (sclc) cells support a requirement for balanced signaling through g(q) and g(12/13) proteins leading to intracellular ca2+ mobilization, pkc activation and regulation of the erk and jnk map kinase pathways.

SIGNOR-107025

Q14393

O00712

0

transcriptional regulation

down-regulates quantity

0.2

By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development

SIGNOR-268882

Q8IUC6

O60603

2

binding

up-regulates activity

0.608

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-266746

P54646

Q8IYT8

0

phosphorylation

down-regulates

0.304

We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I

SIGNOR-173089

Q16539

Q92993

1

phosphorylation

up-regulates activity

0.321

We found that phosphorylation of Tip60-T158 was increased by p38\u03b1 isolated from Dox- or \u03b3-radiation-treated cells over that from untreated cells (Figure xref ), indicating that DNA damage induces the protein kinase activity of p38\u03b1 towards Tip60-T158.

SIGNOR-278958

P35222

Q5VWQ8

0

relocalization

down-regulates quantity

0.299

DAB2IP prevents β-catenin nuclear translocation.

SIGNOR-254755

P02708

O14904

2

binding

up-regulates

0.2

We identified five wnts (wnt9a, wnt9b, wnt10b, wnt11, and wnt16) that are able to stimulate achr clustering, of which wnt9a and wnt11 are expressed abundantly in developing muscles.

SIGNOR-195972

Q14596

Q9GZQ8

2

binding

down-regulates

0.557

We performed glutathione s-transferase (gst) pull-down assays using extracts from hek293 cells overexpressing an ha-tagged nbr1(d50r) mutant, which lacks the ability to bind p62 (lamark et al., 2003) (figures s1a and s1b, available online), and gst fusions of six human atg8 homologs: gabarap, gabarapl1, gabarapl2, lc3a, lc3b, and lc3c. Indeed, nbr1 interacted with all these members of the mammalian atg8 protein family. downregulation of either lc3 or gabarap (or both) family members leads to stabilization and p62-dependent aggregation of nbr1.

SIGNOR-184252

O75496

O14965

0

phosphorylation

up-regulates activity

0.51

Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis.|Thr25 of geminin is phosphorylated by Aurora-A.

SIGNOR-278509

P12931

P63244

1

phosphorylation

up-regulates

0.2

We found that rack1 is a src substrate. Moreover, src activity is necessary for both the tyrosine phosphorylation of rack1 and the binding of rack1 to src's sh2 domain that occur following pkc activation. To identify the tyrosine(s) on rack1 that is phosphorylated by src, we generated and tested a series of rack1 mutants. We found that src phosphorylates rack1 on tyr 228 and/or tyr 246

SIGNOR-94800

P36897

Q9H0M0

0

ubiquitination

down-regulates

0.533

Similar to smurfs, wwp1 associated with smad7 and induced its nuclear export, and enhanced binding of smad7 to tgf-beta type i receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, wwp1 inhibited phosphorylation of smad2 induced by tgf-beta. Wwp1 thus negatively regulates tgf-beta signaling in cooperation with smad7

SIGNOR-126581

P24752

P48163

1

acetylation

up-regulates activity

0.249

PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation.

SIGNOR-275571

P49790

Q92973

0

relocalization

up-regulates activity

0.499

TNPO1 only mediates the nuclear import of a subset of proteins.|Among TNPO1 cargos, the most extensively characterized is the RNA binding protein heterogeneous nuclear ribonucleoprotein 1 (hnRNPA1) (27), which functions in several processes including mRNA biogenesis and promotion of transcription factor activity (28–30). NPC protein NUP153 is also a target for TNPO1-mediated nuclear import

SIGNOR-262100

Q8NG68

P68366

1

tyrosination

down-regulates

0.286

Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization

SIGNOR-176927

P61586

P12931

0

phosphorylation

down-regulates activity

0.668

When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity

SIGNOR-271701

Q15796

P28482

0

phosphorylation

up-regulates

0.722

We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity.

SIGNOR-91714

Q10571

Q9BQG0

2

binding

up-regulates activity

0.2

Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300.

SIGNOR-256021

P06239

P10747

1

phosphorylation

up-regulates

0.754

We demonstrate that emt can phosphorylate all four tyrosines of the cd28 tail, in contrast to lck, which phosphorylates only tyrosine 173. Together with evidence that in vivo, tyrosines other than tyrosine 173 become phosphorylated following cd28 stimulation, this finding suggests that, like lck, one function of emt during cd28 signaling is phosphorylation of the receptor

SIGNOR-45524

P50148

Q86VW2

2

binding

up-regulates activity

0.587

P63RhoGEF is autoinhibited by the Dbl homology (DH)-associated pleckstrin homology (PH) domain; activated Galpha(q) relieves this autoinhibition by interacting with a highly conserved C-terminal extension of the PH domain

SIGNOR-256493

Q86YJ5

P31994

1

ubiquitination

down-regulates quantity by destabilization

0.2

MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.

SIGNOR-271541

P54646

Q8N122

1

phosphorylation

down-regulates activity

0.693

These results suggest that AMPK activation can induce phosphorylation of both serine 722 and serine 792.|Raptor phosphorylation is required for inhibition of mTORC1 by AMPK

SIGNOR-163463

O43148

Q9BTL3

2

binding

up-regulates activity

0.2

Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM.

SIGNOR-268344

Q6PEY2

Q5SQI0

0

acetylation

up-regulates quantity by stabilization

0.267

Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules

SIGNOR-272248

P20333

Q9Y575

2

binding

down-regulates quantity by destabilization

0.397

While the ankyrin repeats of ASB3 interact with the C-terminal 37 amino acids of TNF-R2, the SOCS box of ASB3 is responsible for recruiting the E3 ubiquitin ligase adaptors Elongins-B/C, leading to TNF-R2 ubiquitination on multiple lysine residues within its C-terminal region. Downregulation of ASB3 expression by a small interfering RNA inhibited TNF-R2 degradation and potentiated TNF-R2-mediated cytotoxicity. The data presented here implicate ASB3 as a negative regulator of TNF-R2-mediated cellular responses to TNF-alpha by direct targeting of TNF-R2 for ubiquitination and proteasome-mediated degradation

SIGNOR-271546

Q13085

P17612

0

phosphorylation

down-regulates activity

0.2

TC1 = Ser-2Ser(P)-Met-3Ser(P)-Gly-Leu; TC2 = Arg-Met-1Ser(P)-Phe- Cyclic-AMP-dependent protein kinase phosphorylates sites 1 and 2 exclusively, whereas the AMP-activated protein kinase phosphorylates sites 1 and 3, plus at least one other minor site.[…]The results suggest that phosphorylation of site 3 is primarily responsible for the large decrease in Vmax produced by the AMP-activated protein kinase, while phosphorylation of site 1 may be primarily responsible for the increase in A0.5 for citrate and more modest depression of Vmax produced by cyclic-AMP-dependent protein kinase and ACK2

SIGNOR-267714

A1A4S6

P61586

1

gtpase-activating protein

down-regulates activity

0.668

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-260465

Q92985

Q9Y4K3

0

ubiquitination

up-regulates activity

0.732

We have shown that TRAF6 E3 ligase promotes IRF7 K63-linked ubiquitination that is required for EBV LMP1 activation of IRF7 [ xref ]; however, A20, a member with both E3 ligase and deubiquitinase activities in the OTU family, inhibits LMP1-stimulated IRF7 activity by acting as a deubiquitinase [ xref ].

SIGNOR-278788

P43119

P63092

2

binding

up-regulates activity

0.53

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-256806

Q9ULB1

P58417

2

binding

up-regulates

0.548

Purification of neurexin ialpha revealed that it is tightly complexed to a secreted glycoprotein called neurexophilin 1

SIGNOR-62775

O43426

O96013

0

phosphorylation

up-regulates activity

0.2

We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.

SIGNOR-263024

Q7Z6E9

Q8NAP3

1

ubiquitination

down-regulates quantity by destabilization

0.423

Thus, RBBP6 induces ZBTB38 protein degradation, and this depends on the activity of the proteasome.We next tested whether RBBP6 might directly ubiquitinate ZBTB38.|We show that ZBTB38 is directly ubiquitinated by RBBP6 in human and mouse cells, in a process that is independent of p53 and MDM2, and leads to proteasomal degradation.

SIGNOR-278594

P60520

Q8IXH6

2

binding

up-regulates

0.602

Tp53inp2 binds to lc3 as well as to lc3-related proteins gabarap and gabarap-like2.

SIGNOR-182611

P09874

Q9P1Y6

0

ubiquitination

down-regulates quantity by destabilization

0.2

Furthermore, PHRF1 mediates PARP1 polyubiquitination for proteasomal degradation.

SIGNOR-278774

Q9Y4K3

O00635

0

polyubiquitination

down-regulates quantity by destabilization

0.43

As an E3 ligase, TRIM38 bound to TRAF6 and promoted K48-linked polyubiquitination, which led to the proteasomal degradation of TRAF6.

SIGNOR-272009

P56703

O75084

2

binding

up-regulates activity

0.743

These experiments suggest that activation of the Wnt/β-catenin pathway by Wnt3 is mediated in part through FZD7 in HCC cells.

SIGNOR-280437

P48729

P35222

1

phosphorylation

down-regulates

0.791

Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome

SIGNOR-165022

P45984

P50616

1

phosphorylation

down-regulates

0.34

Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro.

SIGNOR-91067

P28336

P08949

2

binding

up-regulates

0.767

These neuropeptides, including gastrin-releasing peptide, neuromedin b, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric g proteins.

SIGNOR-107022

Q9Y2X9

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

GSK-3beta phosphorylation-dependent degradation of ZNF281 by beta-TrCP2 suppresses colorectal cancer progression|

SIGNOR-264890

P38405

P29274

2

binding

up-regulates activity

0.315

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-256909

Q15796

P29590

2

binding

up-regulates activity

0.549

Cytoplasmic pml physically interacts with smad2/3 and sara (smad anchor for receptor activation) and is required for association of smad2/3 with sara and for the accumulation of sara and tgf-beta receptor in the early endosome.

SIGNOR-128738

P15884

P30874

1

transcriptional regulation

up-regulates quantity by expression

0.358

Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain.

SIGNOR-261618

P42224

P14316

2

binding

up-regulates activity

0.547

We show that IRF-2 forms a complex with STAT1 and the cytokine-responsive region of the TAP1 promoter in any TPO or IFN-gamma target cells tested. Interaction of IRF-2 and STAT1 on the promoter depends on the DNA-binding domain of IRF-2.

SIGNOR-254532

P49841

P98170

1

phosphorylation

up-regulates activity

0.394

We now demonstrate that XIAP is phosphorylated by GSK3 at threonine 180, and that an alanine mutant (XIAPT180A) exhibits decreased Wnt activity compared to wild-type XIAP in cultured human cells and in Xenopus embryos.

SIGNOR-277390

P84022

P26367

2

binding

down-regulates activity

0.399

The paired domain of Pax6 interacts with the MH1 domain of Smad3. Smad3 prevents Pax6 paired domain from binding DNA

SIGNOR-251875

Q13627

P16220

1

phosphorylation

up-regulates activity

0.487

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

SIGNOR-279989

P28324

Q9Y5U4

1

transcriptional regulation

up-regulates quantity by expression

0.2

Under these conditions, a significant reduction in INSIG2 expression was only observed when SAP1a siRNA was used. These observations provide supporting evidence that SAP1a may be one of the transactivators of the human INSIG2 promoter.

SIGNOR-261592

Q13315

P49959

2

phosphorylation

up-regulates

0.2

In this report, we showed that atm phosphorylates a p95 peptide (ser-343) and a mre11 peptide (ser-264) in vitro, suggesting that atm may regulate the function of p95?Mre11? Rad50 repair complex in response to dna damage.

SIGNOR-73366

P03956

O00755

0

transcriptional regulation

up-regulates quantity by expression

0.261

Because MMP1 is also another direct target of the canonical Wnt pathway (22), Wnt7a overexpression upregulated MMP1/10 to degrade the extracellular matrix and to facilitate UBC cell invasion.

SIGNOR-278868

P03372

Q92731

2

binding

up-regulates

0.527

It was recently shown that er? And er? Could form a heterodimer complex both in vitro and in vivo

SIGNOR-64427

P17612

P16220

1

phosphorylation

up-regulates activity

0.581

Using a combination of in vitro explant assays, mutant analysis and gene delivery into mouse embryos cultured ex vivo, we demonstrate that adenylyl cyclase signalling via PKA and its target transcription factor CREB are required for WNT-directed myogenic gene expression.

SIGNOR-131307

P30291

Q13153

0

phosphorylation

down-regulates

0.299

Kinases targeted sequentially to the neck, cla4/pak and cdc5/polo, are responsible for stepwise phosphorylation and down-regulation of swe1.

SIGNOR-123528

P35398

Q99743

1

transcriptional regulation

up-regulates quantity by expression

0.665

Direct Regulation of the NPAS2 Promoter by RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.

SIGNOR-267980

P61204

Q9Y6D6

0

guanine nucleotide exchange factor

up-regulates activity

0.366

Brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) is an approximately 200-kDa brefeldin A-inhibited guanine nucleotide-exchange protein that preferentially activates ADP-ribosylation factor 1 (ARF1) and ARF3.

SIGNOR-272148

P18146

P10645

1

transcriptional regulation

up-regulates quantity by expression

0.2

Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.

SIGNOR-254265

Q92945

Q9UKA9

2

binding

up-regulates activity

0.463

Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.

SIGNOR-261268

Q13546

2

phosphorylation

up-regulates activity

0.2

These data suggest that Ser14/15, Ser20, Ser161 and Ser166 represent autophosphorylation sites in vitro, detected in the RIP1 kinase assay (Fig. 1)

SIGNOR-276159

Q09472

P12755

2

binding

down-regulates

0.2

Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling.

SIGNOR-72664

Q96SB4

Q07955

1

phosphorylation

up-regulates

0.799

These results suggest that the formation of complexes between sf2/asf and srpks, which is influenced by the phosphorylation state of sf2/asf, may have regulatory roles in the assembly and localization of this splicing factor.

SIGNOR-66465

Q99638

Q92547

2

binding

up-regulates

0.826

The 9-1-1 complex functions as a clamp, encircling the dna, and recruits the brct domain-containing protein topbp1 in a phospho-dependent manner

SIGNOR-179382

P07948

Q13568

1

phosphorylation

down-regulates activity

0.329

Lyn Kinase Suppresses the Transcriptional Activity of IRF5. Here, we found that Lyn physically interacted with IRF5 to inhibit ubiquitination and phosphorylation of IRF5 in the TLR-MyD88 pathway, thereby suppressing the transcriptional activity of IRF5 in a manner independent of Lyn's kinase activity.

SIGNOR-277247

P63000

Q96N67

0

guanine nucleotide exchange factor

up-regulates activity

0.545

As a GEF, Dock7 exchanges GDP for GTP on Cdc42 and Rac1, causing their activation, followed by activation of downstream effectors, including the dephosphorylation (activation) of cofilin, a key regulator of actin turnover.

SIGNOR-261887

P33981

O96017

2

phosphorylation

up-regulates

0.292

Ttk/hmps1 directly phosphorylates chk2 on thr-68 in vitro.ablation of ttk expression using small interfering rna results not only in reduced chk2 thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which ttk functions upstream from chk2 in response to dna damage

SIGNOR-132665

P48431

O95071

0

polyubiquitination

down-regulates quantity by destabilization

0.256

We identified UBR5 as a major ubiquitin E3 ligase that induces SOX2 degradation through ubiquitinating SOX2 at lysine 115.

SIGNOR-277446

P28482

Q9NZV8

1

phosphorylation

up-regulates activity

0.367

We determined that the Kv4.2 C-terminal cytoplasmic domain is an effective ERK2 substrate, and that it is phosphorylated at three sites: Thr(602), Thr(607), and Ser(616). Phosphorylation of the Kv4.2 channel by ERK during LTP induction may lead to increased excitability and membrane depolarization of neurons, which would increase the magnitude of the calcium influx and the probability of triggering LTP.

SIGNOR-262935

P49841

Q9NP62

1

phosphorylation

down-regulates quantity by destabilization

0.2

We demonstrated that GSK-3beta mediates phosphorylation of GCM1 on Ser322, which is recognized by the F-box protein, FBW2, to promote GCM1 ubiquitination and degradation.

SIGNOR-278940

Q06124

P31260

1

dephosphorylation

up-regulates

0.373

We also identified hoxa10 as a substrate for shp2 in undifferentiated myeloid cells, an effect that diminished during myelopoiesis. However, a constitutively active form of shp2 dephosphorylated hoxa10 throughout ex vivo myelopoiesis and sustained repression of hoxa10 target genes involved in phagocyte effector functions.

SIGNOR-182475

Q8WZ73

Q6MZQ0

1

polyubiquitination

down-regulates quantity by destabilization

0.261

RFFL is an E3 ligase for PRR5L.

SIGNOR-271495

P38936

O15119

0

transcriptional regulation

down-regulates quantity by repression

0.304

TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS

SIGNOR-249602

Q14807

P06493

0

phosphorylation

up-regulates activity

0.344

Cdc2-mediated phosphorylation of kid controls its distribution to spindle and chromosomes. We identify ser427 and thr463 as m phase-specific phosphorylation sites and cdc2-cyclin b as a thr463 kinase. Kid with a thr463 to alanine mutation fails to be localized on chromosomes and is only detected along spindles, although it retains the ability to bind dna or chromosomes

SIGNOR-100964

P17252

Q9H3Q1

1

phosphorylation

down-regulates activity

0.2

Cdc42 effector protein-4 (CEP4) was recently identified by our laboratory to be a substrate of multiple PKC isoforms in non-transformed MCF-10A human breast cells. MS/MS analysis verified that Ser(18) and Ser(80) were directly phosphorylated by PKCα in vitro. Phosphorylation of CEP4 severely diminished its affinity for Cdc42 while promoting Rac activation and formation of filopodia (microspikes).

SIGNOR-263160

P13349

P23759

0

transcriptional regulation

up-regulates quantity by expression

0.492

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

SIGNOR-255641

P04637

Q9H0A0

0

acetylation

up-regulates quantity by stabilization

0.337

NAT10 acetylates p53 at K120 and stabilizes p53 by counteracting Mdm2 action. In addition, NAT10 promotes Mdm2 degradation with its intrinsic E3 ligase activity.

SIGNOR-272406

O15247

Q7Z570

0

transcriptional regulation

down-regulates quantity by repression

0.2

ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3).

SIGNOR-269465