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
P06493	O00562	1	phosphorylation	up-regulates	0.465	T287 is phosphorylated by cdk1 during mitosis. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis.	SIGNOR-124642
A2RUS2	Q8IYT8	0	phosphorylation	up-regulates activity	0.2	ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.	SIGNOR-264733
Q9UKV5	O15503	1	ubiquitination	down-regulates quantity by destabilization	0.525	The ubiquitination of Insig-1 is mediated by gp78 and regulated by sterols.\|gp78 mediates the degradation of Insig-1 and Insig-2.	SIGNOR-278567
Q8TAS1	P02686	1	phosphorylation	down-regulates	0.2	Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1.	SIGNOR-143485
P17676	P04150	2	binding	up-regulates activity	0.46	The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin	SIGNOR-250566
P05771	P08670	1	phosphorylation	up-regulates quantity	0.2	PKCbeta induces vimentin phosphorylation in MCP-1-activated human monocytes.	SIGNOR-278984
O00459	P03372	2	binding	up-regulates	0.545	Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k.	SIGNOR-140473
Q13315	Q969R5	1	phosphorylation	up-regulates activity	0.2	L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.	SIGNOR-266785
P31749	P41279	1	phosphorylation	up-regulates activity	0.558	Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator.	SIGNOR-252572
Q9UHD2	Q14980	1	phosphorylation	up-regulates activity	0.2	Our studies now reveal TBK1 as another kinase that phosphorylates NuMA and that is required for its association with dynein and for localization of NuMA to the centrosomes in mitotic cells.	SIGNOR-278432
P11362	P11362	2	phosphorylation	up-regulates	0.2	Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways.	SIGNOR-98626
O14964	P00533	0	phosphorylation	up-regulates activity	0.637	We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation	SIGNOR-100246
Q92974	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.806	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-260529
Q13261	P52333	1	null	up-regulates	0.501	Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256226
Q13107	Q9ULA0	0	cleavage	down-regulates quantity by destabilization	0.2	A further analysis showed that the hydrolysis pathway contributes to DNPEP-mediated degradation of USP4 (Supporting Information Figs. S3A–S3F). The interaction between USP4 and DNPEP was confirmed by coIP assays	SIGNOR-275652
Q92481	P04637	2	binding	up-regulates quantity by stabilization	0.335	These data suggest that AP-2Œ≤ enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2Œ≤ interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2Œ≤ up-regulates the transcription of the CRYAB gene through stabilizing p53.	SIGNOR-255422
Q9BQQ3	P53350	0	phosphorylation	down-regulates quantity	0.729	As GRASP65 is a substrate of cdc2 and polo-like kinase, manipulation of GRASP65 level may affect the localization and activity of these kinases in cell cycle progression, as suggested by a previous study ( ).\|During mitosis, GRASP65 is phosphorylated by two mitotic kinases, cdc2 and polo-like kinase (plk), which leads to GRASP65 deoligomerization and thus Golgi unstacking ( xref , xref ).	SIGNOR-279554
Q8TAQ2	P51531	2	binding	up-regulates	0.9	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65435
P78527	P00519	1	phosphorylation	up-regulates activity	0.513	We show that DNA-PK phosphorylates and activates c-Abl in vitro.	SIGNOR-279268
Q8WUI4	Q7KZI7	0	phosphorylation	down-regulates	0.344	We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function	SIGNOR-149583
Q04721	Q9Y219	2	binding	up-regulates	0.635	Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2	SIGNOR-81367
Q07954	P17612	0	phosphorylation	up-regulates activity	0.324	LRP phosphorylation is mediated by PKA at residue serine 76 of its cytoplasmic tail and that this phosphorylation contributes to receptor-mediated endocytosis.	SIGNOR-250000
O75962	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.692	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-260579
P38405	Q9BXC1	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-256900
O95835	P46937	1	phosphorylation	down-regulates quantity by destabilization	0.84	We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition	SIGNOR-218034
O95140	Q9BXM7	0	phosphorylation	down-regulates quantity	0.81	If PINK1 is responsible for the degradation of Mfn2, then silencing PINK1 should induce mitochondrial fusion by upregulating Mfn2 expression.\|We show that downregulation of Mfn2 is induced by proteasomal degradation triggered by PINK1, which phosphorylates Mfn2 at S442.	SIGNOR-278208
P55072	P31749	0	phosphorylation	up-regulates	0.509	Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I	SIGNOR-252491
P05556	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.	SIGNOR-265664
Q07866	O14656	2	binding	up-regulates activity	0.39	We identified the light chain subunit (KLC1) of kinesin-I as an interacting partner for torsinA, with binding occurring between the tetratricopeptide repeat domain of KLC1 and the carboxyl-terminal region of torsinA. Coimmunoprecipitation analysis demonstrated that wildtype torsinA and kinesin-I form a complex in vivo. These studies suggest that wild-type torsinA undergoes anterograde transport along microtubules mediated by kinesin and may act as a molecular chaperone regulating kinesin activity and/or cargo binding.	SIGNOR-261172
P09493	P53355	0	phosphorylation	up-regulates activity	0.277	We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling.	SIGNOR-262845
P01308	P14735	0	cleavage	down-regulates quantity by destabilization	0.719	IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds	SIGNOR-260986
P12931	P43146	2	binding	up-regulates activity	0.535	Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.	SIGNOR-268372
Q13188	Q9NRM7	1	phosphorylation	up-regulates	0.609	Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.	SIGNOR-175801
Q9Y5X2	P23458	0	phosphorylation	up-regulates activity	0.341	IFNγ induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKβ to the JAK1 complex.	SIGNOR-273647
O95390	P61160	2	binding	up-regulates	0.2	Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2.	SIGNOR-144147
Q92529-2	P04629	0	phosphorylation	up-regulates activity	0.778	We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo.	SIGNOR-273915
Q9BTA9	P53350	2	binding	up-regulates activity	0.2	Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1.	SIGNOR-265036
Q13099	O75665	2	binding	up-regulates activity	0.412	Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length.	SIGNOR-251973
P41236	P68400	0	phosphorylation	up-regulates activity	0.307	Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action.	SIGNOR-250929
P17252	Q16820	1	phosphorylation	down-regulates quantity	0.2	These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.	SIGNOR-263172
Q9NPH3	Q9H0E2	2	binding	down-regulates activity	0.638	Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)	SIGNOR-251979
P25054	O14640	2	binding	down-regulates activity	0.696	Dvl-1 inhibits Axin-promoted GSK-3_-dependent phosphorylation of _-catenin and APC, leading to beta-catenin stabilization.	SIGNOR-167951
O15350	O14965	0	phosphorylation	down-regulates activity	0.449	Aurora-A inhibits p73 and p53 transactivation functions through a common molecular mechanism.\|We report that Aurora-A phosphorylation of p73 at serine235 abrogates its transactivation function and causes cytoplasmic sequestration in a complex with the chaperon protein mortalin.	SIGNOR-278263
Q15858	Q96PU5	0	ubiquitination	down-regulates quantity by destabilization	0.334	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253458
Q14814	Q13627	0	phosphorylation	down-regulates activity	0.411	DYRK1A phosphorylates MEF2D and decreases its transcriptional activity	SIGNOR-277901
O75385	O60260	1	phosphorylation	up-regulates activity	0.2	Furthermore, the Parkin band shift induced by catalytically active WT ULK1 was diminished by treatment of cell lysates with lambda-phosphatase, as was the mobility of ULK1 itself (XREF_FIG).\|Parkin is phosphorylated by ULK1 at Ser 108 in its recently described nine amino acid ACT element at this early time point	SIGNOR-279663
P31939	Q9UM73	0	phosphorylation	up-regulates activity	0.377	ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity. ATIC activity is enhanced in the presence of NPM-ALK in vitro.The ATIC activity is enhanced by NPM-ALK in HEK-293T-Rex cells.	SIGNOR-276171
O75385	Q13131	2	phosphorylation	down-regulates activity	0.572	Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.	SIGNOR-173047
P17252	P28698	0	transcriptional regulation	up-regulates quantity by expression	0.384	The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity.	SIGNOR-256337
P19174	Q9UM73	2	binding	up-regulates	0.546	Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1.	SIGNOR-122082
Q16635	P06493	0	phosphorylation	down-regulates quantity by destabilization	0.266	Our studies suggest that phosphorylation and degradation of TAZ by Cdk1 may play important roles in apoptosis induced by antitubulin drugs.	SIGNOR-278240
Q96KB5	P05412	1	phosphorylation	up-regulates activity	0.43	TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.\|These data confirm the phosphorylation of c-Jun by TOPK at serine 63 and 73 during the development of resistance to EGFR-targeted TKIs.	SIGNOR-278156
P23759	P13349	1	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
Q9UQ80	Q05655	0	phosphorylation	up-regulates	0.509	Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb	SIGNOR-170348
Q96RR4	P49840	0	phosphorylation	down-regulates	0.269	Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.	SIGNOR-198122
Q03113	O15552	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-257342
P54646	O00418	1	phosphorylation	up-regulates activity	0.498	Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity.	SIGNOR-250158
Q13131	P41235	1	phosphorylation	down-regulates activity	0.285	Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect	SIGNOR-101101
Q9H1A4	P53350	0	phosphorylation	up-regulates	0.524	Our analysis revealed an unexpected and unprecedented complexity of mitotic phosphorylation sites and suggests that other kinases than cdk1 and plk1 also contribute to apc phosphorylation.	SIGNOR-119881
P21580	Q86VP1	2	binding	up-regulates activity	0.683	Tx1bp1 appears to be a novel a20-binding protein which mediate the anti-apoptotic activity of a20; tax1bp1 phosphorylation was pivotal for cytokine-dependent interactions among tax1bp1, a20, itch and rnf11 and downregulation of signaling by the transcription factor nf-Kb.	SIGNOR-69921
P23760	Q9UJU2	2	binding	up-regulates activity	0.427	Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1.	SIGNOR-162100
Q9UIF7	Q92547	2	binding	up-regulates	0.373	Binding of myh directly participates in atr and topbp1 activation in dna damage signaling, leading to apoptosis.	SIGNOR-173972
P07333	Q6ZMJ4	2	binding	up-regulates activity	0.912	CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK	SIGNOR-277714
Q13315	P00519	1	phosphorylation	up-regulates	0.744	Ataxia telangiectasia mutant protein activates c-abl tyrosine kinase in response to ionizing radiation. Atm kinase domain corrects this defect, as it phosphorylates the c-abl tyrosine kinase in vitro at ser 465, leading to the activation of c-abl.	SIGNOR-48818
P49137	P16220	1	phosphorylation	up-regulates activity	0.691	Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2.	SIGNOR-166619
P30559	P14416	2	binding	up-regulates activity	0.374	Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling.	SIGNOR-270333
Q08379	Q9BQQ3	2	binding	up-regulates quantity by stabilization	0.879	Previous studies have implicated the GM130–GRASP65 complex in diverse Golgi functions. Therefore, GM130–GRASP65 interactions are required for Golgi ribbon formation.\|A surprising clue came from the observation that GM130 was required for stability of GRASP65.	SIGNOR-260601
O00329	P01112	2	binding	up-regulates	0.662	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-175192
P62993	P21802	0	phosphorylation	up-regulates	0.773	Inhibition of basal fgf receptor signaling by dimeric grb2.	SIGNOR-197980
P49841	Q07820	1	phosphorylation	down-regulates quantity by destabilization	0.5	MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1.	SIGNOR-251242
O95149	Q6ZN04	0	polyubiquitination	down-regulates quantity by destabilization	0.556	HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation.	SIGNOR-272079
Q5SGD2	O75460	1	dephosphorylation	up-regulates activity	0.309	Overall, our study establishes that PP2Ce mediated IRE1 regulation in ER stress signaling is a potentially important molecular basis for its genetic contribution to metabolic syndrome.Lin et al. [36] have reported that different durations and composition of ER stress signaling pathways can dictate cell fate and the balance between survival and death.\|Recombinant wildtype PP2Ce, but not a phosphatase-dead mutant (PP2Ce-D302A), effectively dephosphorylated the phosphor-Ser724 site of IRE1\u03b1 protein (p-IRE1\u03b1) (A).	SIGNOR-277074
P28482	P04049	1	phosphorylation	down-regulates activity	0.632	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. \| Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.\|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-249441
P49137	O95453	1	phosphorylation	down-regulates	0.375	Mk2 phosphorylates parn, blocking gadd45_ mrna degradation. Parn can serve as a direct substrate for mk2, and demonstrating that ser-557 is the dominant mk2 phosphorylation site.	SIGNOR-168377
P12931	P48736	0	phosphorylation	up-regulates activity	0.365	PI3Kγ mediated phosphorylation of Src enhances Src activity protein kinase activity of PI3K phosphorylates serine residue 70 on Src to enhance its activity and induce EGFR transactivation following βAR stimulation.	SIGNOR-277225
P45452	P00748	1	cleavage	down-regulates quantity by destabilization	0.313	The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377\|However, no activity of Factor XII can be observed after MMPinduced cleavage.	SIGNOR-263609
P23409	Q06413	0	transcriptional regulation	up-regulates quantity by expression	0.565	Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis.	SIGNOR-238652
Q00534	P42771	2	binding	down-regulates	0.871	In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm.	SIGNOR-140412
P01106	Q9Y6K1	2	binding	up-regulates activity	0.712	Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the speciﬁc methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the speciﬁcity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc.	SIGNOR-255806
P11831	P68400	0	phosphorylation	up-regulates activity	0.552	Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.\| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated.	SIGNOR-250955
P24941	P49459	1	phosphorylation	up-regulates	0.374	Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity.	SIGNOR-116508
Q05655	P07550	1	phosphorylation	down-regulates activity	0.352	We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling.	SIGNOR-248855
Q96AX9	Q9Y219	1	ubiquitination	up-regulates	0.809	Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2.	SIGNOR-137922
P15153	Q13153	2	binding	up-regulates	0.778	This report shows that rac1 binds to and stimulates the kinase activity of pak1 approximately 2- and 4-5-fold, respectively, better than rac2.	SIGNOR-59546
P08754	Q96LB1	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-257172
Q16539	P78356	1	phosphorylation	down-regulates	0.2	Inhibition of pip4kbeta activity occurs through the direct phosphorylation of pip4kbeta at ser326 by the p38 stress-activated protein kinase.	SIGNOR-149359
Q9UNE7	O95863	1	ubiquitination	down-regulates quantity by destabilization	0.289	These results indicate that CHIP can ubiquitylate and degrade Snail in a GSK\u20103\u03b2\u2010independent manner.\|These results suggest that CHIP negatively regulates the stability of Snail through inducing its proteasomal degradation.	SIGNOR-278545
Q7Z6J0	Q16584	2	binding	up-regulates	0.502	Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks.	SIGNOR-97006
P10070	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.562	The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3.	SIGNOR-249590
P01275-PRO_0000011258	P43220	2	binding	up-regulates activity	0.782	GLP-1 and GIP exert their physiological actions via stimulation of the two G protein-coupled receptors (GPCRs): the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR), respectively.	SIGNOR-278133
P63000	Q8TCU6	0	guanine nucleotide exchange factor	up-regulates activity	0.719	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-260569
P25963	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-271451
P62258	Q9GZM8	2	binding	up-regulates activity	0.667	14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. 14-3-3ε binds to NUDEL phosphorylated by cyclin-dependent kinase (cdk5) and maintains NUDEL phosphorylation. Deficiency of 14-3-3ε causes mislocalization of the NUDEL/LIS1 complex from axons, suggesting that 14-3-3ε regulates the axonal targeting of the NUDEL/LIS1 complex by sustaining NUDEL phosphorylation	SIGNOR-252160
O43318	Q01638	2	binding	up-regulates activity	0.2	The activated heterodimer complex recruits downstream signaling components, including myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor (IL-1R)–associated kinase, tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), and transforming growth factor (TGF)-β–activated kinase 1 (TAK1) complex, resulting in TAK1 activation. TAK1 subsequently activates downstream kinases inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKα) and IKKβ, which phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor (IκB) proteins. These events ultimately lead to activation of the transcription factor NF-κB and induction of downstream effector genes	SIGNOR-277716
Q99750	P13349	2	binding	down-regulates activity	0.37	We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals.	SIGNOR-240433
P30305	P45983	0	phosphorylation	down-regulates quantity by destabilization	0.284	Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).	SIGNOR-276352
O60343	P31751	0	phosphorylation	down-regulates activity	0.642	AKT2 phosphorylation blocks AS160 function enhancing GLUT4 intracellular vesicular transport, and as such promotes glucose uptake following insulin release .\|Notable mechanisms promoting this involves AKT2 mediated phosphorylation of the Rab-GTPase-activating protein TBC1D4, also known as AS160.	SIGNOR-280179
P25116	P00747	0	cleavage	down-regulates activity	0.624	Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site.	SIGNOR-263572
P23443	O94763	1	phosphorylation	down-regulates activity	0.344	Here we report that the prefoldin chaperone URI represents a mitochondrial substrate of S6K1. In growth factor-deprived or rapamycin-treated cells, URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria, thereby inhibiting the activity of the bound enzyme. Growth factor stimulation induces disassembly of URI/PP1gamma complexes through S6K1-mediated phosphorylation of URI at serine 371.	SIGNOR-262943
Q14344	Q92633	2	binding	up-regulates	0.456	The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits).	SIGNOR-230761

P06493

O00562

1

phosphorylation

up-regulates

0.465

T287 is phosphorylated by cdk1 during mitosis. Phosphorylation of nir2 by cdk1 facilitates its dissociation from the golgi apparatus, and phospho-nir2(ps382) is localized in the cleavage furrow and midbody during cytokinesis.

SIGNOR-124642

A2RUS2

Q8IYT8

0

phosphorylation

up-regulates activity

0.2

ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12.

SIGNOR-264733

Q9UKV5

O15503

1

ubiquitination

down-regulates quantity by destabilization

0.525

The ubiquitination of Insig-1 is mediated by gp78 and regulated by sterols.|gp78 mediates the degradation of Insig-1 and Insig-2.

SIGNOR-278567

Q8TAS1

P02686

1

phosphorylation

down-regulates

0.2

Phosphorylation decreased the ability of mbp to polymerize actin and to bundle actin filaments but had no effect on the dissociation constant of the mbp-actin complex or on the ability of ca2+-calmodulin to dissociate the complex. The most significant effect of phosphorylation on the mbp-actin complex was a dramatic reduction in its ability to bind to negatively charged lipid bilayers. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of mbp as the unique site phosphorylated by kis. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1.

SIGNOR-143485

P17676

P04150

2

binding

up-regulates activity

0.46

The differentiation of 3T3-L1 preadipocytes is regulated in part by a cascade of transcriptional events involving activation of the CCAAT/enhancer-binding proteins (C/EBPs) and peroxisome proliferator-activated receptor gamma (PPARgamma) by dexamethasone (DEX), 3-isobutyl-1-methylxanthine (MIX), and insulin

SIGNOR-250566

P05771

P08670

1

phosphorylation

up-regulates quantity

0.2

PKCbeta induces vimentin phosphorylation in MCP-1-activated human monocytes.

SIGNOR-278984

O00459

P03372

2

binding

up-regulates

0.545

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

SIGNOR-140473

Q13315

Q969R5

1

phosphorylation

up-regulates activity

0.2

L3MBTL2 links RNF8 and RNF168 in the DNA double strand break response. The protein kinase ATM phosphorylates L3MBTL2, which recruits it to the DNA lesion by promoting the interaction between MDC1 and L3MBTL2. L3MBTL2 is subsequently ubiquitinated by RNF8, which acts as a docking site for RNF168, thereby recruiting the ubiquitin ligase to the damage site. RNF168, in turn, ubiquitinates H2A-type histones to amplify the DNA damage response and recruit downstream DNA repair proteins for proper DSB signaling.

SIGNOR-266785

P31749

P41279

1

phosphorylation

up-regulates activity

0.558

Akt-dependent phosphorylation of Cot occurs exclusively on serines 400 and 413. Akt to phosphorylate Cot at two sites in the carboxy-terminal domain, at least one of which may promote binding of substrates or coactivators to Cot, or alternatively may relieve binding of a negative regulator.

SIGNOR-252572

Q9UHD2

Q14980

1

phosphorylation

up-regulates activity

0.2

Our studies now reveal TBK1 as another kinase that phosphorylates NuMA and that is required for its association with dynein and for localization of NuMA to the centrosomes in mitotic cells.

SIGNOR-278432

P11362

2

phosphorylation

up-regulates

0.2

Fgfr signaling is under the control of tyrosine phosphorylation to elicit activation of cellular signaling cascades. Ligand binding induces receptor dimerization and transphosphorylation. Fgfr1 contains eleven tyrosine residues (tyr154, tyr280, tyr307, tyr463, tyr585, tyr605, tyr653, tyr654, tyr730 and tyr766), some of which are directly involved regulating the activity of the receptor and others bind to activate substrates leading to the activation of various transduction pathways.

SIGNOR-98626

O14964

P00533

0

phosphorylation

up-regulates activity

0.637

We have analysed hrs phosphorylation in response to epidermal growth factor (egf) stimulation and show that the evolutionary conserved tyrosines y329 and y334 provide the principal phosphorylation sitesover-expression of wild-type hrs or a double mutant, y329/334f, defective in egf-dependent phosphorylation, substantially retard egf receptor (egfr) degradation

SIGNOR-100246

Q92974

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.806

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-260529

Q13261

P52333

1

null

up-regulates

0.501

Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated

SIGNOR-256226

Q13107

Q9ULA0

0

cleavage

down-regulates quantity by destabilization

0.2

A further analysis showed that the hydrolysis pathway contributes to DNPEP-mediated degradation of USP4 (Supporting Information Figs. S3A–S3F). The interaction between USP4 and DNPEP was confirmed by coIP assays

SIGNOR-275652

Q92481

P04637

2

binding

up-regulates quantity by stabilization

0.335

These data suggest that AP-2Œ≤ enhances transactivation of p53 and regulates CRYAB transcription via p53. Further study demonstrated that AP-2Œ≤ interacts with p53 and augments its protein stability. Taken together, our results indicate that AP-2Œ≤ up-regulates the transcription of the CRYAB gene through stabilizing p53.

SIGNOR-255422

Q9BQQ3

P53350

0

phosphorylation

down-regulates quantity

0.729

As GRASP65 is a substrate of cdc2 and polo-like kinase, manipulation of GRASP65 level may affect the localization and activity of these kinases in cell cycle progression, as suggested by a previous study ( ).|During mitosis, GRASP65 is phosphorylated by two mitotic kinases, cdc2 and polo-like kinase (plk), which leads to GRASP65 deoligomerization and thus Golgi unstacking ( xref , xref ).

SIGNOR-279554

Q8TAQ2

P51531

2

binding

up-regulates

0.9

The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.

SIGNOR-65435

P78527

P00519

1

phosphorylation

up-regulates activity

0.513

We show that DNA-PK phosphorylates and activates c-Abl in vitro.

SIGNOR-279268

Q8WUI4

Q7KZI7

0

phosphorylation

down-regulates

0.344

We further show that emk and c-tak1 phosphorylate class iia hdacs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function

SIGNOR-149583

Q04721

Q9Y219

2

binding

up-regulates

0.635

Binding of delta1, jagged1, and jagged2 to notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of notch2

SIGNOR-81367

Q07954

P17612

0

phosphorylation

up-regulates activity

0.324

LRP phosphorylation is mediated by PKA at residue serine 76 of its cytoplasmic tail and that this phosphorylation contributes to receptor-mediated endocytosis.

SIGNOR-250000

O75962

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.692

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-260579

P38405

Q9BXC1

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-256900

O95835

P46937

1

phosphorylation

down-regulates quantity by destabilization

0.84

We show that YAP is phosphorylated by Lats on Ser 381 in one of the HXRXXS motifs, and this phosphorylation provides the priming signal for CK1delta/epsilon to phosphorylate a phosphodegron in YAP. The phosphorylated phosphodegron recruits beta-TRCP, leading to YAP ubiquitination and degradation under conditions of elevated Hippo pathway activity, such as cell contact inhibition

SIGNOR-218034

O95140

Q9BXM7

0

phosphorylation

down-regulates quantity

0.81

If PINK1 is responsible for the degradation of Mfn2, then silencing PINK1 should induce mitochondrial fusion by upregulating Mfn2 expression.|We show that downregulation of Mfn2 is induced by proteasomal degradation triggered by PINK1, which phosphorylates Mfn2 at S442.

SIGNOR-278208

P55072

P31749

0

phosphorylation

up-regulates

0.509

Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I

SIGNOR-252491

P05556

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.

SIGNOR-265664

Q07866

O14656

2

binding

up-regulates activity

0.39

We identified the light chain subunit (KLC1) of kinesin-I as an interacting partner for torsinA, with binding occurring between the tetratricopeptide repeat domain of KLC1 and the carboxyl-terminal region of torsinA. Coimmunoprecipitation analysis demonstrated that wildtype torsinA and kinesin-I form a complex in vivo. These studies suggest that wild-type torsinA undergoes anterograde transport along microtubules mediated by kinesin and may act as a molecular chaperone regulating kinesin activity and/or cargo binding.

SIGNOR-261172

P09493

P53355

0

phosphorylation

up-regulates activity

0.277

We identified, for the first time, death-associated protein kinase 1 (DAP kinase 1) as the kinase that phosphorylates tropomyosin-1 in response to ERK activation by hydrogen peroxide (H(2)O(2)). We also report that the phosphorylation of tropomyosin-1 mediated by DAP kinase occurs on Ser283. Our finding that tropomyosin-1 is phosphorylated downstream of ERK and DAP kinase and that it helps regulate the formation of stress fibers will aid understanding the role of this protein in regulating the endothelial functions associated with cytoskeletal remodeling.

SIGNOR-262845

P01308

P14735

0

cleavage

down-regulates quantity by destabilization

0.719

IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds

SIGNOR-260986

P12931

P43146

2

binding

up-regulates activity

0.535

Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.

SIGNOR-268372

Q13188

Q9NRM7

1

phosphorylation

up-regulates

0.609

Activation of mst1/2 leads to phosphorylation and activation of their direct substrates, lats1/2.

SIGNOR-175801

Q9Y5X2

P23458

0

phosphorylation

up-regulates activity

0.341

IFNγ induced JAK1-mediated phosphorylation of SNX8 at Tyr95 and Tyr126, which promoted the recruitment of IKKβ to the JAK1 complex.

SIGNOR-273647

O95390

P61160

2

binding

up-regulates

0.2

Here we demonstrate using genetic and biochemical studies that actriib and its subfamily receptor, actriia, cooperatively mediate the gdf11 signal in patterning the axial vertebrae, and that gdf11 binds to both actriia and actriib, and induces phosphorylation of smad2.

SIGNOR-144147

Q92529-2

P04629

0

phosphorylation

up-regulates activity

0.778

We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo.

SIGNOR-273915

Q9BTA9

P53350

2

binding

up-regulates activity

0.2

Here, we report that the activation of Plk1 requires WAC, a WW domain-containing adaptor protein with a coiled-coil region that predominantly localizes to the nucleus in interphase. Cyclin-dependent kinase 1 (Cdk1) phosphorylates WAC, priming its direct interaction with the polo-box domain of Plk1.

SIGNOR-265036

Q13099

O75665

2

binding

up-regulates activity

0.412

Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length.

SIGNOR-251973

P41236

P68400

0

phosphorylation

up-regulates activity

0.307

Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action.

SIGNOR-250929

P17252

Q16820

1

phosphorylation

down-regulates quantity

0.2

These findings suggest that activation of a protein kinase, presumably PKC, mediates PMA-induced hmeprinβ shedding. By labeling COS-1 cells transfected with mutant constructs lacking the potential phosphorylation sites, we identified Ser687 as the main 32P-acceptor. These data provide evidence that the cytoplasmic domain of hmeprinβ can function as a PKC substrate.

SIGNOR-263172

Q9NPH3

Q9H0E2

2

binding

down-regulates activity

0.638

Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)

SIGNOR-251979

P25054

O14640

2

binding

down-regulates activity

0.696

Dvl-1 inhibits Axin-promoted GSK-3_-dependent phosphorylation of _-catenin and APC, leading to beta-catenin stabilization.

SIGNOR-167951

O15350

O14965

0

phosphorylation

down-regulates activity

0.449

Aurora-A inhibits p73 and p53 transactivation functions through a common molecular mechanism.|We report that Aurora-A phosphorylation of p73 at serine235 abrogates its transactivation function and causes cytoplasmic sequestration in a complex with the chaperon protein mortalin.

SIGNOR-278263

Q15858

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.334

The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).

SIGNOR-253458

Q14814

Q13627

0

phosphorylation

down-regulates activity

0.411

DYRK1A phosphorylates MEF2D and decreases its transcriptional activity

SIGNOR-277901

O75385

O60260

1

phosphorylation

up-regulates activity

0.2

Furthermore, the Parkin band shift induced by catalytically active WT ULK1 was diminished by treatment of cell lysates with lambda-phosphatase, as was the mobility of ULK1 itself (XREF_FIG).|Parkin is phosphorylated by ULK1 at Ser 108 in its recently described nine amino acid ACT element at this early time point

SIGNOR-279663

P31939

Q9UM73

0

phosphorylation

up-regulates activity

0.377

ATIC and VASP phosphorylation is dependent on NPM-ALK kinase activity. ATIC activity is enhanced in the presence of NPM-ALK in vitro.The ATIC activity is enhanced by NPM-ALK in HEK-293T-Rex cells.

SIGNOR-276171

O75385

Q13131

2

phosphorylation

down-regulates activity

0.572

Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.

SIGNOR-173047

P17252

P28698

0

transcriptional regulation

up-regulates quantity by expression

0.384

The luciferase reporter assay results revealed that the presence of both MZF-1 and Elk-1 significantly contributed to the upregulation of PKCα gene transcription activity.

SIGNOR-256337

P19174

Q9UM73

2

binding

up-regulates

0.546

Proteins that interact with alk tyrosine kinase play important roles in mediating downstream cellular signals. Previously reported proteins in the alk signal pathway were identified including pi3-k, jak2, jak3, stat3, grb2, irs, and plcgamma1.

SIGNOR-122082

Q16635

P06493

0

phosphorylation

down-regulates quantity by destabilization

0.266

Our studies suggest that phosphorylation and degradation of TAZ by Cdk1 may play important roles in apoptosis induced by antitubulin drugs.

SIGNOR-278240

Q96KB5

P05412

1

phosphorylation

up-regulates activity

0.43

TOPK promotes lung cancer resistance to EGFR tyrosine kinase inhibitors by phosphorylating and activating c-Jun.|These data confirm the phosphorylation of c-Jun by TOPK at serine 63 and 73 during the development of resistance to EGFR-targeted TKIs.

SIGNOR-278156

P23759

P13349

1

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

Q9UQ80

Q05655

0

phosphorylation

up-regulates

0.509

Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb

SIGNOR-170348

Q96RR4

P49840

0

phosphorylation

down-regulates

0.269

Cdk5 and gsk3 phosphorylate ser-129, ser-133, and ser-137. Mutation of ser-129, ser-133, and ser-137 increases autonomous activity with little change in ca2 /cam-dependent activity.

SIGNOR-198122

Q03113

O15552

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-257342

P54646

O00418

1

phosphorylation

up-regulates activity

0.498

Stimulation of the AMP-activated Protein Kinase Leads to Activation of Eukaryotic Elongation Factor 2 Kinase and to Its Phosphorylation at a Novel Site, Serine 398. phosphorylation of eEF2 kinase at Ser-398 leads to an increase in its activity.

SIGNOR-250158

Q13131

P41235

1

phosphorylation

down-regulates activity

0.285

Here we demonstrate that ampk directly phosphorylates hnf4 and represses its transcriptional activity. Ampk-mediated phosphorylation of hnf4 on serine 304 had a 2-fold effect

SIGNOR-101101

Q9H1A4

P53350

0

phosphorylation

up-regulates

0.524

Our analysis revealed an unexpected and unprecedented complexity of mitotic phosphorylation sites and suggests that other kinases than cdk1 and plk1 also contribute to apc phosphorylation.

SIGNOR-119881

P21580

Q86VP1

2

binding

up-regulates activity

0.683

Tx1bp1 appears to be a novel a20-binding protein which mediate the anti-apoptotic activity of a20; tax1bp1 phosphorylation was pivotal for cytokine-dependent interactions among tax1bp1, a20, itch and rnf11 and downregulation of signaling by the transcription factor nf-Kb.

SIGNOR-69921

P23760

Q9UJU2

2

binding

up-regulates activity

0.427

Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1.

SIGNOR-162100

Q9UIF7

Q92547

2

binding

up-regulates

0.373

Binding of myh directly participates in atr and topbp1 activation in dna damage signaling, leading to apoptosis.

SIGNOR-173972

P07333

Q6ZMJ4

2

binding

up-regulates activity

0.912

CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK

SIGNOR-277714

Q13315

P00519

1

phosphorylation

up-regulates

0.744

Ataxia telangiectasia mutant protein activates c-abl tyrosine kinase in response to ionizing radiation. Atm kinase domain corrects this defect, as it phosphorylates the c-abl tyrosine kinase in vitro at ser 465, leading to the activation of c-abl.

SIGNOR-48818

P49137

P16220

1

phosphorylation

up-regulates activity

0.691

Neverthless, some transcription factors, such as e47, er81, srf and creb are also phosphorylated by mk2.

SIGNOR-166619

P30559

P14416

2

binding

up-regulates activity

0.374

Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling. Dopamine D2 receptor (D2R)–oxytocin receptor (OTR) interactions exist within heterocomplexes with facilitatory effects on D2R recognition and Gi/o coupling.

SIGNOR-270333

Q08379

Q9BQQ3

2

binding

up-regulates quantity by stabilization

0.879

Previous studies have implicated the GM130–GRASP65 complex in diverse Golgi functions. Therefore, GM130–GRASP65 interactions are required for Golgi ribbon formation.|A surprising clue came from the observation that GM130 was required for stability of GRASP65.

SIGNOR-260601

O00329

P01112

2

binding

up-regulates

0.662

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85. it was also described that ras interacts with pi3k in a direct manner. lysine residue 227 is essential for the interaction of ras with pi3k

SIGNOR-175192

P62993

P21802

0

phosphorylation

up-regulates

0.773

Inhibition of basal fgf receptor signaling by dimeric grb2.

SIGNOR-197980

P49841

Q07820

1

phosphorylation

down-regulates quantity by destabilization

0.5

MCL-1 was phosphorylated by GSK-3 at a conserved GSK-3 phosphorylation site (S159). S159 phosphorylation of MCL-1 was induced by IL-3 withdrawal or PI3K inhibition and prevented by AKT or inhibition of GSK-3, and it led to increased ubiquitinylation and degradation of MCL-1.

SIGNOR-251242

O95149

Q6ZN04

0

polyubiquitination

down-regulates quantity by destabilization

0.556

HOTAIR associates with E3 ubiquitin ligases bearing RNA-binding domains, Dzip3 and Mex3b, as well as with their respective ubiquitination substrates, Ataxin-1 and Snurportin-1. In this manner, HOTAIR facilitates the ubiquitination of Ataxin-1 by Dzip3 and Snurportin-1 by Mex3b in cells and in vitro, and accelerates their degradation.

SIGNOR-272079

Q5SGD2

O75460

1

dephosphorylation

up-regulates activity

0.309

Overall, our study establishes that PP2Ce mediated IRE1 regulation in ER stress signaling is a potentially important molecular basis for its genetic contribution to metabolic syndrome.Lin et al. [36] have reported that different durations and composition of ER stress signaling pathways can dictate cell fate and the balance between survival and death.|Recombinant wildtype PP2Ce, but not a phosphatase-dead mutant (PP2Ce-D302A), effectively dephosphorylated the phosphor-Ser724 site of IRE1\u03b1 protein (p-IRE1\u03b1) (A).

SIGNOR-277074

P28482

P04049

1

phosphorylation

down-regulates activity

0.632

Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2

SIGNOR-249441

P49137

O95453

1

phosphorylation

down-regulates

0.375

Mk2 phosphorylates parn, blocking gadd45_ mrna degradation. Parn can serve as a direct substrate for mk2, and demonstrating that ser-557 is the dominant mk2 phosphorylation site.

SIGNOR-168377

P12931

P48736

0

phosphorylation

up-regulates activity

0.365

PI3Kγ mediated phosphorylation of Src enhances Src activity protein kinase activity of PI3K phosphorylates serine residue 70 on Src to enhance its activity and induce EGFR transactivation following βAR stimulation.

SIGNOR-277225

P45452

P00748

1

cleavage

down-regulates quantity by destabilization

0.313

The data presented in this study show for the first time the degradation of Factor XII of the blood clotting system by matrix metalloproteinases. MMP-12, MMP-13, and MMP-14 cleave at Gly376Leu377|However, no activity of Factor XII can be observed after MMPinduced cleavage.

SIGNOR-263609

P23409

Q06413

0

transcriptional regulation

up-regulates quantity by expression

0.565

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

SIGNOR-238652

Q00534

P42771

2

binding

down-regulates

0.871

In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm.

SIGNOR-140412

P01106

Q9Y6K1

2

binding

up-regulates activity

0.712

Based on one of these publications, we here showed that the interaction of Dnmt3a with c-myc promote the speciﬁc methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Acellular experiments corroborated and complemented these results by revealing that the speciﬁcity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc.

SIGNOR-255806

P11831

P68400

0

phosphorylation

up-regulates activity

0.552

Casein kinase II (CKII) phosphorylates the mammalian transcription factor serum response factor (SRF) on a serine residue(s) located within a region of the protein spanning amino acids 70 to 92, thereby enhancing its DNA-binding activity in vitro.| Nevertheless, additional mutation of serines 77 and 79 was required before phosphorylation and enhanced binding were completely abolished. Thus, serines 77 and 79 could also be recognized by CKII if serines 83 and 85 were mutated.

SIGNOR-250955

P24941

P49459

1

phosphorylation

up-regulates

0.374

Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity.

SIGNOR-116508

Q05655

P07550

1

phosphorylation

down-regulates activity

0.352

We investigate the role of the beta 2-adrenergic receptor phosphorylation by protein kinase C in this regulatory process. Mutation of the serine-261, -262, -344 and -345 of the beta 2-adrenergic receptor prevented the phorbol-ester-induced phosphorylation of the receptor. This mutation also abolished the phorbol-ester-induced decrease in high-affinity agonist binding and potency of the beta 2-adrenergic receptor. We suggest that protein kinase C mediated phosphorylation of the receptor promotes its functional uncoupling.

SIGNOR-248855

Q96AX9

Q9Y219

1

ubiquitination

up-regulates

0.809

Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2.

SIGNOR-137922

P15153

Q13153

2

binding

up-regulates

0.778

This report shows that rac1 binds to and stimulates the kinase activity of pak1 approximately 2- and 4-5-fold, respectively, better than rac2.

SIGNOR-59546

P08754

Q96LB1

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-257172

Q16539

P78356

1

phosphorylation

down-regulates

0.2

Inhibition of pip4kbeta activity occurs through the direct phosphorylation of pip4kbeta at ser326 by the p38 stress-activated protein kinase.

SIGNOR-149359

Q9UNE7

O95863

1

ubiquitination

down-regulates quantity by destabilization

0.289

These results indicate that CHIP can ubiquitylate and degrade Snail in a GSK\u20103\u03b2\u2010independent manner.|These results suggest that CHIP negatively regulates the stability of Snail through inducing its proteasomal degradation.

SIGNOR-278545

Q7Z6J0

Q16584

2

binding

up-regulates

0.502

Taken together, these findings support a model in which apoptotic stimuli or posh overexpression induce direct association between posh and inactive mlks.

SIGNOR-97006

P10070

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.562

The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3.

SIGNOR-249590

P01275-PRO_0000011258

P43220

2

binding

up-regulates activity

0.782

GLP-1 and GIP exert their physiological actions via stimulation of the two G protein-coupled receptors (GPCRs): the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR), respectively.

SIGNOR-278133

P63000

Q8TCU6

0

guanine nucleotide exchange factor

up-regulates activity

0.719

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-260569

P25963

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-271451

P62258

Q9GZM8

2

binding

up-regulates activity

0.667

14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. 14-3-3ε binds to NUDEL phosphorylated by cyclin-dependent kinase (cdk5) and maintains NUDEL phosphorylation. Deficiency of 14-3-3ε causes mislocalization of the NUDEL/LIS1 complex from axons, suggesting that 14-3-3ε regulates the axonal targeting of the NUDEL/LIS1 complex by sustaining NUDEL phosphorylation

SIGNOR-252160

O43318

Q01638

2

binding

up-regulates activity

0.2

The activated heterodimer complex recruits downstream signaling components, including myeloid differentiation primary response protein 88 (MyD88), IL-1 receptor (IL-1R)–associated kinase, tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6), and transforming growth factor (TGF)-β–activated kinase 1 (TAK1) complex, resulting in TAK1 activation. TAK1 subsequently activates downstream kinases inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKα) and IKKβ, which phosphorylate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor (IκB) proteins. These events ultimately lead to activation of the transcription factor NF-κB and induction of downstream effector genes

SIGNOR-277716

Q99750

P13349

2

binding

down-regulates activity

0.37

We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals.

SIGNOR-240433

P30305

P45983

0

phosphorylation

down-regulates quantity by destabilization

0.284

Recently, we showed that Cdc25B is degraded rapidly by non-genotoxic stimuli that activate stress-responsive MAPKs, such as Jun N-terminal kinase (JNK) and p38 (Uchida et al., 2009). Our results suggested that these kinases phosphorylate specific Ser residues in the N-terminal region (S101 and S103) to induce Cdc25B degradation.Here, we report that Cdc25B was ubiquitylated by SCF(βTrCP) E3 ligase upon phosphorylation at two Ser residues in the βTrCP-binding-motif-like sequence D(94)AGLCMDSPSP(104).

SIGNOR-276352

O60343

P31751

0

phosphorylation

down-regulates activity

0.642

AKT2 phosphorylation blocks AS160 function enhancing GLUT4 intracellular vesicular transport, and as such promotes glucose uptake following insulin release .|Notable mechanisms promoting this involves AKT2 mediated phosphorylation of the Rab-GTPase-activating protein TBC1D4, also known as AS160.

SIGNOR-280179

P25116

P00747

0

cleavage

down-regulates activity

0.624

Plasmin mediates the lysis of fibrin clots and could in different studies activate platelets or inhibit the responses induced by thrombin (41-43). Our study favors a net inactivating effect on PAR1 despite minor cleavage at Arg41, on the basis of preferential cleavage at positions Arg70 and Lys76, COOH-terminal to the Arg41-Ser42 activation site.

SIGNOR-263572

P23443

O94763

1

phosphorylation

down-regulates activity

0.344

Here we report that the prefoldin chaperone URI represents a mitochondrial substrate of S6K1. In growth factor-deprived or rapamycin-treated cells, URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria, thereby inhibiting the activity of the bound enzyme. Growth factor stimulation induces disassembly of URI/PP1gamma complexes through S6K1-mediated phosphorylation of URI at serine 371.

SIGNOR-262943

Q14344

Q92633

2

binding

up-regulates

0.456

The receptor, now called lpa1, is a gpcr that couples to heterotrimeric g proteins (gi, gq, g12/13alpha subunits).

SIGNOR-230761