GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 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
P12821	P01019	1	cleavage	up-regulates activity	0.782	Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide.	SIGNOR-253326
P05112	P78552	1	binding	up-regulates	0.782	It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1.	SIGNOR-100759
P01275-PRO_0000011258	P43220	1	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
Q07325	P49682	1	binding	up-regulates activity	0.782	The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells.	SIGNOR-260970
Q14289	P56945	1	phosphorylation	up-regulates activity	0.782	Pyk2 knockdown also decreased p130Cas.\|p130Cas and paxillin can be phosphorylated by Fak or Pyk2, and bind directly to these kinases.	SIGNOR-280100
P01275	P43220	1	binding	up-regulates	0.782	In the present study we stably expressed the rat b-cell glp-i receptor in cho cells and studied binding characteristics and receptor activation utilizing the naturally occurring receptor agonist glp-i(7-36)-amide (glp-i), the proglucagon-derived glp-i-related peptide oxyntomodulin, the glp-i receptor agonist exendin-4, and the specific antagonist exendin	SIGNOR-34855
P02647	P04180	1	binding	up-regulates activity	0.782	Activation of LCAT by apolipoprotein (apo) A-I on nascent (discoidal) high density lipoproteins (HDL) is essential for formation of mature (spheroidal) HDL during the antiatherogenic process of reverse cholesterol transport. After attachment of LCAT to discoidal HDL, the helix 5/5 domains in apoA-I form amphipathic presentation tunnels for migration of hydrophobic acyl chains and amphipathic UC from the bilayer to the phospholipase A2-like and esterification active sites of LCAT, respectively.	SIGNOR-252103
Q9BXW4	Q9NT62	1	binding	up-regulates activity	0.782	Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe	SIGNOR-191552
Q86Y01	P46531	1	ubiquitination	up-regulates activity	0.781	The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway.	SIGNOR-85942
P27361	P05412	1	phosphorylation	up-regulates	0.781	Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein.	SIGNOR-91379
P40225	P40238	1	binding	up-regulates	0.781	Thrombopoietin(tpo) controls the formation of megakaryocytes and platelets from hematopoietic stem cells via activation of the c-mplreceptorand multiple downstream signal transduction pathways.	SIGNOR-113955
Q16690	P28482	1	dephosphorylation	down-regulates	0.781	Here we demonstrate that dusp5, an inducible nuclear phosphatase, interacts specifically with erk2 via a kinase interaction motif (kim) within its amino-terminal noncatalytic domain. This binding determines the substrate specificity of dusp5 in vivo, as it inactivates erk2 but not jun n-terminal protein kinase or p38 map kinase.	SIGNOR-134049
P51617	Q9HAT8	2	phosphorylation	up-regulates activity	0.781	The phosphorylation of Pellino2 by activated IRAK1 and IRAK4 could trigger and modulate the translocation of IRAKs from complex I to complex II.	SIGNOR-278947
O14757	P54132	1	phosphorylation	down-regulates quantity by destabilization	0.781	We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges.	SIGNOR-276909
P18031	P12931	1	dephosphorylation	up-regulates activity	0.781	Incubation of the inactivated c-Src with PTP1B results in a dose-dependent reactivation of c-Src tyrosine kinase activity. Incubation of c-Src with 2 or 10 g of PTP1B results in partial or full restoration of c-Src kinase activity, respectively. The activation is accompanied by dephosphorylation of c-Src, both of Tyr-419 and of Tyr-530	SIGNOR-245299
Q15628	Q13158	1	binding	up-regulates activity	0.781	Tradd recruits fadd	SIGNOR-177958
Q96PU5	Q15796	1	ubiquitination	down-regulates activity	0.781	Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation	SIGNOR-217622
Q9Y275	O14836	1	binding	up-regulates	0.781	Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys.	SIGNOR-81360
Q9HAT8	P51617	2	ubiquitination	up-regulates	0.781	These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4.	SIGNOR-159058
Q96GD4	O95235	1	phosphorylation	down-regulates activity	0.781	We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878.	SIGNOR-262659
O14757	P04637	1	phosphorylation	up-regulates activity	0.78	Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage.	SIGNOR-217861
P45983	P15336	1	phosphorylation	up-regulates	0.78	Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain.	SIGNOR-33914
P63165	P29590	1	sumoylation	up-regulates	0.78	We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins\|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites\| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation.	SIGNOR-261786
Q8IU57	P23458	1	binding	up-regulates	0.78	Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain.	SIGNOR-124480
P10145	P25024	1	binding	up-regulates	0.78	Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades.	SIGNOR-107920
Q96GD4	Q9H0H5	1	phosphorylation	up-regulates activity	0.78	It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. \| the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1	SIGNOR-250590
Q07889	P01111	1	guanine nucleotide exchange factor	up-regulates activity	0.78	Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras	SIGNOR-110566
Q14527	P12004	1	ubiquitination	up-regulates activity	0.78	HLTF promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen (PCNA) that is required for maintaining genomic stability.	SIGNOR-278608
P12644	Q13873	1	binding	up-regulates	0.78	Bmp-4 bound to alk-3 and alk-6 efficiently	SIGNOR-35763
Q14232	P20042	1	guanine nucleotide exchange factor	up-regulates activity	0.78	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269129
Q8WU20	Q06124	1	phosphorylation	up-regulates	0.78	In addition to the direct interactions with grb2, tyrosine-phosphorylated frs2 forms a complex with the sh2 domain-containing protein tyrosine phosphatase shp2. This interaction results in tyrosine phosphorylation of shp2 and complex formation between shp2 and grb2. the catalytic activity of shp2 is essential for a sustained map kinase response and for potentiation of fgf-induced neurite outgrowth in pc12 cells	SIGNOR-58196
O95476	Q14693	1	dephosphorylation	up-regulates activity	0.78	Dullard significantly dephosphorylates mouse lipin 1b only in BHK cells (Fig. 5A). This is most clearly seen by using the antibody prepared against the phosphorylation site Ser-106.\|Dephosphorylation of lipin results in its translocation to the nuclear envelope and endoplasmic reticulum membranes from the cytosol and generation of diacylglycerol	SIGNOR-248346
P16333	O00401	1	binding	up-regulates	0.78	Nck and cdc42 activate n-wasp by redundant mechanisms.	SIGNOR-107634
Q14674	O60216	1	cleavage	down-regulates quantity by destabilization	0.78	In order to segregate sister chromatids to opposite poles in anaphase, cohesin has to be removed from chromosomes. In budding yeast, the prevalent mode of cohesin removal is by proteolytic cleavage of the Scc1 subunit at the onset of anaphase by the endopeptidase separase	SIGNOR-275537
O00206	P58753	1	binding	up-regulates activity	0.78	Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2.	SIGNOR-252064
Q7Z412	Q13608	1	binding	up-regulates activity	0.78	Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions.	SIGNOR-253614
Q9BUB5	P06730	1	phosphorylation	up-regulates	0.779	Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e.	SIGNOR-166646
P01106	P38936	1	transcriptional regulation	down-regulates quantity by repression	0.779	C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a	SIGNOR-102740
P03952	P01042	1	cleavage	up-regulates activity	0.779	Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1).	SIGNOR-263548
P18031	P35568	1	dephosphorylation	down-regulates	0.779	Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein.	SIGNOR-74852
Q13418	P31749	1	phosphorylation	up-regulates	0.779	Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation.	SIGNOR-252597
P04629	Q8WU20	1	binding	up-regulates	0.779	The signaling adapter frs-2 competes with shc for binding to the nerve growth factor receptor trka:a model for discriminating proliferation and differentiation	SIGNOR-65955
P04629	Q92529-2	1	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
Q06187	P16885	1	phosphorylation	up-regulates	0.778	By measuring the ability of human plcgamma2 to restore calcium responses to the b-cell receptor stimulation or oxidative stress in a b-cell line (dt40) deficient in plcgamma2, we have demonstrated that two tyrosine residues, tyr(753) and tyr(759), were important for the plcgamma2 signaling function.Of the two kinases that previously have been proposed to phosphorylate plcgamma2, btk, and syk, purified btk had much greater ability to phosphorylate recombinant plcgamma2 in vitro, whereas syk efficiently phosphorylated adapter protein blnk.	SIGNOR-111069
Q15796	Q9HAU4	2	binding	up-regulates activity	0.778	We show that in the presence of TGF-beta signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases.Thus, stimulation by TGF-beta can induce the assembly of a Smad2-Smurf2 ubiquitin ligase complex that functions to target substrates for degradation.	SIGNOR-108490
P01116	P48736	1	binding	up-regulates	0.778	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.	SIGNOR-59819
O75593	Q15796	1	binding	up-regulates activity	0.778	FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-beta, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1.	SIGNOR-108333
Q92918	Q13094	1	phosphorylation	up-regulates	0.778	The serine/threonine kinase hpk-1 phosphorylates serine 376 of slp-76 and induces the interaction with 14-3-3 proteins	SIGNOR-153613
O14965	P04637	1	phosphorylation	up-regulates activity	0.778	The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A	SIGNOR-120836
P15153	Q13153	1	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
P28482	P04637	1	phosphorylation	up-regulates activity	0.778	In summary, our results suggest that phosphorylation of p53Thr55 by ERK2 is important for doxorubicin-induced p53 activation and cell death.	SIGNOR-279068
P01189	P32245	1	binding	up-regulates activity	0.778	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268710
Q9HAU4	Q15796	2	ubiquitination	down-regulates activity	0.778	The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway.	SIGNOR-236133
P12931	P03372	1	phosphorylation	up-regulates	0.778	Although the molecular mechanisms underlying ligand-independent activation of era are not completely understood, phosphorylation of a serine residue in af1 has been implicated in the response to epidermal growth factor. Era is also a target for tyrosine phosphorylation, anda single tyrosine residue located immediately adjacent to af2 has been identified as a substrate for src-family tyrosine kinases.	SIGNOR-55857
P50750	P24928	1	phosphorylation	up-regulates	0.777	Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself	SIGNOR-203528
P01275	P47871	1	binding	up-regulates	0.777	In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function.	SIGNOR-198504
P10911	P60953	1	guanine nucleotide exchange factor	up-regulates activity	0.777	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-260558
Q8NFA2	Q86UR1	1	relocalization	up-regulates activity	0.777	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner\|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein\|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264709
Q00535	Q9UD71	1	phosphorylation	up-regulates activity	0.777	We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism.	SIGNOR-250671
P21802	Q8WU20	1	phosphorylation	up-regulates activity	0.777	In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.	SIGNOR-236950
P42345	Q8IYT8	1	phosphorylation	down-regulates	0.777	Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2	SIGNOR-183961
Q9NR81	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.777	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-260530
P09341	P25025	1	binding	up-regulates activity	0.777	CXCL1 produces cellular chemotactic activity by binding to the CXC chemokine receptor 2 (CXCR2). In PC, this chemokine has been associated with a variety of carcinogenic mechanisms, including oncogene-induced senescence (OIS), angiogenesis, cancer metastasis, and immunosuppressive microenvironments	SIGNOR-277717
P06493	O60566	1	phosphorylation	up-regulates	0.777	Here, we demonstrate that bubr1 is phosphorylated on the cdk1 site t620, which triggers the recruitment of plk1 and phosphorylation of bubr1 by plk1 both in vitro and in vivo. Phosphorylation does not appear to be required for spindle checkpoint function but instead is important for the stability of kinetochore-microtubule (kt-mt) interactions	SIGNOR-157642
P61278	P31391	1	binding	up-regulates	0.777	The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity.	SIGNOR-82496
Q8WXE9	P21579	1	binding	up-regulates quantity	0.777	the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval. the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively.	SIGNOR-264115
P01241	P16471	1	binding	up-regulates	0.777	Hprl does not bind to the hgh receptor, but hgh binds to both the hghr and hprlr, and mutagenesis studies have shown that the receptor-binding sites on hgh overlap.	SIGNOR-35575
O14625	P49682	1	binding	up-regulates activity	0.777	The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells.	SIGNOR-260971
O43612	O43614	1	binding	up-regulates	0.776	Identification and initial biological characterization of two orexins as well as their two receptors	SIGNOR-55848
P50750	O00267	1	phosphorylation	up-regulates	0.776	We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif	SIGNOR-143939
Q13705	Q15796	1	phosphorylation	up-regulates activity	0.776	It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains	SIGNOR-254984
Q5JTC6	P35222	1	binding	down-regulates activity	0.776	We show that Amer1 binds directly to beta-catenin via a novel interaction motif, the REA repeats. This amino acid motif, including the core sequence arginine, glutamic acid and alanine, and this REA repeats mediate binding of Amer1 to the armadillo repeats of beta-catenin. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the plasma membrane.	SIGNOR-217950
O60716	P33151	1	binding	up-regulates quantity by stabilization	0.776	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252126
Q8N2Q7	P78352	1	relocalization	up-regulates activity	0.776	Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.	SIGNOR-264191
Q92837	P49841	2	binding	up-regulates	0.776	The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway	SIGNOR-58219
O95150	Q93038	1	binding	up-regulates	0.776	The ligand of dr3 is tl1a	SIGNOR-103078
P51532	O14746	1	binding	up-regulates	0.776	Tert activates wnt reporter plasmids in a brg1-dependent manner.	SIGNOR-186607
P23443	P23588	1	phosphorylation	up-regulates	0.776	S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.	SIGNOR-123997
P49841	Q92837	2	phosphorylation	down-regulates activity	0.776	Protein kinase A (PKA) was found to phosphorylate Ser188 in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled beta-adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser188. GSK-3 was also able to phosphorylate FRAT1 at Ser188 and other residues in vitro or when overexpressed in intact cells. Phosphorylation of Ser188 by PKA inhibited the ability of FRAT1 to activate beta-catenin-dependent transcription.	SIGNOR-276057
Q16539	P42574	1	phosphorylation	down-regulates	0.775	Consequently, p38-mapk can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response.	SIGNOR-122099
Q9BXM7	Q8IXI2	1	phosphorylation	down-regulates quantity by destabilization	0.775	PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C).	SIGNOR-272728
Q96PU5	P37088	1	ubiquitination	down-regulates quantity by destabilization	0.775	The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane.	SIGNOR-251948
P31749	P55211	1	phosphorylation	down-regulates activity	0.775	Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity	SIGNOR-252581
Q04759	Q9BXL7	1	phosphorylation	up-regulates activity	0.775	NF-kappaB activation is triggered by PKCteta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCteta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane\|we demonstrate that PP2A removes PKCteta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.	SIGNOR-249193
P78352	Q9P244	1	binding	up-regulates activity	0.775	SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses.	SIGNOR-264095
P29597	P42224	1	phosphorylation	up-regulates activity	0.775	Co-expression of Stat1 with Tyk2, Jak1, or Jak2 resulted in the specific tyrosine phosphorylation of Stat1 at Tyr701Phosphorylation of purified Stat1 was necessary and sufficient for the acquisition of DNA binding activity.	SIGNOR-246943
P12931	P01112	1	phosphorylation	down-regulates activity	0.775	Src binds to and phosphorylates GTP-, but not GDP-, loaded Ras on a conserved Y32 residue within the switch I region in vitro and that in vivo, Ras-Y32 phosphorylation markedly reduces the binding to effector Raf and concomitantly increases binding to GTPase-activating proteins and the rate of GTP hydrolysis	SIGNOR-252093
P42574	P09874	1	cleavage	down-regulates activity	0.775	Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process	SIGNOR-116178
Q13315	P54132	1	phosphorylation	up-regulates	0.775	Mitotic phosphorylation of blm was partially dependent on atm, and phosphorylation sites on blm were identified. A phosphospecific antibody against one of these sites (thr-99) revealed radiation-induced phosphorylation, which was defective in ataxia-telangiectasia cells. These data suggest that atm and blm function together in recognizing abnormal dna structures by direct interaction and that these phosphorylation sites in blm are important for radiosensitivity status but not for sce frequency.	SIGNOR-88010
P43405	P19174	1	phosphorylation	up-regulates activity	0.775	Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771.	SIGNOR-246576
P41221	Q01974	1	binding	up-regulates	0.775	Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation\|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis.	SIGNOR-199647
P45983	Q07817	1	phosphorylation	down-regulates	0.775	By site-directed mutagenesis studies, we have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in prostate cancer cells. Further studies with the inhibitor of jun kinase (jnk) and phosphorylation mutant of bcl-xl reveal the augmentative role of jnk-mediated bcl-xl phosphorylation in apoptosis of prostate cancer cells. In summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl to permit prostate cancer cells to die by apoptosis	SIGNOR-99219
P35222	P46531	1	binding	up-regulates	0.775	Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential.	SIGNOR-236858
Q96G74	Q13114	1	deubiquitination	down-regulates activity	0.775	TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains. DUBA selectively cleaved the lysine-63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1.	SIGNOR-265873
Q13459	P61586	1	gtpase-activating protein	down-regulates activity	0.774	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-260509
O00253	P32245	1	binding	down-regulates	0.774	Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r,.	SIGNOR-51104
Q9NZD4	P69905	1	binding	up-regulates quantity by stabilization	0.774	α-Hemoglobin stabilizing protein (AHSP) binds α-hemoglobin (Hb), avoiding its precipitation and its pro-oxidant activity.	SIGNOR-251770
O60674	P48357	2	phosphorylation	up-regulates activity	0.774	LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2.	SIGNOR-263494
P00738	P68871	1	binding	down-regulates quantity	0.774	Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers.	SIGNOR-251815
P48357	O60674	2	binding	up-regulates activity	0.774	Janus kinase 2 (JAK2) is associated with LEPRb and autophosphorylates in response to leptin. JAK2 also phosphorylates LEPRb, STAT3, and multiple other downstream molecules.	SIGNOR-263491

P12821

P01019

1

cleavage

up-regulates activity

0.782

Angiotensin I-converting enzyme is a zinc metallopeptidase that plays an important role in blood pressure regulation by cleaving the inactive decapeptide angiotensin I to angiotensin II, a potent vasopressor octapeptide.

SIGNOR-253326

P05112

P78552

1

binding

up-regulates

0.782

It is now known that this alternate receptor is a heterodimer, the type ii il-4 receptor or the il-13 receptor, which is comprised of IL-4R And IL-13R1.

SIGNOR-100759

P01275-PRO_0000011258

P43220

1

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

Q07325

P49682

1

binding

up-regulates activity

0.782

The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells.

SIGNOR-260970

Q14289

P56945

1

phosphorylation

up-regulates activity

0.782

Pyk2 knockdown also decreased p130Cas.|p130Cas and paxillin can be phosphorylated by Fak or Pyk2, and bind directly to these kinases.

SIGNOR-280100

P01275

P43220

1

binding

up-regulates

0.782

In the present study we stably expressed the rat b-cell glp-i receptor in cho cells and studied binding characteristics and receptor activation utilizing the naturally occurring receptor agonist glp-i(7-36)-amide (glp-i), the proglucagon-derived glp-i-related peptide oxyntomodulin, the glp-i receptor agonist exendin-4, and the specific antagonist exendin

SIGNOR-34855

P02647

P04180

1

binding

up-regulates activity

0.782

Activation of LCAT by apolipoprotein (apo) A-I on nascent (discoidal) high density lipoproteins (HDL) is essential for formation of mature (spheroidal) HDL during the antiatherogenic process of reverse cholesterol transport. After attachment of LCAT to discoidal HDL, the helix 5/5 domains in apoA-I form amphipathic presentation tunnels for migration of hydrophobic acyl chains and amphipathic UC from the bilayer to the phospholipase A2-like and esterification active sites of LCAT, respectively.

SIGNOR-252103

Q9BXW4

Q9NT62

1

binding

up-regulates activity

0.782

Lc3-i is activated by the same atg7 involved in atg12 conjugation, transferred to atg3, a second e2-like enzyme, and finally conjugated to pe

SIGNOR-191552

Q86Y01

P46531

1

ubiquitination

up-regulates activity

0.781

The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway.

SIGNOR-85942

P27361

P05412

1

phosphorylation

up-regulates

0.781

Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein.

SIGNOR-91379

P40225

P40238

1

binding

up-regulates

0.781

Thrombopoietin(tpo) controls the formation of megakaryocytes and platelets from hematopoietic stem cells via activation of the c-mplreceptorand multiple downstream signal transduction pathways.

SIGNOR-113955

Q16690

P28482

1

dephosphorylation

down-regulates

0.781

Here we demonstrate that dusp5, an inducible nuclear phosphatase, interacts specifically with erk2 via a kinase interaction motif (kim) within its amino-terminal noncatalytic domain. This binding determines the substrate specificity of dusp5 in vivo, as it inactivates erk2 but not jun n-terminal protein kinase or p38 map kinase.

SIGNOR-134049

P51617

Q9HAT8

2

phosphorylation

up-regulates activity

0.781

The phosphorylation of Pellino2 by activated IRAK1 and IRAK4 could trigger and modulate the translocation of IRAKs from complex I to complex II.

SIGNOR-278947

O14757

P54132

1

phosphorylation

down-regulates quantity by destabilization

0.781

We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3β- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates.Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges.

SIGNOR-276909

P18031

P12931

1

dephosphorylation

up-regulates activity

0.781

Incubation of the inactivated c-Src with PTP1B results in a dose-dependent reactivation of c-Src tyrosine kinase activity. Incubation of c-Src with 2 or 10 g of PTP1B results in partial or full restoration of c-Src kinase activity, respectively. The activation is accompanied by dephosphorylation of c-Src, both of Tyr-419 and of Tyr-530

SIGNOR-245299

Q15628

Q13158

1

binding

up-regulates activity

0.781

Tradd recruits fadd

SIGNOR-177958

Q96PU5

Q15796

1

ubiquitination

down-regulates activity

0.781

Through its ww domain, nedd4l specifically recognizes a tgf-beta-induced phosphothr-protyr motif in the linker region, resulting in smad2/3 polyubiquitination and degradation

SIGNOR-217622

Q9Y275

O14836

1

binding

up-regulates

0.781

Tumor necrosis factor (tnf) receptor superfamily member taci is a high affinity receptor for tnf family members april and blys.

SIGNOR-81360

Q9HAT8

P51617

2

ubiquitination

up-regulates

0.781

These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4.

SIGNOR-159058

Q96GD4

O95235

1

phosphorylation

down-regulates activity

0.781

We identify MKlp2 as an essential protein for promoting abscission, which may regulate tethering and stabilizing of the PM to the microtubule cytoskeleton. Aurora B phosphorylation of MKlp2 S878 in the LAM is a key inhibitory signal for abscission. Conversely, B56-PP2A promotes abscission by opposing Aurora B phosphorylation of MKlp2 S878.

SIGNOR-262659

O14757

P04637

1

phosphorylation

up-regulates activity

0.78

Phosphorylation by chk1 of at least three of these sites, Ser366, Ser378, and Thr387, was induced by DNA damage.

SIGNOR-217861

P45983

P15336

1

phosphorylation

up-regulates

0.78

Activating transcription factor-2 (atf2) was found to be a target of the jnk signal transduction pathway. Atf2 was phosphorylated by jnk on two closely spaced threonine residues within the nh2-terminal activation domain.

SIGNOR-33914

P63165

P29590

1

sumoylation

up-regulates

0.78

We have shown previously that wild type PML, but not PML-RARalpha, is covalently modified by the sentrin family of ubiquitin-like proteins|We show that Lys65 in the RING finger domain, Lys160 in the B1 Box, and Lys490 in the nuclear localization signal contributes three major sentrinization sites| Furthermore, the triple substitution mutant is localized predominantly to the nucleoplasm, in contrast to wild type PML, which is localized to the nuclear bodies. Thus, sentrinization of PML, in the context of the RING finger and the B1 box, regulates nuclear body formation.

SIGNOR-261786

Q8IU57

P23458

1

binding

up-regulates

0.78

Each r1-type chain (il-10r1, il-20r1, il-22r1, ifn-_r1 and ifn-_r1) is associated with jak1 tyrosine kinase and mediates recruitment of a variety of signaling molecules after being phosphorylated on its intracellular domain.

SIGNOR-124480

P10145

P25024

1

binding

up-regulates

0.78

Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades.

SIGNOR-107920

Q96GD4

Q9H0H5

1

phosphorylation

up-regulates activity

0.78

It was found that the 5A fragment in which five Ser/Thr residues were substituted with Ala (S144A/T145A/S185A/T186A/S187A) fully prevented phosphorylation (Fig. 5B), confirming that Aurora B primarily phosphorylates five Ser/Thr residues in the basic region of MgcRacGAP. | the strong phosphorylation of the basic region of MgcRacGAP by Aurora B kinase was demonstrated, and this phosphorylation prevents the inhibition of MgcRacGAP GAP activity by PRC1

SIGNOR-250590

Q07889

P01111

1

guanine nucleotide exchange factor

up-regulates activity

0.78

Sos and Ras-GRF are two families of guanine nucleotide exchange factors that activate Ras proteins in cells. Sos proteins are ubiquitously expressed and are activated in response to cell-surface tyrosine kinase stimulation Sos1 and Ras-GRF1 activate the Ras proteins Ha-Ras, N-Ras, and Ki-Ras

SIGNOR-110566

Q14527

P12004

1

ubiquitination

up-regulates activity

0.78

HLTF promotes the Lys-63-linked polyubiquitination of proliferating cell nuclear antigen (PCNA) that is required for maintaining genomic stability.

SIGNOR-278608

P12644

Q13873

1

binding

up-regulates

0.78

Bmp-4 bound to alk-3 and alk-6 efficiently

SIGNOR-35763

Q14232

P20042

1

guanine nucleotide exchange factor

up-regulates activity

0.78

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269129

Q8WU20

Q06124

1

phosphorylation

up-regulates

0.78

In addition to the direct interactions with grb2, tyrosine-phosphorylated frs2 forms a complex with the sh2 domain-containing protein tyrosine phosphatase shp2. This interaction results in tyrosine phosphorylation of shp2 and complex formation between shp2 and grb2. the catalytic activity of shp2 is essential for a sustained map kinase response and for potentiation of fgf-induced neurite outgrowth in pc12 cells

SIGNOR-58196

O95476

Q14693

1

dephosphorylation

up-regulates activity

0.78

Dullard significantly dephosphorylates mouse lipin 1b only in BHK cells (Fig. 5A). This is most clearly seen by using the antibody prepared against the phosphorylation site Ser-106.|Dephosphorylation of lipin results in its translocation to the nuclear envelope and endoplasmic reticulum membranes from the cytosol and generation of diacylglycerol

SIGNOR-248346

P16333

O00401

1

binding

up-regulates

0.78

Nck and cdc42 activate n-wasp by redundant mechanisms.

SIGNOR-107634

Q14674

O60216

1

cleavage

down-regulates quantity by destabilization

0.78

In order to segregate sister chromatids to opposite poles in anaphase, cohesin has to be removed from chromosomes. In budding yeast, the prevalent mode of cohesin removal is by proteolytic cleavage of the Scc1 subunit at the onset of anaphase by the endopeptidase separase

SIGNOR-275537

O00206

P58753

1

binding

up-regulates activity

0.78

Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-_B, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2.

SIGNOR-252064

Q7Z412

Q13608

1

binding

up-regulates activity

0.78

Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions.

SIGNOR-253614

Q9BUB5

P06730

1

phosphorylation

up-regulates

0.779

Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e.

SIGNOR-166646

P01106

P38936

1

transcriptional regulation

down-regulates quantity by repression

0.779

C-myc also directly represses transcription of cdk kinase inhibitors including p27kip1, p21cip1, p15ink4b and p16ink4a

SIGNOR-102740

P03952

P01042

1

cleavage

up-regulates activity

0.779

Bradykinin is a nonapeptide composed of the sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg and functions as an inflammatory mediator. BK is the product of the kallikrein–kinin system following activation of FXII. FXIIa leads to proteolysis of PK, and the resulting PKa cleaves HK to generate BK (Figure 1).

SIGNOR-263548

P18031

P35568

1

dephosphorylation

down-regulates

0.779

Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the Grb2 adaptor protein.

SIGNOR-74852

Q13418

P31749

1

phosphorylation

up-regulates

0.779

Ilk can phosphorylate pkb-akt on serine-473, whereas kinase-deficient ilk severely inhibits endogenous phosphorylation of pkb-akt on serine-473, demonstrating that ilk is involved in agonist stimulated, pi(3)k-dependent, pkb-akt activation.

SIGNOR-252597

P04629

Q8WU20

1

binding

up-regulates

0.779

The signaling adapter frs-2 competes with shc for binding to the nerve growth factor receptor trka:a model for discriminating proliferation and differentiation

SIGNOR-65955

P04629

Q92529-2

1

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

Q06187

P16885

1

phosphorylation

up-regulates

0.778

By measuring the ability of human plcgamma2 to restore calcium responses to the b-cell receptor stimulation or oxidative stress in a b-cell line (dt40) deficient in plcgamma2, we have demonstrated that two tyrosine residues, tyr(753) and tyr(759), were important for the plcgamma2 signaling function.Of the two kinases that previously have been proposed to phosphorylate plcgamma2, btk, and syk, purified btk had much greater ability to phosphorylate recombinant plcgamma2 in vitro, whereas syk efficiently phosphorylated adapter protein blnk.

SIGNOR-111069

Q15796

Q9HAU4

2

binding

up-regulates activity

0.778

We show that in the presence of TGF-beta signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases.Thus, stimulation by TGF-beta can induce the assembly of a Smad2-Smurf2 ubiquitin ligase complex that functions to target substrates for degradation.

SIGNOR-108490

P01116

P48736

1

binding

up-regulates

0.778

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.

SIGNOR-59819

O75593

Q15796

1

binding

up-regulates activity

0.778

FAST-2 also interacts directly with Smad2, a cytoplasmic protein which is translocated to the nucleus in response to TGF-beta, and forms a multimeric complex with Smad2 and Smad4 on the activin response element, a high-affinity binding site for FAST-1.

SIGNOR-108333

Q92918

Q13094

1

phosphorylation

up-regulates

0.778

The serine/threonine kinase hpk-1 phosphorylates serine 376 of slp-76 and induces the interaction with 14-3-3 proteins

SIGNOR-153613

O14965

P04637

1

phosphorylation

up-regulates activity

0.778

The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A

SIGNOR-120836

P15153

Q13153

1

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

P28482

P04637

1

phosphorylation

up-regulates activity

0.778

In summary, our results suggest that phosphorylation of p53Thr55 by ERK2 is important for doxorubicin-induced p53 activation and cell death.

SIGNOR-279068

P01189

P32245

1

binding

up-regulates activity

0.778

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

SIGNOR-268710

Q9HAU4

Q15796

2

ubiquitination

down-regulates activity

0.778

The ability of smurf2 to promote smad2 destruction required the hect catalytic activity of smurf2 and depended on the proteasome-dependent pathway.

SIGNOR-236133

P12931

P03372

1

phosphorylation

up-regulates

0.778

Although the molecular mechanisms underlying ligand-independent activation of era are not completely understood, phosphorylation of a serine residue in af1 has been implicated in the response to epidermal growth factor. Era is also a target for tyrosine phosphorylation, anda single tyrosine residue located immediately adjacent to af2 has been identified as a substrate for src-family tyrosine kinases.

SIGNOR-55857

P50750

P24928

1

phosphorylation

up-regulates

0.777

Cyclin-dependent kinase 9 (cdk9) promotes elongation by rna polymerase ii (rnapii), mrna processing, and co-transcriptional histone modification. Cdk9 phosphorylates multiple targets, including the conserved rnapii elongation factor spt5 and rnapii itself

SIGNOR-203528

P01275

P47871

1

binding

up-regulates

0.777

In contrast, stimulation of gs-coupled receptors by glucagon or epinephrine activates lats1/2 kinase activity, thereby inhibiting yap function.

SIGNOR-198504

P10911

P60953

1

guanine nucleotide exchange factor

up-regulates activity

0.777

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-260558

Q8NFA2

Q86UR1

1

relocalization

up-regulates activity

0.777

Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation

SIGNOR-264709

Q00535

Q9UD71

1

phosphorylation

up-regulates activity

0.777

We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism.

SIGNOR-250671

P21802

Q8WU20

1

phosphorylation

up-regulates activity

0.777

In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.

SIGNOR-236950

P42345

Q8IYT8

1

phosphorylation

down-regulates

0.777

Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2

SIGNOR-183961

Q9NR81

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.777

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-260530

P09341

P25025

1

binding

up-regulates activity

0.777

CXCL1 produces cellular chemotactic activity by binding to the CXC chemokine receptor 2 (CXCR2). In PC, this chemokine has been associated with a variety of carcinogenic mechanisms, including oncogene-induced senescence (OIS), angiogenesis, cancer metastasis, and immunosuppressive microenvironments

SIGNOR-277717

P06493

O60566

1

phosphorylation

up-regulates

0.777

Here, we demonstrate that bubr1 is phosphorylated on the cdk1 site t620, which triggers the recruitment of plk1 and phosphorylation of bubr1 by plk1 both in vitro and in vivo. Phosphorylation does not appear to be required for spindle checkpoint function but instead is important for the stability of kinetochore-microtubule (kt-mt) interactions

SIGNOR-157642

P61278

P31391

1

binding

up-regulates

0.777

The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity.

SIGNOR-82496

Q8WXE9

P21579

1

binding

up-regulates quantity

0.777

the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively .Stonin-2 and AP-2 are also Required for Efficient Synaptotagmin-1 Retrieval. the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively.

SIGNOR-264115

P01241

P16471

1

binding

up-regulates

0.777

Hprl does not bind to the hgh receptor, but hgh binds to both the hghr and hprlr, and mutagenesis studies have shown that the receptor-binding sites on hgh overlap.

SIGNOR-35575

O14625

P49682

1

binding

up-regulates activity

0.777

The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells.

SIGNOR-260971

O43612

O43614

1

binding

up-regulates

0.776

Identification and initial biological characterization of two orexins as well as their two receptors

SIGNOR-55848

P50750

O00267

1

phosphorylation

up-regulates

0.776

We describe an evolutionarily conserved repetitive heptapeptide motif (consensus = g-s-r/q-t-p) in the c-terminal region (ctr) of hspt5, which, like the c-terminal domain (ctd) of rna pol ii, is highly phosphorylated by p-tefb. Thr-4 residues of the ctr repeats are functionally important phosphorylation sites. In vitro, thr-4 phosphorylation is critical for the elongation activation activity of dsif

SIGNOR-143939

Q13705

Q15796

1

phosphorylation

up-regulates activity

0.776

It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains

SIGNOR-254984

Q5JTC6

P35222

1

binding

down-regulates activity

0.776

We show that Amer1 binds directly to beta-catenin via a novel interaction motif, the REA repeats. This amino acid motif, including the core sequence arginine, glutamic acid and alanine, and this REA repeats mediate binding of Amer1 to the armadillo repeats of beta-catenin. The data suggest that Amer1 exerts its negative regulatory role in Wnt signaling by acting as a scaffold protein for the beta-catenin destruction complex and promoting stabilization of Axin at the plasma membrane.

SIGNOR-217950

O60716

P33151

1

binding

up-regulates quantity by stabilization

0.776

To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.

SIGNOR-252126

Q8N2Q7

P78352

1

relocalization

up-regulates activity

0.776

Like NRXNs, NLGNs bind to intracellular PDZ-domain proteins, but in contrast to NRXNs, NLGNs bind to class I PDZ domains such as those contained in PSD95, a postsynaptic MAGUK protein65. PSD95 and its homologues are centrally involved in recruiting glutamate receptors at postsynaptic sites66. Similarly to CASK, PSD95 binds to intracellular adaptor proteins, and especially to GKAP (a protein that binds to the guanylate-kinase domain of PSD95), which, in turn, binds to SHANK proteins (Fig. 1b). A possible role of these interactions is to recruit postsynaptic adaptor proteins to the site of synaptic junctions.

SIGNOR-264191

Q92837

P49841

2

binding

up-regulates

0.776

The frat family consists of three members: frat-1, -2, and -3. It has been shown that different sites of frat-1 interact with gsk-3 and dvl-1 and that wnt-1 disintegrates the complex formation of frat-1, dvl-1, and axin, resulting in the activation of the wnt signaling pathway

SIGNOR-58219

O95150

Q93038

1

binding

up-regulates

0.776

The ligand of dr3 is tl1a

SIGNOR-103078

P51532

O14746

1

binding

up-regulates

0.776

Tert activates wnt reporter plasmids in a brg1-dependent manner.

SIGNOR-186607

P23443

P23588

1

phosphorylation

up-regulates

0.776

S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.

SIGNOR-123997

P49841

Q92837

2

phosphorylation

down-regulates activity

0.776

Protein kinase A (PKA) was found to phosphorylate Ser188 in vitro as well as in intact cells. Importantly, activation of endogenous cAMP-coupled beta-adrenergic receptors with norepinephrine stimulated the phosphorylation of FRAT1 at Ser188. GSK-3 was also able to phosphorylate FRAT1 at Ser188 and other residues in vitro or when overexpressed in intact cells. Phosphorylation of Ser188 by PKA inhibited the ability of FRAT1 to activate beta-catenin-dependent transcription.

SIGNOR-276057

Q16539

P42574

1

phosphorylation

down-regulates

0.775

Consequently, p38-mapk can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response.

SIGNOR-122099

Q9BXM7

Q8IXI2

1

phosphorylation

down-regulates quantity by destabilization

0.775

PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. in Miro1, Ser156 (homologous to Ser182 in Drosophila) and Thr298, 299 (homologous to Ser324, 325 in Drosophila, Figure 6C).

SIGNOR-272728

Q96PU5

P37088

1

ubiquitination

down-regulates quantity by destabilization

0.775

The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane.

SIGNOR-251948

P31749

P55211

1

phosphorylation

down-regulates activity

0.775

Akt phosphorylated recombinant casp9 in vitro on serine-196 and inhibited its protease activity

SIGNOR-252581

Q04759

Q9BXL7

1

phosphorylation

up-regulates activity

0.775

NF-kappaB activation is triggered by PKCteta-dependent phosphorylation of Carma1 after TCR/CD28 co-stimulation. PKCteta-phosphorylated Carma1 was suggested to function as a molecular scaffold that recruits preassembled Bcl10-Malt1 complexes to the membrane|we demonstrate that PP2A removes PKCteta-dependent phosphorylation of Ser645 in Carma1, and show that maintenance of this phosphorylation is correlated with increased T-cell activation.

SIGNOR-249193

P78352

Q9P244

1

binding

up-regulates activity

0.775

SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. Interactions between SALMs 1–3 and PSD-95 family proteinscould serve a number of functions. SALM1 and SALM2, which lack the ability to interact with a presynaptic ligand and thus cannot be directly targeted to sites of early synaptic adhesion, may require PSD-95 binding for their localization to early synapses.

SIGNOR-264095

P29597

P42224

1

phosphorylation

up-regulates activity

0.775

Co-expression of Stat1 with Tyk2, Jak1, or Jak2 resulted in the specific tyrosine phosphorylation of Stat1 at Tyr701Phosphorylation of purified Stat1 was necessary and sufficient for the acquisition of DNA binding activity.

SIGNOR-246943

P12931

P01112

1

phosphorylation

down-regulates activity

0.775

Src binds to and phosphorylates GTP-, but not GDP-, loaded Ras on a conserved Y32 residue within the switch I region in vitro and that in vivo, Ras-Y32 phosphorylation markedly reduces the binding to effector Raf and concomitantly increases binding to GTPase-activating proteins and the rate of GTP hydrolysis

SIGNOR-252093

P42574

P09874

1

cleavage

down-regulates activity

0.775

Caspase-3 cleaves parp-1. During cd95-mediated apoptosis proteolytic inactivation of parp-1 by caspases prevents atp depletion and thereby ensures the execution of the apoptotic process

SIGNOR-116178

Q13315

P54132

1

phosphorylation

up-regulates

0.775

Mitotic phosphorylation of blm was partially dependent on atm, and phosphorylation sites on blm were identified. A phosphospecific antibody against one of these sites (thr-99) revealed radiation-induced phosphorylation, which was defective in ataxia-telangiectasia cells. These data suggest that atm and blm function together in recognizing abnormal dna structures by direct interaction and that these phosphorylation sites in blm are important for radiosensitivity status but not for sce frequency.

SIGNOR-88010

P43405

P19174

1

phosphorylation

up-regulates activity

0.775

Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771.

SIGNOR-246576

P41221

Q01974

1

binding

up-regulates

0.775

Wnt5a induces ROR1/ROR2 heterooligomerization to enhance leukemia chemotaxis and proliferation|Evolutionarily conserved receptor tyrosine kinase–like orphan receptor-1 and -2 (ROR1/2) are considered distinct receptors for Wnt5a and are implicated in noncanonical Wnt signaling in organogenesis and cancer metastasis.

SIGNOR-199647

P45983

Q07817

1

phosphorylation

down-regulates

0.775

By site-directed mutagenesis studies, we have identified that serine 62 is the necessary site for taxol- or 2-me-induced bcl-xl phosphorylation in prostate cancer cells. Further studies with the inhibitor of jun kinase (jnk) and phosphorylation mutant of bcl-xl reveal the augmentative role of jnk-mediated bcl-xl phosphorylation in apoptosis of prostate cancer cells. In summary, our studies suggest that the phosphorylation of bcl-xl by stress response kinase signaling might oppose the anti-apoptotic function of bcl-xl to permit prostate cancer cells to die by apoptosis

SIGNOR-99219

P35222

P46531

1

binding

up-regulates

0.775

Beta-catenin can regulate the level and transcriptional activity of the notch1 and notch1 intracellular domain (nicd). The in vivo and in vitro results demonstrate that beta-catenin binds with notch1 and nicd, for which its armadillo repeat domain is essential.

SIGNOR-236858

Q96G74

Q13114

1

deubiquitination

down-regulates activity

0.775

TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains. DUBA selectively cleaved the lysine-63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1.

SIGNOR-265873

Q13459

P61586

1

gtpase-activating protein

down-regulates activity

0.774

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-260509

O00253

P32245

1

binding

down-regulates

0.774

Recombinant agouti-related protein was a potent, selective antagonist of mc3r and mc4r,.

SIGNOR-51104

Q9NZD4

P69905

1

binding

up-regulates quantity by stabilization

0.774

α-Hemoglobin stabilizing protein (AHSP) binds α-hemoglobin (Hb), avoiding its precipitation and its pro-oxidant activity.

SIGNOR-251770

O60674

P48357

2

phosphorylation

up-regulates activity

0.774

LRb signaling is initiated by leptin binding to the extracellular domain of the LRb dimer, leading to Jak2 transphosphorylation and activation. Activated Jak2 mediates the tyrosine phosphorylation of Tyr985 and Tyr1138of LRb. These phosphotyrosine residues immediately function as binding sites (double-ended lines) for SHP-2 and STAT3, both of which quickly become tyrosine-phosphorylated by Jak2.

SIGNOR-263494

P00738

P68871

1

binding

down-regulates quantity

0.774

Haptoglobin forms a complex of extremely high affinity with Hb via a well-characterized globin site. Our results show that upon Hb-haptoglobin binding, the globin radical, loses its ability to be terminated by forming globin dimers.

SIGNOR-251815

P48357

O60674

2

binding

up-regulates activity

0.774

Janus kinase 2 (JAK2) is associated with LEPRb and autophosphorylates in response to leptin. JAK2 also phosphorylates LEPRb, STAT3, and multiple other downstream molecules.

SIGNOR-263491