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
Q8IYT8	O75143	2	phosphorylation	up-regulates	0.75	Ulks directly phosphorylates atg13.	SIGNOR-184126
P24941	Q08050	1	phosphorylation	up-regulates activity	0.75	We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins.	SIGNOR-250731
Q13009	P63000	1	binding	up-regulates	0.75	Lpa-induced rac activation requires tiam1	SIGNOR-94691
O43921	P29322	1	binding	up-regulates	0.75	The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. Therefore, eph receptors mediate signals that can override cell adhesion.	SIGNOR-52269
O76064	P61088	1	binding	up-regulates	0.75	The rnf8 ring domain signals ubc13 to sites of damage, which is sufficient for dna damage signal transduction.	SIGNOR-179823
Q99075	Q15303	1	binding	up-regulates	0.75	It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response.	SIGNOR-67009
P52797	P29322	1	binding	up-regulates	0.75	Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor	SIGNOR-52387
P63000	Q13177	1	binding	up-regulates activity	0.75	A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.	SIGNOR-248250
P15056	P36507	1	phosphorylation	up-regulates	0.75	We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l.	SIGNOR-42664
Q02750	P28482	2	phosphorylation	up-regulates activity	0.75	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-236447
P55010	O60841	1	relocalization	up-regulates activity	0.75	eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC.	SIGNOR-269122
P28482	Q02750	2	phosphorylation	down-regulates activity	0.75	We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling.	SIGNOR-236335
O75143	Q8IYT8	2	binding	up-regulates	0.75	He mammalian atg13 binds both ulk1 and ulk2 and mediates the interaction of the ulk proteins with fip200. The binding of atg13 stabilizes and activates ulk and facilitates the phosphorylation of fip200 by ulk	SIGNOR-184123
P15498	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.75	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260580
P12931	P42229	1	phosphorylation	up-regulates	0.75	Src can thus directly tyrosine-phosphorylate the activation site of stat5 (tyr 694 in stat5a), and src may contribute to epo-induced signal transduction via stat5.	SIGNOR-111078
P05412	P84022	1	binding	down-regulates activity	0.75	These results indicate that interaction between Smad3 and c-Jun may repress Smad3 transcriptional activity.	SIGNOR-256284
P53350	Q9H8V3	1	phosphorylation	up-regulates activity	0.75	Phosphorylation of Ect2 by Plk1 during anaphase might alleviate this intramolecular inhibition by dissociating the Ect2 amino from the carboxyl terminus.\|Together with the presence of a prominent microtubule array at the midzone, these data suggest that Plk1 is not essential for the formation of the central spindle at anaphase.The specific failure of Ect2 to localize to the midzone raised the interesting possibility that Plk1 might trigger the initiation of cytokinesis by promoting the interaction of Ect2 with centralspindlin and, thereby, Ect2 activation and recruitment to the central spindle.	SIGNOR-279553
O43921	Q9UF33	1	binding	up-regulates	0.75	Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8)	SIGNOR-65419
P04049	Q02750	2	phosphorylation	up-regulates activity	0.749	Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.	SIGNOR-235987
Q06124	P09619	2	dephosphorylation	down-regulates activity	0.749	Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.\|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a\|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides	SIGNOR-248669
P17813	Q9UK05	1	binding	up-regulates activity	0.749	Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays.	SIGNOR-276656
P04637	P10415	1	binding	down-regulates activity	0.749	Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis	SIGNOR-99712
Q15119	P31749	1	phosphorylation	up-regulates activity	0.749	PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a gain control for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity	SIGNOR-249630
P06241	O43561	1	phosphorylation	up-regulates	0.749	Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk.	SIGNOR-149174
Q96GD4	O43683	1	phosphorylation	up-regulates activity	0.749	Although our analysis identified only one of the 15 sites implicated in Bub1-Mad1 interaction, it suggests that following its rapamycin-induced dimerization, Ipl1 phosphorylates Bub1, and potentially Mad1, to drive eSAC signaling.	SIGNOR-279010
O95278	Q9UQK1	1	dephosphorylation	up-regulates quantity by stabilization	0.749	We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.	SIGNOR-276239
P09619	Q06124	2	phosphorylation	up-regulates activity	0.749	Upon PDGF stimulation, SHPTP2 binds to the PDGFR and becomes tyrosine-phosphorylated. We have identified tyrosine-542 (pY542TNI) as the major in vivo site of SHPTP2 tyrosine phosphorylation. phosphorylation of SHPTP2 couples Grb2 to PDGFR in vivo, providing a mechanism for Ras activation by PDGFR and for positive signaling via SHPTP2 and Csw.	SIGNOR-250260
P78352	Q9ULH4	1	binding	up-regulates activity	0.749	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-264094
Q13492	Q00610	1	binding	up-regulates	0.749	Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro	SIGNOR-144683
Q02750	P04049	2	phosphorylation	up-regulates activity	0.749	In addition, though MEK-1 was able to induce C-Raf phosphorylation at the S338 site, which was shown to play a role in C-Raf activation by certain growth factors [ xref ], MEK-1 was able to bind and activate the S338/339A C-Raf mutant, suggesting that the MEK-1-induced C-Raf activation does not require phosphorylation at these sites ( xref , lanes 4, 5, left panel and lanes 6\u20139, right panel).\|MEK-1-induced C-Raf activation is Ras independent.	SIGNOR-279627
P24941	P01106	1	phosphorylation	up-regulates quantity by stabilization	0.749	Cdk2 phosphorylates c-Myc at Ser62 to suppress its ubiquitination modification/degradation, resulting in enhanced stability of c-Myc [ xref ].	SIGNOR-279808
P06239	P16410	1	phosphorylation	up-regulates quantity by stabilization	0.749	Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218. Phosphorylation of Y201 correlated with accumulation of CTLA-4 on the cell surface.	SIGNOR-251370
O15530	P31749	1	phosphorylation	up-regulates	0.748	We have partially purified a kinase from brain extract that phosphorylates Ser473 of PKBalpha in a PtdIns(3,4,5)P3-dependent manner and that is immunoprecipitated with PDK1 antibodies.	SIGNOR-67367
P27361	Q15796	1	phosphorylation	down-regulates	0.748	These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3	SIGNOR-66778
Q07817	Q16611	1	binding	down-regulates	0.748	Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax	SIGNOR-152983
Q9UBF6	P49427	1	polyubiquitination	down-regulates activity	0.748	SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34.	SIGNOR-271443
Q13882	Q07666	1	phosphorylation	up-regulates	0.748	Sik/brk is the first identified tyrosine kinase that can phosphorylate sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle	SIGNOR-80020
P56975	Q15303	1	binding	up-regulates	0.748	The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.	SIGNOR-26251
O43542	Q06609	1	binding	up-regulates quantity by stabilization	0.748	XRCC3 activation is essential for the recruitment of RAD51 to the sites of DNA lesions. It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation.	SIGNOR-262667
O60462	P49767	2	binding	up-regulates	0.748	By in vitro binding studies we found that both vegf-c and vegf-d interact with np2, vegf-c in a heparin-independent and vegf-d in a heparin-dependent manner.	SIGNOR-147530
Q9UHF5	Q9NRM6	1	binding	up-regulates	0.748	Here we report on the discovery of a novel il-17 homolog (il-17b), together with the identification of a novel cell surface receptor that specifically binds to it. We detail the molecular cloning, tissue distribution, and expression of both il-17b and il-17br, describe thein vivo activity of il-17b, and demonstrate binding to il-17br.	SIGNOR-76544
P42345	P40763	1	phosphorylation	up-regulates	0.748	Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor	SIGNOR-146915
P67775	P31751	1	dephosphorylation	down-regulates activity	0.748	Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.	SIGNOR-248632
P49767	O60462	2	binding	up-regulates	0.748	The functional importance of the interaction of np2 with the lymphangiogenic growth factors was demonstrated by cointernalization of np2 along with vegfr-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with vegf-c or vegf-d.	SIGNOR-147611
Q13489	Q13546	1	polyubiquitination	up-regulates activity	0.747	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272713
O43660	P52272	1	binding	up-regulates activity	0.747	hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay.	SIGNOR-239444
P35070	P00533	1	binding	up-regulates	0.747	Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4.	SIGNOR-121953
P41221	Q01973	1	binding	up-regulates	0.747	Ror1 and ror2 bind wnt5a.	SIGNOR-196133
Q96B97	P22681	1	binding	up-regulates	0.747	The cin85 sh3 domains interact with c-cbl, an e3 ubiquitin ligase, via an unconventional pxxxpr ligand sequence, with the highest affinity displayed by the sh3-b domain. Interaction with cin85 recruits c-cbl to the amap1 complex where its ubiquitination activity is necessary for cancer cells to develop an invasive phenotype and to degrade the matrix.	SIGNOR-203139
O60542	Q9GZZ7	1	binding	up-regulates	0.747	Glial cell line-derived neurotrophic factor (gdnf) family ligands signal through receptor complex consisting of a glycosylphosphatidylinositol-linked gdnf family receptor (gfr) alpha subunit and the transmembrane receptor tyrosine kinase ret.	SIGNOR-85162
O15111	P19838	1	phosphorylation	down-regulates quantity by destabilization	0.747	All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391).	SIGNOR-70449
P45984	P04637	1	phosphorylation	up-regulates	0.747	These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells.	SIGNOR-115835
Q13535	Q13315	1	phosphorylation	up-regulates activity	0.747	Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment	SIGNOR-150870
O15130	Q9GZQ6	1	binding	up-regulates	0.747	Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems	SIGNOR-82916
O43524	P46527	1	transcriptional regulation	up-regulates quantity	0.747	AFX transcriptionally activates p27kip1, resulting in increased protein levels.	SIGNOR-238610
P49674	O15169	1	phosphorylation	up-regulates	0.747	We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms.	SIGNOR-87444
Q15418	P16220	1	phosphorylation	up-regulates activity	0.747	The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival.	SIGNOR-72117
Q9H2P9	P13639	1	methylation	down-regulates activity	0.747	Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5.	SIGNOR-261146
Q8IYT8	Q8TDY2	1	phosphorylation	up-regulates activity	0.747	When mTOR is inhibited, ULK1 and ULK2 activate and phosphorylate ATG13 and FIP200.	SIGNOR-280159
P28482	P84022	1	phosphorylation	down-regulates activity	0.746	Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3	SIGNOR-161613
Q9UKB1	P35222	1	binding	down-regulates	0.746	We conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin. we found that the binding of beta-trcp to beta-catenin was direct.	SIGNOR-65429
Q9ULC4	O43583	1	binding	up-regulates activity	0.746	The MCT-1 protein modifies mRNA translational profiles through its interaction with DENR/DRP, a protein containing an SUI1 domain involved in recognition of the translation initiation codon.	SIGNOR-269674
Q8IX07	P23769	1	transcriptional regulation	down-regulates quantity by repression	0.746	GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.	SIGNOR-256061
Q96CJ1	P55199	1	binding	up-regulates	0.746	The eaf1-related eaf2 protein is also a positive regulator of ell elongation activity	SIGNOR-138540
P31785	P52333	1	binding	up-regulates	0.746	Jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation.	SIGNOR-178491
Q9GZX6	Q969J5	2	binding	down-regulates	0.746	We identified a gene encoding a protein of 231 aa, showing 33 and 34% amino acid identity with the extracellular domains of the il-22 receptor and of the il-20r/cytokine receptor family 2-8,the recombinant protein was found to bind il-10-related t cell-derived inducible factor/il-22, and to inhibit the activity of this cytokine on hepatocytes and intestinal epithelial cells. We propose to name this natural cytokine antagonist il-22bp for il-22 binding protein. respectively, but lacking the transmembrane and cytoplasmic domains	SIGNOR-86110
Q9NR31	O95487	1	binding	up-regulates quantity	0.746	Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.	SIGNOR-265300
Q969J5	Q9GZX6	2	binding	up-regulates	0.746	Il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4.	SIGNOR-86113
Q9UKA1	P48200	1	binding	down-regulates quantity by destabilization	0.746	We found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2. The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus.	SIGNOR-271882
Q9H488	P46531	1	binding	up-regulates	0.745	Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling.	SIGNOR-104627
Q9Y618	P37231	1	transcriptional regulation	down-regulates quantity by repression	0.745	In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.	SIGNOR-253508
P53779	Q9UPT6	2	phosphorylation	up-regulates	0.745	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134533
Q13451	P04150	1	binding	down-regulates	0.745	When not associated with glucocorticoids, glucocorticoid receptors are predominantly found in the cytoplasm as part of a multimeric molecular chaperone complex that includes several heat shock proteins (HSPs), such as HSP70 and HSP90, the HSP90_binding protein p23 (also known as PTGES3) and proteins that help to bind HSP90 such as FK506_binding protein 5 (FKBP5).	SIGNOR-251666
P10147	P51681	1	binding	up-regulates activity	0.745	The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days.	SIGNOR-251724
Q9UHD0	Q9UHF4	1	binding	up-regulates	0.745	Il-19 signals only through the type i il-20r complex.	SIGNOR-110671
Q05397	Q14247	1	phosphorylation	down-regulates activity	0.745	FAK directly phosphorylates cortactin at Y421 and Y466 and over-expression of cortactin Y421, Y466, and Y482 mutated to phenylalanine (3YF) prevented FAK-enhanced FA turnover and cell motility.\|GFP-FAK re-expression in FAK-/- MEFs enhances FA turnover (XREF_FIG) and cortactin knockdown slows FA turnover (XREF_FIG).	SIGNOR-278283
Q05923	P28482	1	dephosphorylation	down-regulates	0.745	Pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively.	SIGNOR-40915
P24941	Q9UM11	1	phosphorylation	down-regulates activity	0.745	A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.	SIGNOR-250732
Q8N163	Q96EB6	1	binding	down-regulates activity	0.745	Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.	SIGNOR-267663
Q9UPT6	P53779	2	binding	up-regulates	0.745	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-134555
Q9HCE7	Q13485	1	ubiquitination	down-regulates activity	0.745	Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes.	SIGNOR-236096
Q07817	Q07812	1	binding	down-regulates	0.745	The presence of an anti-apoptotic molecule such as bcl-2 or bcl-xl can inhibit the activation of bax following a death signal.	SIGNOR-59141
P61812	P36897	1	binding	up-regulates	0.745	Tgf-? Signaling mediates a wide range of biological activities in development and disease. Tgf-? Ligands signal through heterodimeric type i and type ii receptors (tgf-? Receptor type i [t?RI, also known as alk5 and tgfbr1] and t?RII) that are members of the serine/threonine kinase family.	SIGNOR-196025
P55347	P40424	1	binding	up-regulates activity	0.745	we show that Pbx proteins exist as stable heterodimers with a novel homeodomain protein, Prep1. Here we show that Prep1-Pbx interaction presents novel structural features: it is independent of DNA binding and of the integrity of their respective homeodomains, and requires sequences in the N-terminal portions of both proteins. The Prep1-Pbx protein-protein interaction is essential for DNA-binding activity.	SIGNOR-241212
O94856	Q12955	1	relocalization	up-regulates quantity	0.745	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266717
P36507	P28482	1	phosphorylation	up-regulates	0.744	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-86709
Q86YM7	Q9Y566	1	binding	up-regulates activity	0.744	It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD	SIGNOR-264243
P52564	Q16539	1	phosphorylation	up-regulates activity	0.744	These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase	SIGNOR-40427
P45985	P53779	1	phosphorylation	up-regulates	0.744	Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19).	SIGNOR-137605
P06239	P29353	1	phosphorylation	up-regulates activity	0.744	We show that during TCR signaling, the tyrosines Y239, Y240 and Y317 of Shc are the primary sites of tyrosine phosphorylation. CD4/Lck-dependent tyrosine phosphorylation on Shc was markedly diminished when Y317 was mutated, suggesting a preference of Lck for the Y317 site. tyrosine phosphorylation of Shc may play a key role in T lymphocyte proliferation via interaction of phosphorylated Shc with downstream molecules involved in activation of Ras and Myc proteins	SIGNOR-251388
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
Q12802	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.744	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-260527
Q96EB6	P98177	1	deacetylation	up-regulates	0.744	Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes.	SIGNOR-124714
Q9Y2H0	Q9UPX8	1	relocalization	up-regulates activity	0.744	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264596
Q14164	Q92844	1	phosphorylation	down-regulates activity	0.743	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262722
Q9H0K1	Q53ET0	1	phosphorylation	down-regulates	0.743	Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2	SIGNOR-142218
P24941	P84022	1	phosphorylation	down-regulates activity	0.743	In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity	SIGNOR-182971
P18433	P12931	2	dephosphorylation	up-regulates activity	0.743	Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B	SIGNOR-248437
P04083	P21462	1	binding	up-regulates activity	0.743	We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2.	SIGNOR-259439
Q06124	P42224	1	dephosphorylation	down-regulates activity	0.743	SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei\|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) \|Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity.	SIGNOR-248673

Q8IYT8

O75143

2

phosphorylation

up-regulates

0.75

Ulks directly phosphorylates atg13.

SIGNOR-184126

P24941

Q08050

1

phosphorylation

up-regulates activity

0.75

We demonstrated that FoxM1B transcriptional activity requires binding of either S-phase or M-phase Cdk-cyclin complexes to mediate efficient Cdk phosphorylation of the FoxM1B Thr 596 residue, which is essential for recruitment of p300/CBP coactivator proteins.

SIGNOR-250731

Q13009

P63000

1

binding

up-regulates

0.75

Lpa-induced rac activation requires tiam1

SIGNOR-94691

O43921

P29322

1

binding

up-regulates

0.75

The activation of eph receptors by their ligands, which are membrane-anchored molecules, involves a cell-cell recognition event that often causes cell repulsion. Therefore, eph receptors mediate signals that can override cell adhesion.

SIGNOR-52269

O76064

P61088

1

binding

up-regulates

0.75

The rnf8 ring domain signals ubc13 to sites of damage, which is sufficient for dna damage signal transduction.

SIGNOR-179823

Q99075

Q15303

1

binding

up-regulates

0.75

It was concluded that her4 is a newly described receptor for hb-egf and that hb-egf can activate two egf receptor subtypes, her1 and her4, but with different biological response.

SIGNOR-67009

P52797

P29322

1

binding

up-regulates

0.75

Receptors of the epha group preferentially interact with glycosylphosphatidylinositol (gpi)-linked ligands (of the ephrin-a subclass, which comprises five ligands), while receptors of the ephb group preferentially interact with transmembrane ligands (of the ephrin-b subclass, which comprises three ligands) (table 1). In either case, binding of a ligand results in eph receptor autophosphorylation on tyrosine residues and activation of the kinase activity of the eph receptor

SIGNOR-52387

P63000

Q13177

1

binding

up-regulates activity

0.75

A new brain serine/threonine protein kinase may be a target for the p21ras-related proteins Cdc42 and Rac1. The kinase sequence is related to that of the yeast protein STE20, implicated in pheromone-response pathways.

SIGNOR-248250

P15056

P36507

1

phosphorylation

up-regulates

0.75

We show that, consequently, b-raf interacts with mek-1 and mek-2 with a better affinity than does c-raf-1, thus strengthening the notion that b-raf is a stronger mek activator than c-raf-l.

SIGNOR-42664

Q02750

P28482

2

phosphorylation

up-regulates activity

0.75

Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.

SIGNOR-236447

P55010

O60841

1

relocalization

up-regulates activity

0.75

eIF5B promotes ribosomal subunit joining, with the help of eIF1A. Upon subunit joining, eIF5B hydrolyzes GTP and is released together with eIF1A. We found that human eIF5 interacts with eIF5B and may help recruit eIF5B to the PIC.

SIGNOR-269122

P28482

Q02750

2

phosphorylation

down-regulates activity

0.75

We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling.

SIGNOR-236335

O75143

Q8IYT8

2

binding

up-regulates

0.75

He mammalian atg13 binds both ulk1 and ulk2 and mediates the interaction of the ulk proteins with fip200. The binding of atg13 stabilizes and activates ulk and facilitates the phosphorylation of fip200 by ulk

SIGNOR-184123

P15498

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.75

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260580

P12931

P42229

1

phosphorylation

up-regulates

0.75

Src can thus directly tyrosine-phosphorylate the activation site of stat5 (tyr 694 in stat5a), and src may contribute to epo-induced signal transduction via stat5.

SIGNOR-111078

P05412

P84022

1

binding

down-regulates activity

0.75

These results indicate that interaction between Smad3 and c-Jun may repress Smad3 transcriptional activity.

SIGNOR-256284

P53350

Q9H8V3

1

phosphorylation

up-regulates activity

0.75

Phosphorylation of Ect2 by Plk1 during anaphase might alleviate this intramolecular inhibition by dissociating the Ect2 amino from the carboxyl terminus.|Together with the presence of a prominent microtubule array at the midzone, these data suggest that Plk1 is not essential for the formation of the central spindle at anaphase.The specific failure of Ect2 to localize to the midzone raised the interesting possibility that Plk1 might trigger the initiation of cytokinesis by promoting the interaction of Ect2 with centralspindlin and, thereby, Ect2 activation and recruitment to the central spindle.

SIGNOR-279553

O43921

Q9UF33

1

binding

up-regulates

0.75

Ephrin-a ligands (named ephrin-a1_ephrin-a5) are anchored in the plasma membrane through a gpi-linkage, and each can bind any of the epha subclass of receptors (epha1_epha8)

SIGNOR-65419

P04049

Q02750

2

phosphorylation

up-regulates activity

0.749

Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.

SIGNOR-235987

Q06124

P09619

2

dephosphorylation

down-regulates activity

0.749

Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides

SIGNOR-248669

P17813

Q9UK05

1

binding

up-regulates activity

0.749

Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays.

SIGNOR-276656

P04637

P10415

1

binding

down-regulates activity

0.749

Mechanistic insights into the mitochondrial function of wtp53 came when it was realized that mitochondrially translocated p53 interacts directly with members of the Bcl-2 family, which are central in governing the induction of mitochondrial outer membrane permeabilization. In response to stress, wtp53 interacts with and neutralizes the anti-apoptotic members Bcl-xL and Bcl-2. This interaction stimulates MOMP and subsequent apoptosis

SIGNOR-99712

Q15119

P31749

1

phosphorylation

up-regulates activity

0.749

PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a gain control for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity

SIGNOR-249630

P06241

O43561

1

phosphorylation

up-regulates

0.749

Both lck and syk, phosphorylate the itam-like motifs on lat at y171y191, which is essential for induction of the interaction of lat with downstream signaling molecules such as grb2, plc-gamma1 and c-cbl, and for activation of mapk-erk.

SIGNOR-149174

Q96GD4

O43683

1

phosphorylation

up-regulates activity

0.749

Although our analysis identified only one of the 15 sites implicated in Bub1-Mad1 interaction, it suggests that following its rapamycin-induced dimerization, Ipl1 phosphorylates Bub1, and potentially Mad1, to drive eSAC signaling.

SIGNOR-279010

O95278

Q9UQK1

1

dephosphorylation

up-regulates quantity by stabilization

0.749

We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.

SIGNOR-276239

P09619

Q06124

2

phosphorylation

up-regulates activity

0.749

Upon PDGF stimulation, SHPTP2 binds to the PDGFR and becomes tyrosine-phosphorylated. We have identified tyrosine-542 (pY542TNI) as the major in vivo site of SHPTP2 tyrosine phosphorylation. phosphorylation of SHPTP2 couples Grb2 to PDGFR in vivo, providing a mechanism for Ras activation by PDGFR and for positive signaling via SHPTP2 and Csw.

SIGNOR-250260

P78352

Q9ULH4

1

binding

up-regulates activity

0.749

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-264094

Q13492

Q00610

1

binding

up-regulates

0.749

Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro

SIGNOR-144683

Q02750

P04049

2

phosphorylation

up-regulates activity

0.749

In addition, though MEK-1 was able to induce C-Raf phosphorylation at the S338 site, which was shown to play a role in C-Raf activation by certain growth factors [ xref ], MEK-1 was able to bind and activate the S338/339A C-Raf mutant, suggesting that the MEK-1-induced C-Raf activation does not require phosphorylation at these sites ( xref , lanes 4, 5, left panel and lanes 6\u20139, right panel).|MEK-1-induced C-Raf activation is Ras independent.

SIGNOR-279627

P24941

P01106

1

phosphorylation

up-regulates quantity by stabilization

0.749

Cdk2 phosphorylates c-Myc at Ser62 to suppress its ubiquitination modification/degradation, resulting in enhanced stability of c-Myc [ xref ].

SIGNOR-279808

P06239

P16410

1

phosphorylation

up-regulates quantity by stabilization

0.749

Lck and Fyn, but not ZAP70, induce tyrosine phosphorylation of CTLA-4 in the cell line HEK293. Phosphorylation of CTLA-4 occurs on both Y201 and Y218. Phosphorylation of Y201 correlated with accumulation of CTLA-4 on the cell surface.

SIGNOR-251370

O15530

P31749

1

phosphorylation

up-regulates

0.748

We have partially purified a kinase from brain extract that phosphorylates Ser473 of PKBalpha in a PtdIns(3,4,5)P3-dependent manner and that is immunoprecipitated with PDK1 antibodies.

SIGNOR-67367

P27361

Q15796

1

phosphorylation

down-regulates

0.748

These results suggest that oncogenic ras, acting through mek1 and erk kinases, induces the phosphorylation of smad2 and smad3

SIGNOR-66778

Q07817

Q16611

1

binding

down-regulates

0.748

Bax is held in check by mcl1, bcl-2, and either bcl2l1 or bcl2l2, or by all four. They bind a primed conformer of bak or bax

SIGNOR-152983

Q9UBF6

P49427

1

polyubiquitination

down-regulates activity

0.748

SAG was found to be the second family member of Rbx (RING box protein) or ROC (Regulator of cullins) or Hrt that is a component of SCF E3 ubiquitin ligase. Indeed, like ROC1/Rbx1/Hrt1, SAG binds to Cul1 and SAG-Cul1 complex has ubiquitin ligase activity to promote poly-ubiquitination of E2/Cdc34.

SIGNOR-271443

Q13882

Q07666

1

phosphorylation

up-regulates

0.748

Sik/brk is the first identified tyrosine kinase that can phosphorylate sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle

SIGNOR-80020

P56975

Q15303

1

binding

up-regulates

0.748

The neuregulins (also called heregulins and neu differentiation factors) nrg-1 and nrg-2 bind erbb-3 and erbb-4;and nrg-3 and nrg-4 bind erbb-4.

SIGNOR-26251

O43542

Q06609

1

binding

up-regulates quantity by stabilization

0.748

XRCC3 activation is essential for the recruitment of RAD51 to the sites of DNA lesions. It is likely that BRCA2 may directly participate in RAD51 recruitment and XRCC3 may stabilize the RAD51 filament which is in part mediated by phosphorylation.

SIGNOR-262667

O60462

P49767

2

binding

up-regulates

0.748

By in vitro binding studies we found that both vegf-c and vegf-d interact with np2, vegf-c in a heparin-independent and vegf-d in a heparin-dependent manner.

SIGNOR-147530

Q9UHF5

Q9NRM6

1

binding

up-regulates

0.748

Here we report on the discovery of a novel il-17 homolog (il-17b), together with the identification of a novel cell surface receptor that specifically binds to it. We detail the molecular cloning, tissue distribution, and expression of both il-17b and il-17br, describe thein vivo activity of il-17b, and demonstrate binding to il-17br.

SIGNOR-76544

P42345

P40763

1

phosphorylation

up-regulates

0.748

Serine phosphorylation and maximal activation of stat3 during cntf signaling is mediated by the rapamycin target mtor. / a stat3 peptide was efficiently phosphorylated on ser727 in a cntf-dependent manner by mtor

SIGNOR-146915

P67775

P31751

1

dephosphorylation

down-regulates activity

0.748

Overexpression of BTBD10 increased phosphorylation levels of Akts at both Thr(308) and Ser(473) while the reduction of the endogenous BTBD10 level resulted in a decrease in the phosphorylation levels of Akts. In vitro analysis indicated that BTBD10 bound to protein phosphatase 2A (PP2A) and inhibited dephosphorylation of Akts by PP2A.

SIGNOR-248632

P49767

O60462

2

binding

up-regulates

0.748

The functional importance of the interaction of np2 with the lymphangiogenic growth factors was demonstrated by cointernalization of np2 along with vegfr-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with vegf-c or vegf-d.

SIGNOR-147611

Q13489

Q13546

1

polyubiquitination

up-regulates activity

0.747

CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.

SIGNOR-272713

O43660

P52272

1

binding

up-regulates activity

0.747

hnRNP-M interacts directly with CDC5L and PLRG1 in vivo. we investigated whether the function of hnRNP-M in alternative splicing was affected by the central region mapped as essential for binding to the CDC5L/PLRG1 proteins. We conclude that loss of the CDC5L/PLRG1 interaction domain in hnRNP-M correlates with a loss of ability to modulate alternative splice site selection in this assay.

SIGNOR-239444

P35070

P00533

1

binding

up-regulates

0.747

Betacellulin is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events;ten growth factors and their erbb specificities are depicted: egf, amphiregulin((ar), and tgfalfa bind erbb-1, betacellulin, heparin binding egf-like growth factor, and epiregulin bing both erbb-1 and erbb-4.

SIGNOR-121953

P41221

Q01973

1

binding

up-regulates

0.747

Ror1 and ror2 bind wnt5a.

SIGNOR-196133

Q96B97

P22681

1

binding

up-regulates

0.747

The cin85 sh3 domains interact with c-cbl, an e3 ubiquitin ligase, via an unconventional pxxxpr ligand sequence, with the highest affinity displayed by the sh3-b domain. Interaction with cin85 recruits c-cbl to the amap1 complex where its ubiquitination activity is necessary for cancer cells to develop an invasive phenotype and to degrade the matrix.

SIGNOR-203139

O60542

Q9GZZ7

1

binding

up-regulates

0.747

Glial cell line-derived neurotrophic factor (gdnf) family ligands signal through receptor complex consisting of a glycosylphosphatidylinositol-linked gdnf family receptor (gfr) alpha subunit and the transmembrane receptor tyrosine kinase ret.

SIGNOR-85162

O15111

P19838

1

phosphorylation

down-regulates quantity by destabilization

0.747

All residues of p105 phosphorylated by ikka are c-terminal; the major phosphorylation region contains three serines (ser923; ser927;ser932) and two threonines (thr927 and thr391).

SIGNOR-70449

P45984

P04637

1

phosphorylation

up-regulates

0.747

These findings strongly suggest that jnks are the major direct signaling mediators of uvb-induced p53 phosphorylation at serine 20. furthermore, phosphorylation of p53 at serine 20 by uvb-activated jnks and uvb-induced p53-dependent transcriptional activity were suppressed in jnk1 or jnk2 knockout (jnk1(-/-) or jnk2(-/-)) cells.

SIGNOR-115835

Q13535

Q13315

1

phosphorylation

up-regulates activity

0.747

Atr-dependent phosphorylation and activation of atm in response to uv treatment or replication fork stalling. Here, we show that atm phosphorylation at ser1981, a characterised autophosphorylation site, is atr-dependent and atm-independent following replication fork stalling or uv treatment

SIGNOR-150870

O15130

Q9GZQ6

1

binding

up-regulates

0.747

Npff specifically bound to npff1 (k(d) = 1.13 nm) and npff2 (k(d) = 0.37 nm), and both receptors were activated by npff in a variety of heterologous expression systems

SIGNOR-82916

O43524

P46527

1

transcriptional regulation

up-regulates quantity

0.747

AFX transcriptionally activates p27kip1, resulting in increased protein levels.

SIGNOR-238610

P49674

O15169

1

phosphorylation

up-regulates

0.747

We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the betBeta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or ? Isoform, all detected in association with axin by lc/ms.

SIGNOR-87444

Q15418

P16220

1

phosphorylation

up-regulates activity

0.747

The rsks phosphorylate the trascription factor creb at serine 133 to promote cell survival.

SIGNOR-72117

Q9H2P9

P13639

1

methylation

down-regulates activity

0.747

Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5.

SIGNOR-261146

Q8IYT8

Q8TDY2

1

phosphorylation

up-regulates activity

0.747

When mTOR is inhibited, ULK1 and ULK2 activate and phosphorylate ATG13 and FIP200.

SIGNOR-280159

P28482

P84022

1

phosphorylation

down-regulates activity

0.746

Phosphorylation of the linker region of smads mediated by erk2, gsk3?, And cdk2/4 negatively regulates smad activity by preventing their relocation to the nucleus, by inhibiting their interactions with coactivators, or by accelerating their degradation;in contrast, erk2 phosphorylated all four smad1 residues almost evenly, while showing a preference for s204 over s208 and s213 in smad3

SIGNOR-161613

Q9UKB1

P35222

1

binding

down-regulates

0.746

We conclude that beta-trcp is a component of an e3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin. we found that the binding of beta-trcp to beta-catenin was direct.

SIGNOR-65429

Q9ULC4

O43583

1

binding

up-regulates activity

0.746

The MCT-1 protein modifies mRNA translational profiles through its interaction with DENR/DRP, a protein containing an SUI1 domain involved in recognition of the translation initiation codon.

SIGNOR-269674

Q8IX07

P23769

1

transcriptional regulation

down-regulates quantity by repression

0.746

GATA-2 induces the expression of GATA-1, which first activates its cofactor FOG-1, and then downregulates GATA-2 cooperatively with FOG-1.

SIGNOR-256061

Q96CJ1

P55199

1

binding

up-regulates

0.746

The eaf1-related eaf2 protein is also a positive regulator of ell elongation activity

SIGNOR-138540

P31785

P52333

1

binding

up-regulates

0.746

Jak3 is associated with the ?c20,21. Cytokine binding mediates the trans-phosphorylation of receptor associated jak kinases, which in turn phosphorylate tyrosine residues on the receptors themselves. The receptor phosphotyrosines serve as docking sites for sh2 domain proteins including the stat family of transcription factors which are activated by jak-mediated phosphorylation.

SIGNOR-178491

Q9GZX6

Q969J5

2

binding

down-regulates

0.746

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

SIGNOR-86110

Q9NR31

O95487

1

binding

up-regulates quantity

0.746

Biogenesis of COPII vesicles is initiated by the activation of the small guanosine triphosphate (GTP)-binding protein secretion-associated Ras-related protein 1 (Sar1) at specialized subdomains of the ER, called ER exit sites (ERES) or transitional ER (tER). Membrane-bound Sar1 then recruits the inner COPII coat subcomplex, the Sec23/24 heterodimer.

SIGNOR-265300

Q969J5

Q9GZX6

2

binding

up-regulates

0.746

Il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4.

SIGNOR-86113

Q9UKA1

P48200

1

binding

down-regulates quantity by destabilization

0.746

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

SIGNOR-271882

Q9H488

P46531

1

binding

up-regulates

0.745

Notch_ is modified in its epidermal growth factor-like domains by the addition of_ fucose_ to serine or threonine residues. O-fucosylation is mediated by protein o-fucosyltransferase 1 and down-regulation of this enzyme by rna interference or mutation of the ofut1 gene in drosophila or by mutation of the pofut1 gene in mouse prevents notch signaling.

SIGNOR-104627

Q9Y618

P37231

1

transcriptional regulation

down-regulates quantity by repression

0.745

In differentiated adipocyte cell lines, SIRT1 inhibits adipogenesis and enhances fat mobilization through lipolysis by suppressing the activity of PPARγ. SIRT1 achieves this by promoting the assembly of a corepressor complex, involving NCoR1 and SMRT, on the promoters of PPARγ target genes to repress their transcription.

SIGNOR-253508

P53779

Q9UPT6

2

phosphorylation

up-regulates

0.745

Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.

SIGNOR-134533

Q13451

P04150

1

binding

down-regulates

0.745

When not associated with glucocorticoids, glucocorticoid receptors are predominantly found in the cytoplasm as part of a multimeric molecular chaperone complex that includes several heat shock proteins (HSPs), such as HSP70 and HSP90, the HSP90_binding protein p23 (also known as PTGES3) and proteins that help to bind HSP90 such as FK506_binding protein 5 (FKBP5).

SIGNOR-251666

P10147

P51681

1

binding

up-regulates activity

0.745

The purpose of this study was to determine whether certain chemokines, which are highly expressed in injured skeletal muscle, are involved in the repair and functional recovery of the muscle after traumatic injury. In wild-type control mice, mRNA transcripts of macrophage inflammatory protein (MIP)-1􏰂, MIP-1􏰃, and monocyte chemoattractant protein (MCP)-1 as well as their major receptors, CCR5 and CCR2, increased after freeze injury and gradu- ally returned to control (uninjured) levels by 14 days.

SIGNOR-251724

Q9UHD0

Q9UHF4

1

binding

up-regulates

0.745

Il-19 signals only through the type i il-20r complex.

SIGNOR-110671

Q05397

Q14247

1

phosphorylation

down-regulates activity

0.745

FAK directly phosphorylates cortactin at Y421 and Y466 and over-expression of cortactin Y421, Y466, and Y482 mutated to phenylalanine (3YF) prevented FAK-enhanced FA turnover and cell motility.|GFP-FAK re-expression in FAK-/- MEFs enhances FA turnover (XREF_FIG) and cortactin knockdown slows FA turnover (XREF_FIG).

SIGNOR-278283

Q05923

P28482

1

dephosphorylation

down-regulates

0.745

Pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively.

SIGNOR-40915

P24941

Q9UM11

1

phosphorylation

down-regulates activity

0.745

A nuclear localization signal conserved in various species was identified in CDH1, and it sufficiently targets green fluorescent protein to the nucleus. Interestingly, a CDH1-4D mutant mimicking the hyperphosphorylated form was constitutively found in the cytoplasm. In further support of the notion that phosphorylation inhibits nuclear import, the nuclear localization signal of CDH1 with two phospho-accepting serine/threonine residues changed into aspartates was unable to drive heterologous protein into the nucleus.

SIGNOR-250732

Q8N163

Q96EB6

1

binding

down-regulates activity

0.745

Here, we report that, in human cell lines, DNA damage triggered the phosphorylation of DBC1 on Thr454 by ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases. Phosphorylated DBC1 bound to and inhibited SIRT1, resulting in the dissociation of the SIRT1-p53 complex and stimulating p53 acetylation and p53-dependent cell death.

SIGNOR-267663

Q9UPT6

P53779

2

binding

up-regulates

0.745

The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.

SIGNOR-134555

Q9HCE7

Q13485

1

ubiquitination

down-regulates activity

0.745

Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes.

SIGNOR-236096

Q07817

Q07812

1

binding

down-regulates

0.745

The presence of an anti-apoptotic molecule such as bcl-2 or bcl-xl can inhibit the activation of bax following a death signal.

SIGNOR-59141

P61812

P36897

1

binding

up-regulates

0.745

Tgf-? Signaling mediates a wide range of biological activities in development and disease. Tgf-? Ligands signal through heterodimeric type i and type ii receptors (tgf-? Receptor type i [t?RI, also known as alk5 and tgfbr1] and t?RII) that are members of the serine/threonine kinase family.

SIGNOR-196025

P55347

P40424

1

binding

up-regulates activity

0.745

we show that Pbx proteins exist as stable heterodimers with a novel homeodomain protein, Prep1. Here we show that Prep1-Pbx interaction presents novel structural features: it is independent of DNA binding and of the integrity of their respective homeodomains, and requires sequences in the N-terminal portions of both proteins. The Prep1-Pbx protein-protein interaction is essential for DNA-binding activity.

SIGNOR-241212

O94856

Q12955

1

relocalization

up-regulates quantity

0.745

Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.

SIGNOR-266717

P36507

P28482

1

phosphorylation

up-regulates

0.744

Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.

SIGNOR-86709

Q86YM7

Q9Y566

1

binding

up-regulates activity

0.744

It has been shown that Homer, a scaffold protein with a single EVH1 domain that binds to Shank, mGluR1, and other postsynaptic proteins (98) (Figure 3), exists as a tetramer, thus allowing it to cross-link several interacting proteins in the PSD

SIGNOR-264243

P52564

Q16539

1

phosphorylation

up-regulates activity

0.744

These data indicate that mkk6 phosphorylates p38 map kinase on thr-180 and tyr-182, the sites of phosphorylation that activate p38 map kinase

SIGNOR-40427

P45985

P53779

1

phosphorylation

up-regulates

0.744

Two mapkks, sek1 and mkk7, synergistically activate jnk. Sek1 prefers the tyr-185 residue, and mkk7 prefers the thr-183 residue (17, 19).

SIGNOR-137605

P06239

P29353

1

phosphorylation

up-regulates activity

0.744

We show that during TCR signaling, the tyrosines Y239, Y240 and Y317 of Shc are the primary sites of tyrosine phosphorylation. CD4/Lck-dependent tyrosine phosphorylation on Shc was markedly diminished when Y317 was mutated, suggesting a preference of Lck for the Y317 site. tyrosine phosphorylation of Shc may play a key role in T lymphocyte proliferation via interaction of phosphorylated Shc with downstream molecules involved in activation of Ras and Myc proteins

SIGNOR-251388

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

Q12802

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.744

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-260527

Q96EB6

P98177

1

deacetylation

up-regulates

0.744

Deacetylation of foxos involves binding of the nad-dependent deacetylase hsir2(sirt1). Accordingly, hsir2(sirt1)-mediated deacetylation precludes foxo inhibition through acetylation and thereby prolongs foxo-dependent transcription of stress-regulating genes.

SIGNOR-124714

Q9Y2H0

Q9UPX8

1

relocalization

up-regulates activity

0.744

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264596

Q14164

Q92844

1

phosphorylation

down-regulates activity

0.743

IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex

SIGNOR-262722

Q9H0K1

Q53ET0

1

phosphorylation

down-regulates

0.743

Phosphorylation on the ser171 residue of crtc2 by ampk and ampk-related kinases, including the salt-inducible kinases (siks), is critical for determining the activity, cellular localization, and degradation of crtc2

SIGNOR-142218

P24941

P84022

1

phosphorylation

down-regulates activity

0.743

In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity

SIGNOR-182971

P18433

P12931

2

dephosphorylation

up-regulates activity

0.743

Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B

SIGNOR-248437

P04083

P21462

1

binding

up-regulates activity

0.743

We show that the mimetic N-terminal annexin 1 peptide Ac1-25 is able to activate and desensitize not only FPR but also FPRL1 and FPRL2.

SIGNOR-259439

Q06124

P42224

1

dephosphorylation

down-regulates activity

0.743

SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei|In SHP-2-/- mouse fibroblast cells, Stat1 phosphorylation at both the tyrosine residue Tyr(701) and the serine residue Ser(727) |Overexpression of SHP-2 in 293T cells inhibited IFNgamma-dependent Stat1 phosphorylation and suppressed Stat1-dependent induction of luciferase activity.

SIGNOR-248673