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
P05156	P01024	1	cleavage	down-regulates activity	0.878	FH also serves as cofactor for the serine protease factor I (FI) that cleaves C3b into iC3b, unable to form C3 convertase (Fig 1B).	SIGNOR-263489
Q13535	Q8WXE1	1	phosphorylation	up-regulates	0.878	When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro.	SIGNOR-129473
P01584	P27930	1	binding	down-regulates	0.878	Interleukin-1 (il-1) interacts with cells through two types of binding molecules, il-1 type i receptor (il-1r i) and il-1r ii. Il-1r ii inhibits il-1 activity by acting as a decoy target for il-1	SIGNOR-38302
Q9H0Y0	O94817	1	binding	up-regulates	0.878	Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein.	SIGNOR-180129
Q13144	P20042	1	guanine nucleotide exchange factor	up-regulates activity	0.877	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-269128
P18509	P41586	1	binding	up-regulates	0.877	Type i pacap receptors bind pacap-27 and -38. the potencies of the two forms of pacap are similar for adenylate cyclase stimulation, whereas pacap-38 is more potent than pacap-27 in phospholipase c activation.	SIGNOR-43225
P31749	P29474	1	phosphorylation	up-regulates	0.877	Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.	SIGNOR-112363
Q99986	O75531	1	phosphorylation	down-regulates	0.877	We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell	SIGNOR-144783
P01008	P00742	1	cleavage	down-regulates activity	0.877	Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1	SIGNOR-264138
Q06330	Q96JK9	1	binding	up-regulates	0.877	When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects.	SIGNOR-176200
P04637	P38936	1	transcriptional regulation	up-regulates quantity by expression	0.876	The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents.	SIGNOR-37145
P09681	P48546	1	binding	up-regulates activity	0.876	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-278134
P13861	P17612	1	binding	down-regulates activity	0.876	Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets	SIGNOR-258752
P01588	P19235	1	binding	up-regulates	0.876	Binding of erythropoietin (epo) to the epo receptor (epor) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of ap-1 transcription factor(s).	SIGNOR-55300
Q7L9L4	Q9NRM7	1	binding	up-regulates	0.876	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1.	SIGNOR-169798
P01116	P15056	1	binding	up-regulates activity	0.876	The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.	SIGNOR-156906
Q92585	Q06330	1	binding	up-regulates	0.875	Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes0	SIGNOR-84919
P20366	P21452	1	binding	up-regulates	0.874	The mammalian tachykinins include substance p, neurokinin a and neurokinin b, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated nk1, nk2 and nk3, respectively. The interaction of tachykinin with its receptor activates gq, which in turn activates phospholipase c to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (ip3) and diacylglycerol (dag).	SIGNOR-44773
Q13315	Q12888	1	phosphorylation	up-regulates	0.873	Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm.	SIGNOR-197615
Q8IU54	Q8IU57	1	binding	up-regulates	0.873	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96174
Q13490	Q12933	2	ubiquitination	down-regulates quantity by destabilization	0.873	Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3.	SIGNOR-182128
Q12933	Q13490	2	binding	up-regulates activity	0.873	The c-iaps associate with traf1 and traf3	SIGNOR-39527
Q9NT62	P60520	1	binding	up-regulates activity	0.873	Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme)	SIGNOR-141926
P62993	Q13480	1	binding	up-regulates	0.873	The gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of gab1 occurs indirectly, via the adapter protein grb2	SIGNOR-235917
O95352	Q9GZQ8	1	binding	up-regulates	0.873	These results indicated that the fap motif of atg7 is indispensable for formation of the atg3-lc3 e2-substrate intermediate through the interaction of atg7 with atg3.	SIGNOR-195239
Q9Y297	P35222	1	ubiquitination	down-regulates	0.872	Here we show that fwd1 (the mouse homologue of slimb/betatrcp), an f-box/wd40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, axin, gsk-3beta and apc. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with fwd1. Fwd1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels.	SIGNOR-67374
Q02297	P21860	1	binding	up-regulates	0.872	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 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.	SIGNOR-26878
Q12834	Q16763	1	binding	up-regulates activity	0.872	Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity	SIGNOR-265082
O95352	Q9H492	1	binding	up-regulates	0.872	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-195236
P42771	Q00534	1	binding	down-regulates	0.871	In addition, cytoplasmic p16 bound cyclin dependent kinase (cdk)4/6, potentially indicating that p16 could have a function in the cytoplasm.	SIGNOR-140412
Q15120	P08559	1	phosphorylation	down-regulates activity	0.871	Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes.	SIGNOR-109647
P06307	P32239	1	binding	up-regulates	0.871	Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b	SIGNOR-66339
P24941	P04637	1	phosphorylation	up-regulates activity	0.871	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-119379
P42773	P11802	1	binding	down-regulates	0.871	The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.	SIGNOR-44598
Q06330	Q8IZL2	1	binding	up-regulates	0.871	When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects	SIGNOR-176197
P01111	P04049	1	relocalization	up-regulates	0.87	The raf family of proteins (raf-1, a-raf, and b-raf) bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.	SIGNOR-175231
P31749	Q12778	1	phosphorylation	down-regulates activity	0.87	Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.	SIGNOR-236163
Q06124	P00533	2	dephosphorylation	down-regulates activity	0.87	Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not	SIGNOR-236424
Q15628	Q12933	1	binding	up-regulates activity	0.87	The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively.	SIGNOR-179446
Q9HAU4	O15105	2	polyubiquitination	down-regulates quantity by destabilization	0.87	Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.	SIGNOR-272940
O15105	Q9HAU4	2	relocalization	up-regulates activity	0.87	Smurf2 is nuclear, but binding to smad7 induces export and recruitment to the activated tgf beta receptor, where it causes degradation of receptors and smad7 via proteasomal and lysosomal pathways.	SIGNOR-104996
P00533	Q06124	2	phosphorylation	up-regulates activity	0.87	EGFRvIII transformation may be due to the enhanced PTPase activity from higher basal SHP-2 Tyr542 phosphorylation induced by EGFRvIII ( xref ).\|These results suggest that EGFRvIII expression recruits SHP-2 to an activated complex and induces SHP-2 Tyr542 and its PTPase activity in GBM cells.	SIGNOR-279460
Q9GZV5	Q15561	1	binding	up-regulates	0.869	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201459
P48730	O15055	1	phosphorylation	down-regulates quantity by destabilization	0.869	Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2).	SIGNOR-268000
P05231	P40189	1	binding	up-regulates activity	0.869	A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes.	SIGNOR-48041
Q9UI10	P05198	1	guanine nucleotide exchange factor	up-regulates activity	0.869	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-269127
P60568	P14784	1	binding	up-regulates	0.869	Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c).	SIGNOR-144540
P08069	P35568	1	phosphorylation	up-regulates	0.868	Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor.	SIGNOR-175665
P40933	Q13261	1	binding	up-regulates	0.868	Interleukin-15 specificity and high affinity binding are conferred by the IL-5-specific but nonsignaling IL-15R alpha subunit, which is structurally similar (but not homologous) to the alpha receptor subunit of IL-2	SIGNOR-157415
Q9GZV5	P28347	1	binding	up-regulates	0.868	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead1?_?_?4.	SIGNOR-192768
Q96JK9	Q99466	2	binding	up-regulates	0.867	Whereas maml1 and maml2 functioned efficiently as coactivators with each of the notch receptors to transactivate a notch target hes1 promoter construct, maml3 functioned more efficiently with icn4 than with other forms of icn.	SIGNOR-94103
P01584	Q9NPH3	1	binding	up-regulates	0.867	The recently described il-1r accessory protein (il-1r acp) interacts with il-1beta and the il-1 type-ir (il-1ri).	SIGNOR-61744
Q9H8S9	Q9NRM7	1	binding	up-regulates	0.867	Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1	SIGNOR-169755
Q99466	Q96JK9	2	binding	up-regulates	0.867	Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo	SIGNOR-94109
P01574	P17181	1	binding	up-regulates	0.867	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-104663
P11362	Q8WU20	1	phosphorylation	up-regulates activity	0.867	As shown in xref , wild type FGFR1c phosphorylated FRS2\u03b1 on tyrosine 196 whereas the V429E mutant did not.	SIGNOR-280013
P23588	P60842	1	binding	up-regulates activity	0.867	Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability	SIGNOR-261293
P15151	Q495A1	1	binding	up-regulates activity	0.867	Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12).	SIGNOR-261425
P18545	P16499	1	binding	down-regulates activity	0.866	Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B	SIGNOR-260010
O60674	P42229	1	phosphorylation	up-regulates activity	0.866	Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein	SIGNOR-249507
P60568	P31785	1	binding	up-regulates	0.866	Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c).	SIGNOR-144543
P41743	Q9NPB6	1	phosphorylation	up-regulates quantity by stabilization	0.866	APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation.	SIGNOR-276432
P10600	P37173	1	binding	up-regulates	0.866	T?RII Is known to bind the isoforms tgf??1 And tgf??3. Binding of these ligands causes recruitment of the type i receptor (t?RI) into a signalling receptor complex followed by activation of t?RI Through transphosphorylation	SIGNOR-104798
Q9Y4K3	Q15750	1	binding	up-regulates activity	0.865	The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.	SIGNOR-205455
O60674	P51692	1	phosphorylation	up-regulates	0.865	Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein	SIGNOR-56894
Q00534	P38936	2	phosphorylation	down-regulates activity	0.864	Here, we show that p21cip1 is associated with k cyclin both in overexpression models and in primary effusion lymphoma cells and is a substrate of the k cyclin/cdk6 complex, resulting in phosphorylation of p21cip1 on serine 130. This phosphoform of p21cip1 appeared unable to associate with cdk2 in vivo.	SIGNOR-144832
Q13362	P67775	1	binding	up-regulates activity	0.864	We have identified by two-hybrid interaction a new human gene family encoding PP2A B subunits. This family, denoted B56, contains three distinct genes, one of which is differentially spliced.	SIGNOR-268155
Q13546	Q9NYJ8	1	binding	up-regulates activity	0.864	TNF_ induced the polyubiquitination of RIP and the association of polyubiquitinated RIP with TAB2.	SIGNOR-128406
P38936	Q00534	2	binding	down-regulates	0.864	P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases	SIGNOR-30030
Q07960	P61586	1	gtpase-activating protein	down-regulates activity	0.864	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-260458
P53350	O43683	2	phosphorylation	up-regulates activity	0.864	Note that PLK1 phosphorylates and activates BUB1 to localize it to the kinetochore, phosphorylates and inhibits the negative regulator PKMYTI and interacts with the G1/S kinase Cdc7p to target it to initiation complexes late in G1.	SIGNOR-279251
P09936	P0CG48	1	cleavage	up-regulates quantity	0.864	These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains	SIGNOR-249693
P30047	P30793	1	binding	down-regulates activity	0.864	The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine	SIGNOR-252203
O43683	P53350	2	binding	up-regulates	0.864	The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609	SIGNOR-147061
P01282	P32241	1	binding	up-regulates	0.864	Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip).	SIGNOR-116122
O94813	Q9HCK4	1	binding	up-regulates activity	0.863	This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation.	SIGNOR-268380
P60953	Q9UQB8	1	binding	up-regulates activity	0.863	We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.	SIGNOR-268424
P10644	P22694	1	binding	down-regulates activity	0.863	Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets	SIGNOR-258755
Q7L590	P09884	1	relocalization	up-regulates quantity by stabilization	0.862	Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin.	SIGNOR-261271
P13236	P51681	1	binding	up-regulates activity	0.862	The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.	SIGNOR-255116
P60520	Q13501	1	binding	up-regulates activity	0.862	P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha	SIGNOR-156307
Q9Y6K9	Q04206	1	phosphorylation	up-regulates activity	0.862	Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.	SIGNOR-129947
Q8N6T3	P84077	1	gtpase-activating protein	up-regulates activity	0.862	The ARFGAP molecule binds to switch 2 and helix α3 to orient ARF1 residues for catalysis, but it supplies neither arginine nor other amino acid side chains to the GTPase active site.	SIGNOR-261915
P22466	O43603	1	binding	up-regulates	0.862	Galanin showed high affinity for the galr1 (ic(50) = 0.097 nm) and galr2 receptors (ic(50) = 0.48 nm).	SIGNOR-73125
Q9Y4P1	O95166	1	cleavage	up-regulates activity	0.861	In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly	SIGNOR-141929
Q9P2Y5	Q14457	1	binding	up-regulates activity	0.861	UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis.	SIGNOR-150825
O95405	P84022	1	binding	up-regulates activity	0.861	We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex.	SIGNOR-62874
P06493	O43683	1	phosphorylation	up-regulates	0.861	The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609	SIGNOR-147065
Q09472	Q02078	1	binding	up-regulates	0.861	Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription.	SIGNOR-232165
Q9NPF7	Q5VWK5	1	binding	up-regulates	0.861	We identify a novel member of the hemopoietin receptor family as a subunit of the receptor for il-23, il-23r.	SIGNOR-87805
P18031	P08069	1	dephosphorylation	down-regulates activity	0.861	Ptp-1b can regulate igf-ir kinase activity and function and that loss of ptp-1b can enhance igf-i-mediated cell survival, growth, and motility in transformed cells.	SIGNOR-115709
Q99466	Q8IZL2	1	binding	up-regulates	0.86	We show here identification of two new members of human mam family (human mastermind-2 (hmam-2) and human mastermind-3 (hmam-3)), which retain characteristics similar to human mastermind-1 (hmam-1) and drosophila mastermind. Both hmam-2 and hmam-3 stabilize and participate in the dna-binding complex rbp-j/cbf-1 protein and the notch intracellular domains that serve as intermediates of the signaling. Both hmam-2 and hmam-3 enhanced the activation of transcription from a target promoter by notch signaling. However, we also show evidence that the activation of the target promoter by notch3 and notch4 is more efficiently potentiated by hmam-2 than by hmam-1 or -3.	SIGNOR-94279
P49841	P35222	1	phosphorylation	down-regulates activity	0.86	Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).	SIGNOR-116528
P10145	P25025	1	binding	up-regulates	0.86	Il-8 activates both the cxcr1 and the cxcr2 on microvascular endothelial cells, using different signal transduction cascades.	SIGNOR-107983
Q13772	P10275	1	binding	up-regulates	0.86	We demonstrated that ara70 and ar physically interact and that ara70 can function as an androgen-dependent coactivator for ar.	SIGNOR-67684
P52294	Q14974	1	binding	up-regulates activity	0.86	Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization.	SIGNOR-260273
Q13535	O96017	1	phosphorylation	up-regulates activity	0.86	Atm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro.Substitution of thr68 with ala reduced the extent of phosphorylation and activation of chk2 in response to ir	SIGNOR-81442
P01241	P10912	1	binding	up-regulates	0.859	The hghr only binds primate gh. Arg43 in hghr interacts with asp171 of hgh.	SIGNOR-34129
P55957	Q07817	1	binding	down-regulates activity	0.859	Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer.	SIGNOR-209675
P98170	P55210	1	binding	down-regulates quantity by destabilization	0.859	Our crystal structure of the complex between xiap (linker-bir2) and caspase-7 surprisingly revealed that the linker is the major determinant of binding and inhibition for the caspase.	SIGNOR-105732

P05156

P01024

1

cleavage

down-regulates activity

0.878

FH also serves as cofactor for the serine protease factor I (FI) that cleaves C3b into iC3b, unable to form C3 convertase (Fig 1B).

SIGNOR-263489

Q13535

Q8WXE1

1

phosphorylation

up-regulates

0.878

When dna is damaged, the atr-atrip complex is recruited to chromatin and is activated to transduce the checkpoint signal, but the precise kinase activation mechanism remains unknown. Here, we show that atrip is phosphorylated in an atr-dependent manner after genotoxic stimuli. The serine 68 and 72 residues are important for the phosphorylation in vivo and are required exclusively for direct modification by atr in vitro.

SIGNOR-129473

P01584

P27930

1

binding

down-regulates

0.878

Interleukin-1 (il-1) interacts with cells through two types of binding molecules, il-1 type i receptor (il-1r i) and il-1r ii. Il-1r ii inhibits il-1 activity by acting as a decoy target for il-1

SIGNOR-38302

Q9H0Y0

O94817

1

binding

up-regulates

0.878

Analogous to ubiquitination, atg12 is conjugated to atg5 by atg7--an e1-like protein--and atg10--an e2-like protein.

SIGNOR-180129

Q13144

P20042

1

guanine nucleotide exchange factor

up-regulates activity

0.877

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-269128

P18509

P41586

1

binding

up-regulates

0.877

Type i pacap receptors bind pacap-27 and -38. the potencies of the two forms of pacap are similar for adenylate cyclase stimulation, whereas pacap-38 is more potent than pacap-27 in phospholipase c activation.

SIGNOR-43225

P31749

P29474

1

phosphorylation

up-regulates

0.877

Recently many investigators have shown that protein phosphorylation of enos by several serine/threonine kinases is a critical control step for no production by endothelial cells. Phosphorylation by amp kinase, akt (or protein kinase b), or protein kinase a on serine 1179 (bovine) or serine 1177 (human) of enos leads to enhanced activity of the enzyme and, thus, augmented production of no.

SIGNOR-112363

Q99986

O75531

1

phosphorylation

down-regulates

0.877

We demonstrate that phosphorylation of ser4 and/or thr2/thr3 abrogates the interaction of baf with dna and reduces its interaction with the lem domain. Coexpression of vrk1 and gfp-baf greatly diminishes the association of baf with the nuclear chromatin/matrix and leads to its dispersal throughout the cell

SIGNOR-144783

P01008

P00742

1

cleavage

down-regulates activity

0.877

Antithrombin (AT), a member of the serine protease inhibitor (SERPIN) superfamily, is a major circulating inhibitor of blood coagulation proteases such as factor (F) IIa (known as thrombin), FXa and, to a lesser extent, FIXa, FXIa and FXIIa. SERPINC1, which encodes AT in humans, is located on chromosome 1q25.1

SIGNOR-264138

Q06330

Q96JK9

1

binding

up-regulates

0.877

When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects.

SIGNOR-176200

P04637

P38936

1

transcriptional regulation

up-regulates quantity by expression

0.876

The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents.

SIGNOR-37145

P09681

P48546

1

binding

up-regulates activity

0.876

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-278134

P13861

P17612

1

binding

down-regulates activity

0.876

Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets

SIGNOR-258752

P01588

P19235

1

binding

up-regulates

0.876

Binding of erythropoietin (epo) to the epo receptor (epor) initiates a signaling cascade resulting in tyrosine phosphorylation of several proteins and induction of ap-1 transcription factor(s).

SIGNOR-55300

Q7L9L4

Q9NRM7

1

binding

up-regulates

0.876

Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1.

SIGNOR-169798

P01116

P15056

1

binding

up-regulates activity

0.876

The raf family of proteins (raf-1, a-raf, and b-raf) is serine/threonine kinases that bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.

SIGNOR-156906

Q92585

Q06330

1

binding

up-regulates

0.875

Maml1 binds to the ankyrin repeat domain of all four mammalian notch receptors, forms a dna-binding complex with icn and rbp-jkappa, and amplifies notch-induced transcription of hes0

SIGNOR-84919

P20366

P21452

1

binding

up-regulates

0.874

The mammalian tachykinins include substance p, neurokinin a and neurokinin b, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated nk1, nk2 and nk3, respectively. The interaction of tachykinin with its receptor activates gq, which in turn activates phospholipase c to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (ip3) and diacylglycerol (dag).

SIGNOR-44773

Q13315

Q12888

1

phosphorylation

up-regulates

0.873

Here we report phosphorylation of 53bp1 at several novel residues, using mass spectrometry and phospho-specific antibodies, and show that ionising radiation-stimulated phosphorylation of these residues requires atm.

SIGNOR-197615

Q8IU54

Q8IU57

1

binding

up-regulates

0.873

Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.

SIGNOR-96174

Q13490

Q12933

2

ubiquitination

down-regulates quantity by destabilization

0.873

Traf3-binding receptors stabilize nik by activating ciap-dependent degradation of traf2 and traf3.

SIGNOR-182128

Q12933

Q13490

2

binding

up-regulates activity

0.873

The c-iaps associate with traf1 and traf3

SIGNOR-39527

Q9NT62

P60520

1

binding

up-regulates activity

0.873

Three human atg8 (hatg8) homologs, lc3, gabarap, and gate-16, have been characterized as modifiers in reactions mediated by hatg7 (an e1-like enzyme) and hatg3 (an e2-like enzyme)

SIGNOR-141926

P62993

Q13480

1

binding

up-regulates

0.873

The gab1 docking protein forms a platform for the assembly of a multiprotein signaling complex downstream from receptor tyrosine kinases. In general, recruitment of gab1 occurs indirectly, via the adapter protein grb2

SIGNOR-235917

O95352

Q9GZQ8

1

binding

up-regulates

0.873

These results indicated that the fap motif of atg7 is indispensable for formation of the atg3-lc3 e2-substrate intermediate through the interaction of atg7 with atg3.

SIGNOR-195239

Q9Y297

P35222

1

ubiquitination

down-regulates

0.872

Here we show that fwd1 (the mouse homologue of slimb/betatrcp), an f-box/wd40-repeat protein, specifically formed a multi-molecular complex with beta-catenin, axin, gsk-3beta and apc. Mutations at the signal-induced phosphorylation site of beta-catenin inhibited its association with fwd1. Fwd1 facilitated ubiquitination and promoted degradation of beta-catenin, resulting in reduced cytoplasmic beta-catenin levels.

SIGNOR-67374

Q02297

P21860

1

binding

up-regulates

0.872

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 direct interaction between heregulin and the two proteins was demonstrated by chemical cross-linking experiments using 125i-heregulin followed by immunoprecipitation with antibodies specific for erbb2 or erbb3.

SIGNOR-26878

Q12834

Q16763

1

binding

up-regulates activity

0.872

Ube2S depends on the cell cycle-dependent association with the APC/C activators Cdc20 and Cdh1 for its activity

SIGNOR-265082

O95352

Q9H492

1

binding

up-regulates

0.872

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-195236

P42771

Q00534

1

binding

down-regulates

0.871

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

SIGNOR-140412

Q15120

P08559

1

phosphorylation

down-regulates activity

0.871

Activity of the mammalian pyruvate dehydrogenase complex is regulated by phosphorylation-dephosphorylation of the alpha subunit of the pyruvate dehydrogenase (e1) component. Phosphorylation is carried out by four pyruvate dehydrogenase kinase (pdk) isoenzymes.

SIGNOR-109647

P06307

P32239

1

binding

up-regulates

0.871

Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b

SIGNOR-66339

P24941

P04637

1

phosphorylation

up-regulates activity

0.871

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-119379

P42773

P11802

1

binding

down-regulates

0.871

The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks,cdk4and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.

SIGNOR-44598

Q06330

Q8IZL2

1

binding

up-regulates

0.871

When bound to the active intracellular domain of notch (nicd), rbpj recruits a coactivator complex, including a mastermind homologue (maml1-3 in mammals), and drives a complex transcriptional program with pervasive phenotypic effects

SIGNOR-176197

P01111

P04049

1

relocalization

up-regulates

0.87

The raf family of proteins (raf-1, a-raf, and b-raf) bind to the effector region of ras-gtp, thus inducing translocation of the protein to the plasma membrane. Once there, raf proteins are activated and phosphorylated by different protein kinases.

SIGNOR-175231

P31749

Q12778

1

phosphorylation

down-regulates activity

0.87

Here we show that the activation of phosphatidylinositol 3 (PI3) kinase by extracellular growth factors induces phosphorylation, nuclear export, and transcriptional inactivation of FKHR1, a member of the FKHR subclass of the forkhead family of transcription factors. Protein kinase B (PKB)/Akt, a key mediator of PI3 kinase signal transduction, phosphorylated recombinant FKHR1 in vitro at threonine-24 and serine-253. Mutants FKHR1(T24A), FKHR1(S253A), and FKHR1(T24A/S253A) were resistant to both PKB/Akt-mediated phosphorylation and PI3 kinase-stimulated nuclear export.

SIGNOR-236163

Q06124

P00533

2

dephosphorylation

down-regulates activity

0.87

Given that substrate trapping occurred in intact cells and that the interaction was very specific, it is highly likely that egfr and gab1 represent physiological shp2 substrates.To further confirm that phosphotyrosyl proteins trapped by SHP2 are target substrates, we carried out an immunocomplex in vitrophosphatase assay.The WT protein partially dephosphorylated both the EGFR and Gab1, whereas the DM protein did not

SIGNOR-236424

Q15628

Q12933

1

binding

up-regulates activity

0.87

The high affinity of the tradd-traf2 interaction is required for efficient suppression of apoptosis upon stimulation of the tumor necrosis factor receptor1 (tnfr1), tnf-receptor-associated death domain (tradd) provides a scaffold for the assembly of complex i at the plasma membrane by binding receptor interacting protein 1 (rip1), tnfreceptor- associated factor 2 ,traf2 these results provide evidence that tradd can serve as an adaptor protein and recruit traf1, traf2, or both to tnfrsf1a. The demonstration that tradd interacts with traf2 and fadd, and can recruit both to tnfrsf1a, suggested that traf2 and fadd may be involved in tnfrsf1a tradd-mediated signaling. That these interactions define two distinct signaling pathways emanating from tradd (figure 9) is supported by the ability of traf2 and fadd to activate nf-kb and induce apoptosis, respectively.

SIGNOR-179446

Q9HAU4

O15105

2

polyubiquitination

down-regulates quantity by destabilization

0.87

Smad7 Recruits Smurf2 to the TGFβ Receptor Complex. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways.

SIGNOR-272940

O15105

Q9HAU4

2

relocalization

up-regulates activity

0.87

Smurf2 is nuclear, but binding to smad7 induces export and recruitment to the activated tgf beta receptor, where it causes degradation of receptors and smad7 via proteasomal and lysosomal pathways.

SIGNOR-104996

P00533

Q06124

2

phosphorylation

up-regulates activity

0.87

EGFRvIII transformation may be due to the enhanced PTPase activity from higher basal SHP-2 Tyr542 phosphorylation induced by EGFRvIII ( xref ).|These results suggest that EGFRvIII expression recruits SHP-2 to an activated complex and induces SHP-2 Tyr542 and its PTPase activity in GBM cells.

SIGNOR-279460

Q9GZV5

Q15561

1

binding

up-regulates

0.869

When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.

SIGNOR-201459

P48730

O15055

1

phosphorylation

down-regulates quantity by destabilization

0.869

Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2. We have now extended our previous studies to show that human casein kinase Idelta (hCKIdelta), the closest homologue to hCKIepsilon, associates with and phosphorylates hPER1 and causes protein instability. Furthermore, we observed that both hCKIdelta and hCKIepsilon phosphorylated and caused protein instability of human period 2 protein (hPER2).

SIGNOR-268000

P05231

P40189

1

binding

up-regulates activity

0.869

A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (il-6) and its a-receptor (il-6ralpha) revealed a hexameric architecture in which the gp130 membrane-distal regions were approximately 100 a apart, in contrast to the close apposition seen between short cytokine receptor complexes.

SIGNOR-48041

Q9UI10

P05198

1

guanine nucleotide exchange factor

up-regulates activity

0.869

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-269127

P60568

P14784

1

binding

up-regulates

0.869

Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c).

SIGNOR-144540

P08069

P35568

1

phosphorylation

up-regulates

0.868

Binding of IGF1 to its receptor leads to activation of its intrinsic tyrosine kinase and autophosphorylation, thus generating docking sites for insulin receptor substrate (IRS), which is also phosphorylated by the IGF1 receptor.

SIGNOR-175665

P40933

Q13261

1

binding

up-regulates

0.868

Interleukin-15 specificity and high affinity binding are conferred by the IL-5-specific but nonsignaling IL-15R alpha subunit, which is structurally similar (but not homologous) to the alpha receptor subunit of IL-2

SIGNOR-157415

Q9GZV5

P28347

1

binding

up-regulates

0.868

When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead1?_?_?4.

SIGNOR-192768

Q96JK9

Q99466

2

binding

up-regulates

0.867

Whereas maml1 and maml2 functioned efficiently as coactivators with each of the notch receptors to transactivate a notch target hes1 promoter construct, maml3 functioned more efficiently with icn4 than with other forms of icn.

SIGNOR-94103

P01584

Q9NPH3

1

binding

up-regulates

0.867

The recently described il-1r accessory protein (il-1r acp) interacts with il-1beta and the il-1 type-ir (il-1ri).

SIGNOR-61744

Q9H8S9

Q9NRM7

1

binding

up-regulates

0.867

Lats1/2 are activated by association with the highly homologous scaffold proteins mps one binder kinase activator-like 1a (mobkl1a) and 1b (mobkl1b), which are collectively referred to as mob1

SIGNOR-169755

Q99466

Q96JK9

2

binding

up-regulates

0.867

Moreover, as determined by using coimmunoprecipitation assays, each maml protein was found to be capable of forming a multiprotein complex with the intracellular domain of each notch receptor (icn1 to -4) and csl in vivo

SIGNOR-94109

P01574

P17181

1

binding

up-regulates

0.867

Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.

SIGNOR-104663

P11362

Q8WU20

1

phosphorylation

up-regulates activity

0.867

As shown in xref , wild type FGFR1c phosphorylated FRS2\u03b1 on tyrosine 196 whereas the V429E mutant did not.

SIGNOR-280013

P23588

P60842

1

binding

up-regulates activity

0.867

Either eIF4B or eIF4H stimulated the initial rate and amplitude of eIF4A-dependent duplex unwinding, and the magnitude of stimulation is dependent on duplex stability

SIGNOR-261293

P15151

Q495A1

1

binding

up-regulates activity

0.867

Poliovirus receptor (PVR/CD155) is a ligand of the paired NK receptors, DNAM-1 (activating) and TIGIT (inhibiting). NK cells can kill cancer cells expressing PVR via the DNAM-1-mediated activating signaling (11,12).

SIGNOR-261425

P18545

P16499

1

binding

down-regulates activity

0.866

Both PDE6C-A and PDE6C-B were potently and similarly inhibited by both Pγ subunits, with Ki values ranging from 33 to 46 pm (Fig. 5). The inhibition analysis revealed no significant differences between PDE6C-A and PDE6C-B

SIGNOR-260010

O60674

P42229

1

phosphorylation

up-regulates activity

0.866

Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein

SIGNOR-249507

P60568

P31785

1

binding

up-regulates

0.866

Il-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits il-2r alpha, il-2r beta, and gamma(c).

SIGNOR-144543

P41743

Q9NPB6

1

phosphorylation

up-regulates quantity by stabilization

0.866

APKC associates and phosphorylates Par6 on S345. aPKC expression stabilizes Par6 protein levels. We show that the aPKC, PKCι, interacts with TGF-β receptors through Par6 and that these proteins localize to the leading edge of migrating cells. Furthermore, Par6 phosphorylation on serine 345 by TGF-β receptors is enhanced in the presence of aPKC. aPKC kinase activity, as well as an association with Par6, were found to be important for Par6 phosphorylation.

SIGNOR-276432

P10600

P37173

1

binding

up-regulates

0.866

T?RII Is known to bind the isoforms tgf??1 And tgf??3. Binding of these ligands causes recruitment of the type i receptor (t?RI) into a signalling receptor complex followed by activation of t?RI Through transphosphorylation

SIGNOR-104798

Q9Y4K3

Q15750

1

binding

up-regulates activity

0.865

The irak1/traf6 complex can also activate jnk and p38 signalling through assembly of a catalytically active tab2-tab3-tak1 complex.

SIGNOR-205455

O60674

P51692

1

phosphorylation

up-regulates

0.865

Jak2 kinase induces tyrosine phosphorylation, dimerization, nuclear translocation, and dna binding of a concomitantly expressed stat5 protein

SIGNOR-56894

Q00534

P38936

2

phosphorylation

down-regulates activity

0.864

Here, we show that p21cip1 is associated with k cyclin both in overexpression models and in primary effusion lymphoma cells and is a substrate of the k cyclin/cdk6 complex, resulting in phosphorylation of p21cip1 on serine 130. This phosphoform of p21cip1 appeared unable to associate with cdk2 in vivo.

SIGNOR-144832

Q13362

P67775

1

binding

up-regulates activity

0.864

We have identified by two-hybrid interaction a new human gene family encoding PP2A B subunits. This family, denoted B56, contains three distinct genes, one of which is differentially spliced.

SIGNOR-268155

Q13546

Q9NYJ8

1

binding

up-regulates activity

0.864

TNF_ induced the polyubiquitination of RIP and the association of polyubiquitinated RIP with TAB2.

SIGNOR-128406

P38936

Q00534

2

binding

down-regulates

0.864

P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage.We Have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases

SIGNOR-30030

Q07960

P61586

1

gtpase-activating protein

down-regulates activity

0.864

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-260458

P53350

O43683

2

phosphorylation

up-regulates activity

0.864

Note that PLK1 phosphorylates and activates BUB1 to localize it to the kinetochore, phosphorylates and inhibits the negative regulator PKMYTI and interacts with the G1/S kinase Cdc7p to target it to initiation complexes late in G1.

SIGNOR-279251

P09936

P0CG48

1

cleavage

up-regulates quantity

0.864

These data suggest that the physiological role of UCH is to hydrolyze small adducts of ubiquitin and to generate free monomeric ubiquitin from ubiquitin proproteins, but not to deubiquitinate ubiquitin-protein conjugates or disassemble polyubiquitin chains

SIGNOR-249693

P30047

P30793

1

binding

down-regulates activity

0.864

The enzyme activity of GTP cyclohydrolase I is controlled by a regulatory protein for this enzyme, GFRP, which is a pentamer of identical subunits. GFRP mediates feedback inhibition of GTP cyclohydrolase I activity by BH4, and the inhibition by BH4 is reversed by phenylalanine

SIGNOR-252203

O43683

P53350

2

binding

up-regulates

0.864

The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609

SIGNOR-147061

P01282

P32241

1

binding

up-regulates

0.864

Pacap binds to a pacap-specific receptor (pac1) and to vpac receptors (vpac1 and vpac2), which share high affinity for vasoactive intestinal polypeptide (vip).

SIGNOR-116122

O94813

Q9HCK4

1

binding

up-regulates activity

0.863

This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation.

SIGNOR-268380

P60953

Q9UQB8

1

binding

up-regulates activity

0.863

We conclude that the interaction of Cdc42 with the partial CRIB motif of IRSp53 relieves an intramolecular, autoinhibitory interaction with the N terminus, allowing the recruitment of Mena to the IRSp53 SH3 domain. This IRSp53:Mena complex initiates actin filament assembly into filopodia.

SIGNOR-268424

P10644

P22694

1

binding

down-regulates activity

0.863

Inactive PKA exists as a holoenzyme, comprised of two regulatory (R) subunits and two catalytic subunits . In the presence of cAMP, the holoenzyme becomes active by binding two cAMP molecules cooperatively to each R subunit, resulting in a conformational change in the R subunits, thus releasing the two C subunits to phosphorylate downstream targets

SIGNOR-258755

Q7L590

P09884

1

relocalization

up-regulates quantity by stabilization

0.862

Mcm10 is an essential eukaryotic protein required for the initiation and elongation phases of chromosomal replication. Specifically, Mcm10 is required for the association of several replication proteins, including DNA polymerase alpha (pol alpha), with chromatin.

SIGNOR-261271

P13236

P51681

1

binding

up-regulates activity

0.862

The investigators showed that myoblasts constitutively express receptors for CCL2 (CCR2), CCL3 (CCR1 and CCR5), and CCL4 (CCR5), and that stimulation with either CCL2 or CCL4 was sufficient to promote myoblast proliferation.

SIGNOR-255116

P60520

Q13501

1

binding

up-regulates activity

0.862

P62 binds both to lc3a and -b and the related gabarap family proteins/this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguisha

SIGNOR-156307

Q9Y6K9

Q04206

1

phosphorylation

up-regulates activity

0.862

Chromatographic fractionation of cell extracts allowed the identification of two distinct enzymatic activities phosphorylating ser-536. Peak 1 represents an unknown kinase, whereas peak 2 contained ikkalpha, ikkbeta, ikkepsilon, and tbk1. collectively, our results provide evidence for at least five kinases that converge on ser-536 of p65 and a novel function for this phosphorylation site in the recruitment of components of the basal transcriptional machinery to the interleukin-8 promoter.

SIGNOR-129947

Q8N6T3

P84077

1

gtpase-activating protein

up-regulates activity

0.862

The ARFGAP molecule binds to switch 2 and helix α3 to orient ARF1 residues for catalysis, but it supplies neither arginine nor other amino acid side chains to the GTPase active site.

SIGNOR-261915

P22466

O43603

1

binding

up-regulates

0.862

Galanin showed high affinity for the galr1 (ic(50) = 0.097 nm) and galr2 receptors (ic(50) = 0.48 nm).

SIGNOR-73125

Q9Y4P1

O95166

1

cleavage

up-regulates activity

0.861

In vivo and in vitro biochemical analyses have shown that human atg4b is an authentic cysteine protease essential for cleavage of the c terminus of each atg8 homolog to expose the c-terminal gly

SIGNOR-141929

Q9P2Y5

Q14457

1

binding

up-regulates activity

0.861

UVRAG interacts with Beclin 1, leading to activation of autophagy and thereof inhibition of tumorigenesis.

SIGNOR-150825

O95405

P84022

1

binding

up-regulates activity

0.861

We now identify SARA (for Smad anchor for receptor activation), a FYVE domain protein that interacts directly with Smad2 and Smad3. SARA functions to recruit Smad2 to the TGFbeta receptor by controlling the subcellular localization of Smad2 and by interacting with the TGFbeta receptor complex.

SIGNOR-62874

P06493

O43683

1

phosphorylation

up-regulates

0.861

The plk1-bub1 interaction requires the polo-box domain (pbd) of plk1 and is enhanced by cyclin-dependent kinase 1 (cdk1)-mediated phosphorylation of bub1 at t609

SIGNOR-147065

Q09472

Q02078

1

binding

up-regulates

0.861

Once released from associated repressors, MEF2 is bound by the p300 coactivator, which possesses histone acetyltransferase activity. Thus, the net result of CaMK signaling to MEF2 complexes is increased histone acetylation (Ac), which relaxes chromatin and stimulates MEF2 target gene transcription.

SIGNOR-232165

Q9NPF7

Q5VWK5

1

binding

up-regulates

0.861

We identify a novel member of the hemopoietin receptor family as a subunit of the receptor for il-23, il-23r.

SIGNOR-87805

P18031

P08069

1

dephosphorylation

down-regulates activity

0.861

Ptp-1b can regulate igf-ir kinase activity and function and that loss of ptp-1b can enhance igf-i-mediated cell survival, growth, and motility in transformed cells.

SIGNOR-115709

Q99466

Q8IZL2

1

binding

up-regulates

0.86

We show here identification of two new members of human mam family (human mastermind-2 (hmam-2) and human mastermind-3 (hmam-3)), which retain characteristics similar to human mastermind-1 (hmam-1) and drosophila mastermind. Both hmam-2 and hmam-3 stabilize and participate in the dna-binding complex rbp-j/cbf-1 protein and the notch intracellular domains that serve as intermediates of the signaling. Both hmam-2 and hmam-3 enhanced the activation of transcription from a target promoter by notch signaling. However, we also show evidence that the activation of the target promoter by notch3 and notch4 is more efficiently potentiated by hmam-2 than by hmam-1 or -3.

SIGNOR-94279

P49841

P35222

1

phosphorylation

down-regulates activity

0.86

Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC).

SIGNOR-116528

P10145

P25025

1

binding

up-regulates

0.86

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

SIGNOR-107983

Q13772

P10275

1

binding

up-regulates

0.86

We demonstrated that ara70 and ar physically interact and that ara70 can function as an androgen-dependent coactivator for ar.

SIGNOR-67684

P52294

Q14974

1

binding

up-regulates activity

0.86

Although ORF6 causes a relocalization of KPNA2 from the cytosol to the ER/Golgi membrane, KPNA2 is not directly involved in the translocation of the STAT1:STAT2:IRF9 (ISGF3) complex into the nucleus; rather, KPNA1 interacts with KPNB1 to initiate ISGF3's nuclear localization.

SIGNOR-260273

Q13535

O96017

1

phosphorylation

up-regulates activity

0.86

Atm- and rad3-related also phosphorylates thr68 in addition to thr26 and ser50, which are not phosphorylated to a significant extent by atm in vitro.Substitution of thr68 with ala reduced the extent of phosphorylation and activation of chk2 in response to ir

SIGNOR-81442

P01241

P10912

1

binding

up-regulates

0.859

The hghr only binds primate gh. Arg43 in hghr interacts with asp171 of hgh.

SIGNOR-34129

P55957

Q07817

1

binding

down-regulates activity

0.859

Overexpression of antiapoptotic proteins including Bcl-XL and/or Bcl-2 contributes to tumor initiation, progression, and resistance to therapy by direct interactions with proapoptotic BH3 proteins. Release of BH3 proteins from antiapoptotic proteins kills some cancer cells and sensitizes others to chemotherapy. Binding of Bcl-XL and Bcl-2 to the BH3 proteins Bad, Bid, and the three major isoforms of Bim was measured for fluorescent protein fusions in live cells using fluorescence lifetime imaging microscopy and fluorescence resonance energy transfer.

SIGNOR-209675

P98170

P55210

1

binding

down-regulates quantity by destabilization

0.859

Our crystal structure of the complex between xiap (linker-bir2) and caspase-7 surprisingly revealed that the linker is the major determinant of binding and inhibition for the caspase.

SIGNOR-105732