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
P48729	P35222	1	phosphorylation	down-regulates	0.791	Specifically, ck1_ phosphorylates _-catenin at s45, which primes this n-terminal region for subsequent phosphorylations by gsk3 at t41, s37 and s33 [7]. These latter two phosphorylations are recognized by the e3-ligase component, _-trcp, for ultimate ubiquitylation and destruction by the proteosome	SIGNOR-165022
Q9H492	Q13501	1	binding	up-regulates	0.791	Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation.	SIGNOR-156353
P04637	P51959	1	transcriptional regulation	up-regulates quantity by expression	0.791	Individual promoter and intron p53-binding motifs from the rat Cyclin G1 promoter region support transcriptional activation by p53 but do not show co-operative activation.	SIGNOR-268961
P26441	P26992	1	binding	up-regulates	0.791	Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr)	SIGNOR-81379
P01133	P04626	1	binding	up-regulates	0.791	To better understand the role of the egfr tyrosine kinase, we analyzed signaling by a kinase-inactive egfr (k721m) in erbb-devoid 32d cells. K721m alone exhibited no detectable signaling capacity, whereas coexpression of k721m with erbb2, but not erbb3 or erbb4, resulted in egf-dependent mitogen-activated protein kinase (mapk) activation. The kinase activity, but not tyrosine phosphorylation, of erbb2 was required for egf-induced mapk activation.	SIGNOR-106497
Q5MJ70	P24941	1	relocalization	up-regulates activity	0.791	Speedy/RINGO A, a noncanonical activator of CDK2, was recently identified as a key regulator for CDK2 recruitment to meiotic telomeres	SIGNOR-263310
O95835	Q9GZV5	1	phosphorylation	down-regulates	0.791	In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus.	SIGNOR-197643
Q14623	Q9Y6C5	1	binding	down-regulates activity	0.791	Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.	SIGNOR-61314
P78509	P98155	1	binding	up-regulates	0.791	The hypothesis that the vldl receptor signals in response to reelin binding was recently supported by studies (37) showing direct binding of reelin to the vldl receptor and changes in tyrosine phosphorylation in response to reelin-vldl receptor association.	SIGNOR-106295
Q13158	Q13546	1	binding	up-regulates activity	0.791	Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8	SIGNOR-191781
Q6UN15	P51003	1	binding	up-regulates	0.791	Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna.	SIGNOR-121700
P23458	P42224	1	phosphorylation	up-regulates activity	0.79	The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosineSH2 domain interactions	SIGNOR-236373
P15018	P40189	1	binding	up-regulates	0.79	Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors.Some Of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2	SIGNOR-48108
P56704	O75581	1	binding	up-regulates activity	0.79	Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin.	SIGNOR-148671
P28482	P05412	1	phosphorylation	up-regulates activity	0.79	Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1.	SIGNOR-201943
Q2M2I8	Q96CW1	1	phosphorylation	up-regulates	0.79	Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis.	SIGNOR-115657
P14598	P13498	1	binding	up-regulates activity	0.79	Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase.	SIGNOR-276625
Q92585	Q9UM47	1	binding	up-regulates	0.79	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 hes1.	SIGNOR-84838
P63000	Q13153	1	binding	up-regulates activity	0.79	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-248236
O95996	P35222	1	relocalization	down-regulates quantity by destabilization	0.79	The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation.	SIGNOR-81545
O95477	P02647	2	binding	up-regulates activity	0.79	The stimulation of cellular cholesterol and phospholipid efflux by apolipoprotein A-I is mediated by the activity of the ATP-binding cassette transporter A1 (ABCA1). ABCA1 forms a high affinity complex with apoA-I by binding amphipathic helices within the apolipoprotein. VFVNFA sequence is required for ABCA1 to form a complex with apoA-I and to transfer cholesterol to the apolipoprotein.	SIGNOR-252100
Q07890	P01112	1	guanine nucleotide exchange factor	up-regulates	0.79	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.	SIGNOR-175262
Q9H0R8	Q13501	1	binding	up-regulates activity	0.79	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-156304
Q9Y4K3	Q9BQ95	1	ubiquitination	down-regulates activity	0.79	Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation	SIGNOR-260370
P02647	O95477	2	binding	up-regulates quantity by stabilization	0.79	ApoA-I stabilization of ABCA1 is mediated by reduced PEST sequence phosphorylation, which in turn leads to decreased calpain proteolysis of ABCA1.	SIGNOR-252101
P50613	P24928	1	phosphorylation	down-regulates	0.789	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120024
P15056	Q02750	1	phosphorylation	up-regulates activity	0.789	Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.	SIGNOR-235475
Q8WUP2	Q14315	1	binding	up-regulates activity	0.789	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton.	SIGNOR-266107
P12931	P40763	1	phosphorylation	up-regulates activity	0.789	In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants.	SIGNOR-247341
Q9UHD2	Q96CV9	2	phosphorylation	up-regulates activity	0.789	Given that TBK1 can phosphorylate OPTN on S177, S473 and S513 in response to mitochondrial depolarization, we explored the function of these events in vivo.\|Phosphorylation of OPTN on S473 and S513 promotes TBK1 activation and recruitment of OPTN to depolarized mitochondria.	SIGNOR-278170
Q13315	Q9BXW9	1	phosphorylation	up-regulates	0.789	These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint	SIGNOR-90117
O15105	P36897	1	binding	down-regulates activity	0.789	SMAD7 functions as an antagonist to TGFB by binding to the TBRI and thus inhibiting activation of SMAD2 and SMAD3.	SIGNOR-64088
Q9NQC7	Q9Y4K3	1	deubiquitination	down-regulates	0.789	The nf-kappab activation by cyld is mediated, at least in part, by the deubiquitination and inactivation of tnfr-associated factor 2 (traf2) and, to a lesser extent, traf6.	SIGNOR-117856
P28562	P45983	1	dephosphorylation	down-regulates	0.789	Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2.	SIGNOR-46079
Q96CV9	Q9UHD2	2	binding	up-regulates activity	0.789	Using biochemical experiments we showed that optineurin interacts with the protein kinase TBK1 and the ubiquitin ligase TRAF3. Furthermore, a mutation in optineurin that prevents the interaction with the small protein modifier ubiquitin (D474N) ablated the negative regulatory function of optineurin.	SIGNOR-262276
Q9Y4G8	P62834	1	guanine nucleotide exchange factor	up-regulates activity	0.789	Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.Increased intracellular concentrations of cAMP enhanced the Rapgef2-dependent activation of Rap1, which in turn associated with B-Raf to enable the activation of ERK and subsequent neuronal- and endocrine-specific cellular outcomes, such as induction of neuroendocrine-specific genes and extension of neuritic processes (neuritogenesis).	SIGNOR-276609
P29597	P52630	1	phosphorylation	up-regulates activity	0.789	JAK1 and TYK2 will phosphorylate and activate STAT1 and STAT2 respectively, leading to the formation of the ternary interferon-stimulated gene factor 3 (ISGF3) complex, composed of STAT1, STAT2 and interferon regulatory factor 9 (IRF9).	SIGNOR-279133
Q13153	P21333	1	phosphorylation	up-regulates	0.789	In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152.	SIGNOR-92065
Q5JTC6	O15169	1	relocalization	up-regulates activity	0.789	Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6.	SIGNOR-171886
O95352	Q9BXW4	1	binding	up-regulates activity	0.789	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-191540
Q92878	P38398	1	binding	up-regulates	0.789	Brca1 interacts in vitro and in vivo with hrad50. Brca1 is important for the cellular responses to dna damage that are mediated by the hrad50-hmre11-p95 complex.	SIGNOR-69701
P04275	P00451	1	binding	up-regulates activity	0.789	Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF	SIGNOR-251967
O00418	P13639	1	phosphorylation	down-regulates	0.788	Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58.	SIGNOR-38556
P23443	P35568	1	phosphorylation	down-regulates quantity by destabilization	0.788	In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8	SIGNOR-236599
P06213	P18031	2	phosphorylation	up-regulates activity	0.788	Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex\| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B	SIGNOR-249370
P18031	P06213	2	dephosphorylation	down-regulates activity	0.788	Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor.	SIGNOR-235499
O95886	Q9UPX8	1	relocalization	up-regulates activity	0.788	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-264593
P04628	O75197	1	binding	up-regulates activity	0.788	Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.	SIGNOR-169645
Q15485	P48740	1	binding	up-regulates activity	0.788	H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway\|Proteolytic activation of complement components by H-ficolin-MASP.	SIGNOR-263411
Q9Y5X1	Q05193	1	binding	up-regulates	0.788	Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes.	SIGNOR-133892
P53350	Q6PGQ7	2	phosphorylation	down-regulates	0.788	Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp).	SIGNOR-178154
O14511	Q15303	1	binding	up-regulates	0.788	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-26211
Q6PGQ7	P53350	2	phosphorylation	up-regulates	0.788	Bora/aurora-a-dependent phosphorylation is a prerequisite for plk1 to promote mitotic entry after a checkpoint-dependent arrest.	SIGNOR-179425
O95817	P11142	1	binding	up-regulates activity	0.788	Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70.	SIGNOR-254116
P08476	Q13705	1	binding	up-regulates activity	0.787	Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.	SIGNOR-235142
P47992	P46094	1	binding	up-regulates	0.787	Scm-1 showed a high-affinity binding to xcr1 with a kd of 10 nm and induced vigorous chemotaxis and calcium mobilization in xcr1-transfected murine l1.2 cells.	SIGNOR-71164
Q13489	O43353	1	polyubiquitination	up-regulates activity	0.787	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-272715
O00141	Q96PU5	1	phosphorylation	down-regulates activity	0.787	Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1.	SIGNOR-263076
Q99959	P15924	1	binding	up-regulates quantity by stabilization	0.787	In contrast to the proper membrane localization of PKP2 and DSP after cotransfection of both WT proteins, mutant PKP2 C796R protein was not able to interact with FLAG-DSP to enable assembly at the junctional plaque, indicating the requirement of functional PKP2 for DSP integration into the desmosome.	SIGNOR-261254
O95278	Q6VVB1	2	binding	up-regulates activity	0.787	Here, we provide evidence indicating that the formation of the laforin–malin complex is positively regulated by AMPK. We show that laforin, but not malin, can interact physically with the catalytic subunit of AMPK and that purified AMPK phosphorylates GST::laforin in vitro.	SIGNOR-271729
P00797	O75787	1	binding	up-regulates	0.787	We report the expression cloning of the human renin receptor complementary dna encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin i and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of map kinases erk1 and erk2	SIGNOR-88416
Q6VVB1	O95278	2	polyubiquitination	down-regulates quantity by destabilization	0.787	Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation.	SIGNOR-271547
P27540	Q16665	1	binding	up-regulates activity	0.787	The functional transcription factor exists as a heterodimeric complex consisting of HIF-1alpha and the aryl hydrocarbon receptor nuclear translocator (ARNT). Association of HIF-1 with ARNT is required for its activity; however, no other role has been ascribed to this interaction.	SIGNOR-253720
P02778	P49682	1	binding	up-regulates activity	0.787	The chemokines CXCL9, 10, and 11 exert their action via CXC chemokine receptor-3 (CXCR3), a receptor highly expressed on activated T cells.	SIGNOR-260969
O96017	P38398	1	phosphorylation	up-regulates	0.787	In this study, we tested the hypothesis that the brca1-mediated regulation of recombination requires the chk2- and atm-dependent phosphorylation sites.	SIGNOR-120575
Q96B86	Q92859	1	binding	down-regulates activity	0.787	Netrin-1-neogenin interactions mediate chemoattractive axon guidance, while RGMa-neogenin interactions repel axons.	SIGNOR-268388
Q13635	Q99835	1	binding	down-regulates activity	0.786	We show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity.	SIGNOR-91709
P40763	P15692	1	transcriptional regulation	up-regulates quantity by expression	0.786	Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells.	SIGNOR-259456
P27361	P28562	2	phosphorylation	up-regulates	0.786	Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein.	SIGNOR-73633
P28562	P27361	2	dephosphorylation	down-regulates activity	0.786	We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively	SIGNOR-248462
Q8WYL5	P23528	1	dephosphorylation	up-regulates activity	0.786	Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.\|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).	SIGNOR-248762
Q9C0C7	Q14457	1	binding	up-regulates activity	0.786	we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2.	SIGNOR-168252
P06307	P32238	1	binding	up-regulates	0.786	Cck8 interacts with nanomolar affinities with two different receptors designated cck-a and cck-b	SIGNOR-68474
P13500	P41597	1	binding	up-regulates activity	0.786	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-255113
O00585	P32248	1	binding	up-regulates	0.786	The regulated expression of the chemokine secondary lymphoid tissue chemokine (slc/ccl21) and its corresponding receptor, ccr7.	SIGNOR-117566
Q9Y275	Q96RJ3	1	binding	up-regulates activity	0.785	Baff specifically binds baff receptor	SIGNOR-135713
O75116	O14974	1	phosphorylation	down-regulates activity	0.785	Rho kinase is known to control smooth muscle contractility by phosphorylating the 110 kDa myosin-targetting subunit (MYPT1) of the myosin-associated form of protein phosphatase 1 (PP1M). Phosphorylation of MYPT1 at Thr695 has previously been reported to inhibit the catalytic activity of PP1. Here, we show that the phosphorylation of Thr850 by Rho kinase dissociates PP1M from myosin, providing a second mechanism by which myosin phosphatase activity is inhibited.	SIGNOR-249164
P61586	O60610	1	null	up-regulates activity	0.785	We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.\|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.	SIGNOR-253108
O14757	P30305	1	phosphorylation	down-regulates activity	0.785	Here, we show that cdc25b is phosphorylated by chk1 in vitro on multiple residues, including s230 and s563.We show that the s230-phosphorylated form of cdc25b is located at the centrosome from early s phase until mitosis. Furthermore, mutation of s230 to alanine increases the mitotic-inducing activity of cdc25b	SIGNOR-149898
Q13535	O60934	1	phosphorylation	up-regulates	0.785	We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint.	SIGNOR-155214
P48729	O15169	1	phosphorylation	up-regulates activity	0.785	Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.\|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling.	SIGNOR-249191
P78423	P49238	1	binding	up-regulates	0.785	Fractalkine/cx3cl1 is a membrane-tethered chemokine that functions as a chemoattractant and adhesion protein by interacting with the receptor cx3cr1.	SIGNOR-109135
P41236	P62136	1	binding	down-regulates	0.785	Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1.	SIGNOR-160651
Q9NYV4	P24928	1	phosphorylation	up-regulates activity	0.784	Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna	SIGNOR-176805
Q8N474	P04628	1	binding	down-regulates	0.784	Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling.	SIGNOR-71423
Q99731	P32248	1	binding	up-regulates activity	0.784	CCL19 and CCL21 are endogenous agonists for the seven-trans membrane receptor CCR7.	SIGNOR-278123
P41221	P34925	1	binding	up-regulates	0.784	Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells.	SIGNOR-258970
P07492	P30550	1	binding	up-regulates	0.784	Indeed, many potent mitogens such as thrombin, lysophosphatidic acid (lpa), gastrin-releasing peptide (grp), endothelin and prostaglandins stimulate cell proliferation by acting on their cognate gpcrs in various cell types.	SIGNOR-152676
P49841	P24385	1	phosphorylation	down-regulates	0.783	Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover.	SIGNOR-144818
P53350	Q9UKT4	1	phosphorylation	down-regulates	0.783	We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity.	SIGNOR-142949
P01350	P32239	1	binding	up-regulates	0.783	A segment of five amino acids in the second extracellular loop of the cck-b receptor was shown to be essential for the high affinity of the natural peptide agonits, gastrin,	SIGNOR-66987
Q96AC1	Q8WUP2	1	binding	up-regulates activity	0.783	Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration.	SIGNOR-266108
P20023	P15391	1	binding	up-regulates activity	0.783	Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling.	SIGNOR-266642
Q8N3J5	P12694	1	dephosphorylation	up-regulates activity	0.783	BCKD is inhibited by phosphorylation of its E1alpha subunit at Ser293, which is catalyzed by BCKD kinase. During BCAA excess, phosphorylated Ser293 (pSer293) becomes dephosphorylated through the concerted inhibition of BCKD kinase and the activity of an unknown intramitochondrial phosphatase. Using unbiased, proteomic approaches, we have found that a mitochondrial-targeted phosphatase, PP2Cm, specifically binds the BCKD complex and induces dephosphorylation of Ser293 in the presence of BCKD substrates	SIGNOR-248758
O43521	Q92843	1	binding	down-regulates	0.783	Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133832
P01189	Q01718	1	binding	up-regulates activity	0.783	Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP).	SIGNOR-268615
P30622	Q14203	1	binding	up-regulates activity	0.782	MT-unbound CLIP-170 can adopt a folded conformation through an intramolecular interaction of its terminal domains. Binding to MTs correlates with the unfolding of CLIP-170, which allows the interaction of the COOH-terminal domain with its binding partners, such as dynactin, resulting in their recruitment to the MT tip. The NH2 terminus of p150Glued binds directly to the COOH terminus of CLIP-170 through its second metal-binding motif.	SIGNOR-252164
Q8WW38	P43694	1	binding	down-regulates activity	0.782	FOG-2 associates physically with the N-terminal zinc finger of GATA-4 both in vitro and in vivo. This interaction appears to modulate specifically the transcriptional activity of GATA-4 because overexpression of FOG-2 in both NIH 3T3 cells and primary rat cardiomyocytes represses GATA-4-dependent transcription from multiple cardiac-restricted promoters.	SIGNOR-236959
P31749	Q96B36	1	phosphorylation	down-regulates activity	0.782	Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40	SIGNOR-252544
O14672	P46531	1	cleavage	up-regulates activity	0.782	ADAM10-mediated Notch1 cleavage is the rate limiting-step for release of the NICD and subsequent activation of Notch1 signaling. In T cells ADAM10-mediated Notch1 shedding controls T cell development	SIGNOR-259838

P48729

P35222

1

phosphorylation

down-regulates

0.791

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

SIGNOR-165022

Q9H492

Q13501

1

binding

up-regulates

0.791

Sqstm1/p62 (named a170 in the mouse;hereafter p62) is the first proposed example of such proteins (bj_?_?Rk_?_?Y et al.,2005). It binds polyubiquitinated protein aggregates via its uba domain and interacts with lc3 on the autophagosome/ this interaction is necessary for autophagic degradation of p62-positive cytoplasmic inclusion bodies containing ubiquitinated proteins. We also demonstrate that alis are indistinguishable from p62 inclusion bodies and that p62 is required for their formation.

SIGNOR-156353

P04637

P51959

1

transcriptional regulation

up-regulates quantity by expression

0.791

Individual promoter and intron p53-binding motifs from the rat Cyclin G1 promoter region support transcriptional activation by p53 but do not show co-operative activation.

SIGNOR-268961

P26441

P26992

1

binding

up-regulates

0.791

Ciliary neurotrophic factor (cntf) is a cytokine supporting the differentiation and survival of various cell types in the peripheral and central nervous systems. Its receptor complex consists of a non-signaling alpha chain, cntfr, and two signaling beta chains, gp130 and the leukemia inhibitory factor receptor (lifr)

SIGNOR-81379

P01133

P04626

1

binding

up-regulates

0.791

To better understand the role of the egfr tyrosine kinase, we analyzed signaling by a kinase-inactive egfr (k721m) in erbb-devoid 32d cells. K721m alone exhibited no detectable signaling capacity, whereas coexpression of k721m with erbb2, but not erbb3 or erbb4, resulted in egf-dependent mitogen-activated protein kinase (mapk) activation. The kinase activity, but not tyrosine phosphorylation, of erbb2 was required for egf-induced mapk activation.

SIGNOR-106497

Q5MJ70

P24941

1

relocalization

up-regulates activity

0.791

Speedy/RINGO A, a noncanonical activator of CDK2, was recently identified as a key regulator for CDK2 recruitment to meiotic telomeres

SIGNOR-263310

O95835

Q9GZV5

1

phosphorylation

down-regulates

0.791

In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus.

SIGNOR-197643

Q14623

Q9Y6C5

1

binding

down-regulates activity

0.791

Biochemical analysis of ptch and ptch2 shows that they both bind to all hedgehog family members with similar affinity and that they can form a complex with smo.Current models suggest that binding of Shh to PTCH prevents the normal inhibition of the seven-transmembrane-protein Smoothened (SMO) by PTCH.

SIGNOR-61314

P78509

P98155

1

binding

up-regulates

0.791

The hypothesis that the vldl receptor signals in response to reelin binding was recently supported by studies (37) showing direct binding of reelin to the vldl receptor and changes in tyrosine phosphorylation in response to reelin-vldl receptor association.

SIGNOR-106295

Q13158

Q13546

1

binding

up-regulates activity

0.791

Rip1 is required for the formation of a rip1/fadd/caspase-8 complex that drives caspase-8 activation, cleavage of bid into tbid, mitochondrial outer membrane permeabilization, full activation of caspase-3 and caspase-dependent apoptosis. Tweak induces assembly of a death-signaling complex containing rip1, fadd, and caspase-8

SIGNOR-191781

Q6UN15

P51003

1

binding

up-regulates

0.791

Recombinant hfip1 is sufficient to stimulate the in vitro polyadenylation activity of pap in a u-rich element-dependent manner. hfip1, cpsf160 and pap form a ternary complex in vitro, suggesting that hfip1 and cpsf160 act together in poly(a) site recognition and in cooperative recruitment of pap to the rna.

SIGNOR-121700

P23458

P42224

1

phosphorylation

up-regulates activity

0.79

The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosineSH2 domain interactions

SIGNOR-236373

P15018

P40189

1

binding

up-regulates

0.79

Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors.Some Of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2

SIGNOR-48108

P56704

O75581

1

binding

up-regulates activity

0.79

Here, we present evidence that lrp6 is internalized with caveolin and that the components of this endocytic pathway are required not only for wnt-3a-induced internalization of lrp6 but also for accumulation of beta-catenin.

SIGNOR-148671

P28482

P05412

1

phosphorylation

up-regulates activity

0.79

Erk also undergoes rapid translocation into the nucleus, where it phosphorylates and activates a variety of transcription factor targets, including sp1, e2f, elk-1, and ap1.

SIGNOR-201943

Q2M2I8

Q96CW1

1

phosphorylation

up-regulates

0.79

Aak1 is enriched at presynaptic terminals, whereas in nonneuronal cells it colocalizes with clathrin and ap2 in clathrin-coated pits and at the leading edge of migrating cells. Aak1 specifically phosphorylates the mu subunit in vitro, and stage-specific assays for endocytosis show that mu phosphorylation by aak1 results in a decrease in ap2-stimulated transferrin internalization. Together, these results provide strong evidence that aak1 is the endogenous mu 2 kinase and plays a regulatory role in clathrin-mediated endocytosis.

SIGNOR-115657

P14598

P13498

1

binding

up-regulates activity

0.79

Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase.

SIGNOR-276625

Q92585

Q9UM47

1

binding

up-regulates

0.79

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 hes1.

SIGNOR-84838

P63000

Q13153

1

binding

up-regulates activity

0.79

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-248236

O95996

P35222

1

relocalization

down-regulates quantity by destabilization

0.79

The tumour-suppressing activity of apc largely involves facilitating the proteasome-mediated degradation of b-cateninit is possible that once exported from the nucleus, apc directs b-catenin along the cytoskeletal network to sites of degradation.

SIGNOR-81545

O95477

P02647

2

binding

up-regulates activity

0.79

The stimulation of cellular cholesterol and phospholipid efflux by apolipoprotein A-I is mediated by the activity of the ATP-binding cassette transporter A1 (ABCA1). ABCA1 forms a high affinity complex with apoA-I by binding amphipathic helices within the apolipoprotein. VFVNFA sequence is required for ABCA1 to form a complex with apoA-I and to transfer cholesterol to the apolipoprotein.

SIGNOR-252100

Q07890

P01112

1

guanine nucleotide exchange factor

up-regulates

0.79

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85.

SIGNOR-175262

Q9H0R8

Q13501

1

binding

up-regulates activity

0.79

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-156304

Q9Y4K3

Q9BQ95

1

ubiquitination

down-regulates activity

0.79

Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation

SIGNOR-260370

P02647

O95477

2

binding

up-regulates quantity by stabilization

0.79

ApoA-I stabilization of ABCA1 is mediated by reduced PEST sequence phosphorylation, which in turn leads to decreased calpain proteolysis of ABCA1.

SIGNOR-252101

P50613

P24928

1

phosphorylation

down-regulates

0.789

Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.

SIGNOR-120024

P15056

Q02750

1

phosphorylation

up-regulates activity

0.789

Activation of mek family kinases requires phosphorylation of two conserved ser/thr residueserine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.

SIGNOR-235475

Q8WUP2

Q14315

1

binding

up-regulates activity

0.789

Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton.

SIGNOR-266107

P12931

P40763

1

phosphorylation

up-regulates activity

0.789

In the present study, we have delineated the mechanism by which Galpha16 stimulates STAT3 in human embryonic kidney 293 cells. A constitutively active Galpha16 mutant, Galpha16QL, stimulated STAT3-dependent luciferase activity as well as the phosphorylation of STAT3 at both Tyr705 and Ser727.The involvement of tyrosine kinases such as c-Src and Janus kinase 2 and 3 (JAK2 and JAK3) in Galpha16QL-induced activation of STAT3 was illustrated by the combined use of selective inhibitors and dominant negative mutants.

SIGNOR-247341

Q9UHD2

Q96CV9

2

phosphorylation

up-regulates activity

0.789

Given that TBK1 can phosphorylate OPTN on S177, S473 and S513 in response to mitochondrial depolarization, we explored the function of these events in vivo.|Phosphorylation of OPTN on S473 and S513 promotes TBK1 activation and recruitment of OPTN to depolarized mitochondria.

SIGNOR-278170

Q13315

Q9BXW9

1

phosphorylation

up-regulates

0.789

These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint

SIGNOR-90117

O15105

P36897

1

binding

down-regulates activity

0.789

SMAD7 functions as an antagonist to TGFB by binding to the TBRI and thus inhibiting activation of SMAD2 and SMAD3.

SIGNOR-64088

Q9NQC7

Q9Y4K3

1

deubiquitination

down-regulates

0.789

The nf-kappab activation by cyld is mediated, at least in part, by the deubiquitination and inactivation of tnfr-associated factor 2 (traf2) and, to a lesser extent, traf6.

SIGNOR-117856

P28562

P45983

1

dephosphorylation

down-regulates

0.789

Jnk1 phosphorylation and activation was inhibited by expression of both mkp1 and mkp2.

SIGNOR-46079

Q96CV9

Q9UHD2

2

binding

up-regulates activity

0.789

Using biochemical experiments we showed that optineurin interacts with the protein kinase TBK1 and the ubiquitin ligase TRAF3. Furthermore, a mutation in optineurin that prevents the interaction with the small protein modifier ubiquitin (D474N) ablated the negative regulatory function of optineurin.

SIGNOR-262276

Q9Y4G8

P62834

1

guanine nucleotide exchange factor

up-regulates activity

0.789

Our data are consistent with a pathway involving the cAMP-mediated activation of Rapgef2, which then stimulates Rap1, leading to increases in B-Raf, MEK, and ERK activity.Increased intracellular concentrations of cAMP enhanced the Rapgef2-dependent activation of Rap1, which in turn associated with B-Raf to enable the activation of ERK and subsequent neuronal- and endocrine-specific cellular outcomes, such as induction of neuroendocrine-specific genes and extension of neuritic processes (neuritogenesis).

SIGNOR-276609

P29597

P52630

1

phosphorylation

up-regulates activity

0.789

JAK1 and TYK2 will phosphorylate and activate STAT1 and STAT2 respectively, leading to the formation of the ternary interferon-stimulated gene factor 3 (ISGF3) complex, composed of STAT1, STAT2 and interferon regulatory factor 9 (IRF9).

SIGNOR-279133

Q13153

P21333

1

phosphorylation

up-regulates

0.789

In flna, the pak1-binding site involves tandem repeat 23 in the carboxyl terminus and phosphorylation takes place on serine 2152.

SIGNOR-92065

Q5JTC6

O15169

1

relocalization

up-regulates activity

0.789

Amer1 binds ck1gamma, recruits axin and gsk3beta to the plasma membrane and promotes complex formation between axin and lrp6.

SIGNOR-171886

O95352

Q9BXW4

1

binding

up-regulates activity

0.789

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-191540

Q92878

P38398

1

binding

up-regulates

0.789

Brca1 interacts in vitro and in vivo with hrad50. Brca1 is important for the cellular responses to dna damage that are mediated by the hrad50-hmre11-p95 complex.

SIGNOR-69701

P04275

P00451

1

binding

up-regulates activity

0.789

Binding of FVIII to VWF is needed to maintain appropriate plasma levels, as FVIII plasma levels and half-life are remarkably reduced in the absence of VWF

SIGNOR-251967

O00418

P13639

1

phosphorylation

down-regulates

0.788

Ef-2 kinase phosphorylates ef-2 at 3 threonine residues: thr-53, thr-56, thr-58. Phosphorylation of thr56 and thr58 was found to be an ordered process, modification of thr56 preceding, and apparently being required for, phosphorylation of thr58.

SIGNOR-38556

P23443

P35568

1

phosphorylation

down-regulates quantity by destabilization

0.788

In this report, we identified insulin receptor substrate 1 (IRS-1), a critical mediator of the insulin/insulin-like growth factor 1 signaling, as a proteolytic target of the CUL7 E3 ligase in a manner that depends on mammalian target of rapamycin and the p70 S6 kinase activities.Elimination of phosphorylation at S307/S312/S527/S636/S639 renders V5-IRS-1 partially resistant to degradation by Fbw8

SIGNOR-236599

P06213

P18031

2

phosphorylation

up-regulates activity

0.788

Tyrosine residues 66, 152 and/or 153 of PTP1B are phosphorylated by the activated insulin receptor and are also necessary for formation of the PTP1B:insulin receptor complex| Furthermore, tyrosine phosphorylation of PTP1B by the insulin receptor tyrosine kinase increases the catalytic activity of PTP1B

SIGNOR-249370

P18031

P06213

2

dephosphorylation

down-regulates activity

0.788

Ptp1b is a protein tyrosine phosphatase that negatively regulates insulin sensitivity by dephosphorylating the insulin receptor.

SIGNOR-235499

O95886

Q9UPX8

1

relocalization

up-regulates activity

0.788

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-264593

P04628

O75197

1

binding

up-regulates activity

0.788

Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.

SIGNOR-169645

Q15485

P48740

1

binding

up-regulates activity

0.788

H-ficolin binds to PSA, a polysaccharide produced by Aerococcus viridans. C4 was activated by H-ficolin preparations bound to PSA which had been coated on ELISA plates. These results indicate that H-ficolin is a second ficolin which is associated with MASPs and sMAP, and which activates the lectin pathway|Proteolytic activation of complement components by H-ficolin-MASP.

SIGNOR-263411

Q9Y5X1

Q05193

1

binding

up-regulates

0.788

Snx9 binds directly to bothdynamin-1 anddynamin-2. Moreover by stimulatingdynaminassembly, snx9 stimulatesdynamin's basal gtpase activity and potentiates assembly-stimulated gtpase activity on liposomes.

SIGNOR-133892

P53350

Q6PGQ7

2

phosphorylation

down-regulates

0.788

Following cdk1-dependent recruitment, plk1 triggers hbora destruction by phosphorylating a recognition site for scf(beta-trcp).

SIGNOR-178154

O14511

Q15303

1

binding

up-regulates

0.788

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-26211

Q6PGQ7

P53350

2

phosphorylation

up-regulates

0.788

Bora/aurora-a-dependent phosphorylation is a prerequisite for plk1 to promote mitotic entry after a checkpoint-dependent arrest.

SIGNOR-179425

O95817

P11142

1

binding

up-regulates activity

0.788

Heat shock cognate protein 70 (Hsc70) regulates protein homeostasis through its reversible interactions with client proteins. Hsc70 has two major domains: a nucleotide-binding domain (NBD), that hydrolyzes ATP, and a substrate-binding domain (SBD), where clients are bound. Members of the BAG family of co-chaperones, including Bag1 and Bag3, are known to accelerate release of both ADP and client from Hsc70.

SIGNOR-254116

P08476

Q13705

1

binding

up-regulates activity

0.787

Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB.

SIGNOR-235142

P47992

P46094

1

binding

up-regulates

0.787

Scm-1 showed a high-affinity binding to xcr1 with a kd of 10 nm and induced vigorous chemotaxis and calcium mobilization in xcr1-transfected murine l1.2 cells.

SIGNOR-71164

Q13489

O43353

1

polyubiquitination

up-regulates activity

0.787

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-272715

O00141

Q96PU5

1

phosphorylation

down-regulates activity

0.787

Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1.

SIGNOR-263076

Q99959

P15924

1

binding

up-regulates quantity by stabilization

0.787

In contrast to the proper membrane localization of PKP2 and DSP after cotransfection of both WT proteins, mutant PKP2 C796R protein was not able to interact with FLAG-DSP to enable assembly at the junctional plaque, indicating the requirement of functional PKP2 for DSP integration into the desmosome.

SIGNOR-261254

O95278

Q6VVB1

2

binding

up-regulates activity

0.787

Here, we provide evidence indicating that the formation of the laforin–malin complex is positively regulated by AMPK. We show that laforin, but not malin, can interact physically with the catalytic subunit of AMPK and that purified AMPK phosphorylates GST::laforin in vitro.

SIGNOR-271729

P00797

O75787

1

binding

up-regulates

0.787

We report the expression cloning of the human renin receptor complementary dna encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin i and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of map kinases erk1 and erk2

SIGNOR-88416

Q6VVB1

O95278

2

polyubiquitination

down-regulates quantity by destabilization

0.787

Here, we demonstrate that malin is a single subunit E3 ubiquitin (Ub) ligase and that its RING domain is necessary and sufficient to mediate ubiquitination. Additionally, malin interacts with and polyubiquitinates laforin, leading to its degradation.

SIGNOR-271547

P27540

Q16665

1

binding

up-regulates activity

0.787

The functional transcription factor exists as a heterodimeric complex consisting of HIF-1alpha and the aryl hydrocarbon receptor nuclear translocator (ARNT). Association of HIF-1 with ARNT is required for its activity; however, no other role has been ascribed to this interaction.

SIGNOR-253720

P02778

P49682

1

binding

up-regulates activity

0.787

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

SIGNOR-260969

O96017

P38398

1

phosphorylation

up-regulates

0.787

In this study, we tested the hypothesis that the brca1-mediated regulation of recombination requires the chk2- and atm-dependent phosphorylation sites.

SIGNOR-120575

Q96B86

Q92859

1

binding

down-regulates activity

0.787

Netrin-1-neogenin interactions mediate chemoattractive axon guidance, while RGMa-neogenin interactions repel axons.

SIGNOR-268388

Q13635

Q99835

1

binding

down-regulates activity

0.786

We show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity.

SIGNOR-91709

P40763

P15692

1

transcriptional regulation

up-regulates quantity by expression

0.786

Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells.

SIGNOR-259456

P27361

P28562

2

phosphorylation

up-regulates

0.786

Mkp-1 was a target in vivo and in vitro for p42(mapk) or p44(mapk), which phosphorylates mkp-1 on two carboxyl-terminal serine residues, serine 359 and serine 364. This phosphorylation did not modify mkp-1's intrinsic ability to dephosphorylate p44(mapk) but led to stabilization of the protein.

SIGNOR-73633

P28562

P27361

2

dephosphorylation

down-regulates activity

0.786

We demonstrate that ERK, JNK, and p38 are activated by distinct combinations of stimuli in T cells that simulate full or partial activation through the T cell receptor. These kinases are regulated by reversible phosphorylation on Tyr and Thr, and the dual specific phosphatases PAC1 and MKP-1 previously have been implicated in the in vivo inactivation of ERK or of ERK and JNK, respectively

SIGNOR-248462

Q8WYL5

P23528

1

dephosphorylation

up-regulates activity

0.786

Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).

SIGNOR-248762

Q9C0C7

Q14457

1

binding

up-regulates activity

0.786

we show that the BECLIN 1-VPS34 complex is tethered to the cytoskeleton through an interaction between the BECLIN 1-interacting protein AMBRA1 and dynein light chains 1/2.

SIGNOR-168252

P06307

P32238

1

binding

up-regulates

0.786

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

SIGNOR-68474

P13500

P41597

1

binding

up-regulates activity

0.786

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-255113

O00585

P32248

1

binding

up-regulates

0.786

The regulated expression of the chemokine secondary lymphoid tissue chemokine (slc/ccl21) and its corresponding receptor, ccr7.

SIGNOR-117566

Q9Y275

Q96RJ3

1

binding

up-regulates activity

0.785

Baff specifically binds baff receptor

SIGNOR-135713

O75116

O14974

1

phosphorylation

down-regulates activity

0.785

Rho kinase is known to control smooth muscle contractility by phosphorylating the 110 kDa myosin-targetting subunit (MYPT1) of the myosin-associated form of protein phosphatase 1 (PP1M). Phosphorylation of MYPT1 at Thr695 has previously been reported to inhibit the catalytic activity of PP1. Here, we show that the phosphorylation of Thr850 by Rho kinase dissociates PP1M from myosin, providing a second mechanism by which myosin phosphatase activity is inhibited.

SIGNOR-249164

P61586

O60610

1

null

up-regulates activity

0.785

We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.

SIGNOR-253108

O14757

P30305

1

phosphorylation

down-regulates activity

0.785

Here, we show that cdc25b is phosphorylated by chk1 in vitro on multiple residues, including s230 and s563.We show that the s230-phosphorylated form of cdc25b is located at the centrosome from early s phase until mitosis. Furthermore, mutation of s230 to alanine increases the mitotic-inducing activity of cdc25b

SIGNOR-149898

Q13535

O60934

1

phosphorylation

up-regulates

0.785

We demonstrate that mrn and atr/atr-interacting protein (trip) interact with each other, and the forkhead-associated/breast cancer c-terminal domains (fha/brct) of nbs1 play a significant role in mediating this interaction. Mutations in the fha/brct domains do not prevent atr activation but specifically impair atr-mediated nbs1 phosphorylation at ser-343, which results in a defect in the s-phase checkpoint.

SIGNOR-155214

P48729

O15169

1

phosphorylation

up-regulates activity

0.785

Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated (Supplementary Figure 3). Three of them (S80, S82, and S473) were also phosphorylated in vitro by CKI and are conserved between axin1 and axin2/conductin.|This suggests that cumulative phosphorylation of axin is required for it to fully downregulate Wnt/beta_catenin signaling.

SIGNOR-249191

P78423

P49238

1

binding

up-regulates

0.785

Fractalkine/cx3cl1 is a membrane-tethered chemokine that functions as a chemoattractant and adhesion protein by interacting with the receptor cx3cr1.

SIGNOR-109135

P41236

P62136

1

binding

down-regulates

0.785

Atm phosphorylates i-2 on serine 43, leading to the dissociation of the pp1-i-2 complex and the activation of pp1.

SIGNOR-160651

Q9NYV4

P24928

1

phosphorylation

up-regulates activity

0.784

Cyck/cdk12 can activate transcription and phosphorylate ser2 in the ctd of rnapii / phosphorylation of serine at position 2 (ser2) is thought to be responsible for productive transcriptional elongation and synthesis of full-length mature mrna

SIGNOR-176805

Q8N474

P04628

1

binding

down-regulates

0.784

Frp inhibits wnt signaling through interactions with wnt and/or formation of nonfunctional complexes with the frizzled receptor. here we demonstrate that frza, a sfrp that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to wnt-1 protein, but not wnt-5a protein, and modulates wnt-1 signaling.

SIGNOR-71423

Q99731

P32248

1

binding

up-regulates activity

0.784

CCL19 and CCL21 are endogenous agonists for the seven-trans membrane receptor CCR7.

SIGNOR-278123

P41221

P34925

1

binding

up-regulates

0.784

Purified human RYK binds to mouse Wnt1, 3a and 5a expressed in HEK293 cells. Separate experiments show that human RYK also immunopreciptitates human VANGL2 when the proteins are co-expressed in HEK293 cells.

SIGNOR-258970

P07492

P30550

1

binding

up-regulates

0.784

Indeed, many potent mitogens such as thrombin, lysophosphatidic acid (lpa), gastrin-releasing peptide (grp), endothelin and prostaglandins stimulate cell proliferation by acting on their cognate gpcrs in various cell types.

SIGNOR-152676

P49841

P24385

1

phosphorylation

down-regulates

0.783

Phosphorylation of cyclin d1 on a single threonine residue near the carboxyl terminus (thr-286) positively regulates proteasomal degradation of d1. Now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover now, we demonstrate that glycogen synthase kinase-3beta (gsk-3beta) phosphorylates cyclin d1 specifically on thr-286, thereby triggering rapid cyclin d1 turnover.

SIGNOR-144818

P53350

Q9UKT4

1

phosphorylation

down-regulates

0.783

We propose that the balance of evi5 and polo-like kinase activities determines the timely accumulation of emi1 and cyclin, ensuring mitotic fidelity.

SIGNOR-142949

P01350

P32239

1

binding

up-regulates

0.783

A segment of five amino acids in the second extracellular loop of the cck-b receptor was shown to be essential for the high affinity of the natural peptide agonits, gastrin,

SIGNOR-66987

Q96AC1

Q8WUP2

1

binding

up-regulates activity

0.783

Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration.

SIGNOR-266108

P20023

P15391

1

binding

up-regulates activity

0.783

Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling.

SIGNOR-266642

Q8N3J5

P12694

1

dephosphorylation

up-regulates activity

0.783

BCKD is inhibited by phosphorylation of its E1alpha subunit at Ser293, which is catalyzed by BCKD kinase. During BCAA excess, phosphorylated Ser293 (pSer293) becomes dephosphorylated through the concerted inhibition of BCKD kinase and the activity of an unknown intramitochondrial phosphatase. Using unbiased, proteomic approaches, we have found that a mitochondrial-targeted phosphatase, PP2Cm, specifically binds the BCKD complex and induces dephosphorylation of Ser293 in the presence of BCKD substrates

SIGNOR-248758

O43521

Q92843

1

binding

down-regulates

0.783

Bim binds prosurvival proteins comparably. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.

SIGNOR-133832

P01189

Q01718

1

binding

up-regulates activity

0.783

Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP).

SIGNOR-268615

P30622

Q14203

1

binding

up-regulates activity

0.782

MT-unbound CLIP-170 can adopt a folded conformation through an intramolecular interaction of its terminal domains. Binding to MTs correlates with the unfolding of CLIP-170, which allows the interaction of the COOH-terminal domain with its binding partners, such as dynactin, resulting in their recruitment to the MT tip. The NH2 terminus of p150Glued binds directly to the COOH terminus of CLIP-170 through its second metal-binding motif.

SIGNOR-252164

Q8WW38

P43694

1

binding

down-regulates activity

0.782

FOG-2 associates physically with the N-terminal zinc finger of GATA-4 both in vitro and in vivo. This interaction appears to modulate specifically the transcriptional activity of GATA-4 because overexpression of FOG-2 in both NIH 3T3 cells and primary rat cardiomyocytes represses GATA-4-dependent transcription from multiple cardiac-restricted promoters.

SIGNOR-236959

P31749

Q96B36

1

phosphorylation

down-regulates activity

0.782

Treatment of these cells with 4-hydroxytamoxifen stimulated the phosphorylation of wt PRAS40 but not the mutant PRAS40 in which Thr-246 was mutated. These results demonstrate that activation of Akt alone is sufficient to induce phosphorylation of PRAS40

SIGNOR-252544

O14672

P46531

1

cleavage

up-regulates activity

0.782

ADAM10-mediated Notch1 cleavage is the rate limiting-step for release of the NICD and subsequent activation of Notch1 signaling. In T cells ADAM10-mediated Notch1 shedding controls T cell development

SIGNOR-259838