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
P25054	P35222	1	binding	down-regulates quantity	0.921	Apc binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. APC cooperates with Axin to promote the phosphorylation of _-catenin by GSK3 [which requires priming phosphorylation by casein kinase 1, _-isoform (CK1_)].	SIGNOR-177230
Q08AM6	Q92562	1	binding	up-regulates quantity by stabilization	0.921	Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction.	SIGNOR-253534
P49841	O15169	1	phosphorylation	up-regulates activity	0.92	Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP	SIGNOR-251221
P15498	P43405	2	binding	up-regulates	0.92	Vav interacts with the tyrosine kinase syk	SIGNOR-107049
P43405	P15498	2	phosphorylation	up-regulates	0.92	Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k.	SIGNOR-107046
P08603	P05156	1	binding	up-regulates activity	0.92	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-263490
O75381	Q92968	1	binding	up-regulates activity	0.92	Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import	SIGNOR-253029
P60953	O00401	1	binding	up-regulates activity	0.919	In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules.	SIGNOR-261868
O75143	Q8TDY2	1	binding	up-regulates	0.919	Atg13 directly binds fip200.	SIGNOR-184120
P25942	Q13114	1	binding	up-regulates activity	0.918	Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3.	SIGNOR-250560
P08603	P01024	1	binding	down-regulates activity	0.918	As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)	SIGNOR-252141
P05231	P08887	1	binding	up-regulates	0.918	We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model.	SIGNOR-137236
Q9GZT9	Q16665	1	hydroxylation	down-regulates quantity by destabilization	0.918	Hypoxia-inducible factor-1 (HIF-1) is a key regulator of erythropoiesis. In this article, we report 3 novel mutations, P378S, A385T, and G206C, on the EGLN1 gene encoding the negative HIF-1α regulator prolyl hydroxylase domain-2 (PHD2) in 3 patients with isolated erythrocytosis. These mutations impair PHD2 protein stability and partially reduce PHD2 activity, leading to increased HIF-1α protein levels in cultured cells.\|Oxygen-dependent hydroxylation by the prolyl hydroxylase domain-2 (PHD2) protein marks HIF-1alpha for ubiquitination by the von Hippel Lindau (VHL) tumor suppressor protein, leading to proteasomal degradation	SIGNOR-261994
P06850	Q13324	1	binding	up-regulates activity	0.917	The actions of CRH are transduced through CRH receptors, which belong to the class II/secretin-like family of the G-protein coupled receptor (GPCR) superfamily (Martin et al. 2005). There are three types of CRH receptors – type 1 (CRHR1), type 2 (CRHR2) and type 3 (CRHR3). Among these, CRHR3 has not been identified in mammals. \|CRH is a high-affinity ligand of CRHR1. It also binds to CRHR2, but with lower affinity	SIGNOR-268611
O75385	O75143	1	phosphorylation	up-regulates	0.917	Ulks directly phosphorylate atg13	SIGNOR-183957
P35222	Q9UJU2	1	binding	up-regulates activity	0.917	Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1	SIGNOR-134219
Q15185	P07900	1	binding	up-regulates activity	0.916	The mutant Hsp90 proteins tested are defective in the binding and ATP hydrolysis-dependent cycling of the co-chaperone p23, which is thought to regulate the binding and release of substrate polypeptide from Hsp90.	SIGNOR-262831
P46019	P15735	1	binding	down-regulates activity	0.916	Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.	SIGNOR-267406
P49767	P35968	1	binding	up-regulates	0.916	Vegf-c is also a ligand for vegfr-2 (12), but the functional significance of this potential interaction in vivo is unknown	SIGNOR-55208
Q13546	Q9Y6K9	1	binding	up-regulates activity	0.915	Interestingly, polyubiquitinated rip1 recruits ikk through the binding between the polyubiquitin chains and nemo, a regulatory subunit of the ikk complex. Mutations of nemo that disrupt its polyubiquitin binding also abolish ikk activation.	SIGNOR-145858
P20810	P07384	1	binding	down-regulates activity	0.915	In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains\|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain	SIGNOR-251582
Q07817	Q14457	1	binding	down-regulates	0.915	The anti-apoptotic proteins bcl-2 and bcl-x(l) bind and inhibit beclin-1, an essential mediator of autophagy.	SIGNOR-154480
Q05397	P49023	1	binding	up-regulates activity	0.914	Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.	SIGNOR-257732
P06213	P35568	1	phosphorylation	up-regulates activity	0.914	All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10).	SIGNOR-235975
P05230	P11362	1	binding	up-regulates activity	0.914	Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity.	SIGNOR-236936
P22301	Q13651	1	binding	up-regulates	0.914	Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling	SIGNOR-67964
Q9P2K8	P05198	1	phosphorylation	down-regulates activity	0.914	Translation initiation factor 2α [eukaryotic translation initiation factor 2α (eIF2α)] kinase phosphorylates serine51 (Ser51) of eIF2α and downregulates cellular protein synthesis.	SIGNOR-246157
P13232	P16871	1	binding	up-regulates	0.914	This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain.	SIGNOR-163548
P98170	Q9NR28	2	ubiquitination	down-regulates quantity by destabilization	0.914	Xiap functions as ubiquitin ligase toward smac to inhibit apoptosis.	SIGNOR-134504
Q9NR28	P98170	2	binding	down-regulates activity	0.914	Smac/diablo, an inhibitor of xiap, is released from mitochondria upon receiving apoptotic stimuli and binds to the bir2 and bir3 domains of xiap, thereby inhibiting its caspase-inhibitory activity	SIGNOR-110831
P06400	Q14209	1	binding	down-regulates	0.914	Cyclin-dependent kinase (cdk) phosphorylation of the retinoblastoma protein (rb) drives cell proliferation through rb complexes with e2f transcription factors and other regulatory proteins.	SIGNOR-197328
Q7Z434	Q9UHD2	1	binding	up-regulates activity	0.913	After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively.	SIGNOR-260145
P51617	Q9Y4K3	2	binding	up-regulates activity	0.913	Il-1 treatment of 293 cells induces the association of traf6 with irak.	SIGNOR-44234
Q14563	O14786	1	binding	up-regulates activity	0.913	Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction.	SIGNOR-261815
O75326	O60486	1	binding	up-regulates	0.913	Plexin-c1 is a receptor for the gpi-anchored semaphorin sema7a. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro.	SIGNOR-71260
O75385	Q8TDY2	1	phosphorylation	up-regulates	0.913	Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks.	SIGNOR-186992
P00533	P29353	1	binding	up-regulates activity	0.913	Adaptors such as Shc, Grb2, Crk or the recently characterised Dok-R protein (Jones Dumont 1999) show a modular structure containing protein protein interaction domains and putative phosphorylation sites and act as signalling platforms which extend the receptors repertoire of activated intracellular pathways.	SIGNOR-107712
Q9Y4K3	P51617	2	ubiquitination	up-regulates activity	0.913	K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B	SIGNOR-252252
Q92793	P04637	1	acetylation	up-regulates activity	0.912	C-terminal acetylation of p53 by p300/CBP and PCAF promotes an open conformation of p53 by preventing the occlusion of the DNA binding domain by the C-terminal tail. This enhances p53 transcriptional activity, leading to growth arrest and/or apoptosis	SIGNOR-261495
Q09472	P04637	1	polyubiquitination	down-regulates quantity by destabilization	0.912	P53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Purified p300 exhibited intrinsic ubiquitin ligase activity that was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300.	SIGNOR-271418
Q6ZMJ4	P07333	1	binding	up-regulates activity	0.912	CSF-1, derived from fibroblasts, tumor cells, etc., is produced in membrane-bound form, secreted glycoproteins and proteoglycans. Currently, CSF-1R is considered to be the sole receptor for CSF-1. These cells regulate macrophage growth, differentiation and function by secreting CSF1. Colony-stimulating factor receptor (CSF1R), a type I single-transmembrane protein, is ubiquitously expressed in myeloid cells such as monocytes, macrophages, neuroglia, and osteoblasts. CSF1R induces receptor homodimerization by binding to either CSF-1 or IL-34, followed by activation of receptor signaling and activation of extracellular pro-cell-survival kinase cascades, including PI3K, ERK1/2, and JNK	SIGNOR-277714
P62993	Q07889	1	relocalization	up-regulates activity	0.912	Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate.	SIGNOR-235773
P63151	P67775	1	binding	down-regulates activity	0.912	Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity	SIGNOR-217875
Q53ET0	P16220	1	binding	up-regulates activity	0.912	The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting	SIGNOR-256102
P62993	Q9UQC2	1	binding	up-regulates	0.911	The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival	SIGNOR-204969
P51531	Q92922	1	binding	up-regulates	0.911	The remodeling activity of brg1 and hbrm is stimulated by baf170/baf155 and is further stimulated when ini1 is added.	SIGNOR-65432
Q96EB6	O43524	1	deacetylation	up-regulates activity	0.911	Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress	SIGNOR-122405
Q92574	Q15382	1	binding	down-regulates activity	0.911	Tsc1 and tsc2 proteins, which together inhibit rheb through the gap activity of tsc2.	SIGNOR-162096
Q8WW43	P49768	1	binding	up-regulates	0.911	Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity.	SIGNOR-97107
Q9UN37	O43633	1	cleavage	up-regulates activity	0.911	Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission.	SIGNOR-260846
P29597	P17181	1	phosphorylation	up-regulates activity	0.91	We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2.	SIGNOR-246934
P39905	P07949	1	binding	up-regulates	0.91	A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling	SIGNOR-49094
P31749	O43524	1	phosphorylation	down-regulates activity	0.91	Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function	SIGNOR-252523
O95631	P43146	1	binding	up-regulates activity	0.91	DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin superfamily. It was originally identified as a prognostic tumor marker and then subsequently found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other important cellular processes.	SIGNOR-268162
P01116	P42336	1	binding	up-regulates	0.91	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism.	SIGNOR-175204
P25445	Q13158	1	binding	up-regulates activity	0.91	Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd.	SIGNOR-176651
Q96RL1	P38398	1	binding	up-regulates	0.91	Rap80 specifically recruits brca1 to dna damage sites and functions with brca1 in g2/m checkpoint control	SIGNOR-155201
Q8WW43	P49810	1	binding	up-regulates	0.909	By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.	SIGNOR-93310
Q14790	Q13546	2	cleavage	down-regulates activity	0.909	These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability.	SIGNOR-71265
Q15628	Q14790	1	binding	up-regulates activity	0.909	Tradd recruits caspase-8	SIGNOR-118591
Q9UMX1	P10070	1	relocalization	down-regulates activity	0.909	We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms	SIGNOR-129065
P05230	P21802	1	binding	up-regulates	0.909	We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2.	SIGNOR-73811
Q13546	Q14790	2	binding	up-regulates activity	0.909	Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex	SIGNOR-104255
Q9UIC8	P67775	1	methylation	up-regulates activity	0.908	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits \|The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1)	SIGNOR-265749
O15273	Q8WZ42	1	binding	up-regulates activity	0.908	TCAP, a core sarcomeric component capping the titin proteins, was identified as a positive hit (Figure 1A). TCAP is a small (19 kDa), highly abundant cytoplasmic protein expressed exclusively in skeletal muscle and the heart (Valle et al., 1997). TCAP interacts with titin through its N-terminal beta sheet to anchor titin to the Z-disc	SIGNOR-264854
O95405	Q15796	1	relocalization	up-regulates activity	0.908	Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor.	SIGNOR-165786
P45983	P05412	1	phosphorylation	up-regulates activity	0.907	JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain.	SIGNOR-250122
Q9UK05	P37023	1	binding	up-regulates	0.907	Finally, we demonstrate that bmp9 and bmp10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of alk1. Taken together, our results suggest that bmp9 and bmp10 are two specific alk1 ligands that may physiologically trigger the effects of alk1 on angiogenesis.	SIGNOR-150260
P78527	Q13426	1	phosphorylation	up-regulates activity	0.907	In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.	SIGNOR-277198
O00512	Q9Y3Y4	1	binding	up-regulates	0.907	Here we report the identification of two segment polarity genes in drosophila, legless (lgs), and pygopus (pygo), and we show that their products are required for wnt signal transduction at the level of nuclear beta-catenin. Lgs encodes the homolog of human bcl9, and we provide genetic and molecular evidence that these proteins exert their function by physically linking pygo to beta-catenin.	SIGNOR-116577
P01584	P14778	1	binding	up-regulates activity	0.906	Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor.	SIGNOR-249511
P01127	P09619	1	binding	up-regulates	0.906	Pdgf-b activates both pdgfr-alpha and pdgfr-beta	SIGNOR-107400
Q14393	P30530	1	binding	up-regulates	0.905	Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function.	SIGNOR-34339
Q9Y570	P67775	1	demethylation	down-regulates activity	0.905	Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits \|Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans.	SIGNOR-265748
P46937	P28347	1	binding	up-regulates	0.905	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201465
Q9NZN5	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.905	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-260539
Q07960	P60953	1	gtpase-activating protein	down-regulates activity	0.905	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-260459
P42771	P11802	1	binding	down-regulates	0.905	The first group, including p16ink4a, p15ink4b,p18ink4cand p19ink4d, is specific for the g1 cdks, cdk4 and cdk6, inhibiting the kinase activity of cyclin d/cdk4-cdk6 complexes on prb.	SIGNOR-44554
Q9NQL2	Q8N122	1	binding	up-regulates	0.905	Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor	SIGNOR-162093
O95352	P60520	1	binding	up-regulates activity	0.905	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-142002
P20810	P17655	1	binding	down-regulates activity	0.904	In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains\|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain	SIGNOR-251609
P42345	Q96B36	1	phosphorylation	down-regulates activity	0.904	We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1.	SIGNOR-178128
Q02297	Q15303	1	binding	up-regulates	0.904	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-122053
Q16828	P28482	2	dephosphorylation	down-regulates activity	0.904	Dual-specificity phosphatase six (DUSP6, MKP3, or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on ERK-2 (MAPK1) to inactivate the ERK-2 kinase.	SIGNOR-277006
P28482	Q16828	2	phosphorylation	down-regulates quantity by destabilization	0.904	In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3.	SIGNOR-132971
P62993	P22681	1	relocalization	up-regulates	0.904	The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization.	SIGNOR-114704
O94907	O75581	1	binding	down-regulates	0.904	We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6.	SIGNOR-109247
P48023	P25445	1	binding	up-regulates activity	0.903	The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl)	SIGNOR-49688
P37231	Q9UBK2	1	transcriptional regulation	up-regulates quantity by expression	0.903	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma\|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263984
O15085	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.903	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-260538
Q13114	Q9UHD2	1	binding	up-regulates activity	0.903	MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1.	SIGNOR-260156
P49674	O15055	1	phosphorylation	down-regulates quantity by destabilization	0.902	Priming-independent clusters located in the C-terminal portion of PER2’s PAS domains are targeted by CK1ε/δ and are required for ubiquitin ligase–mediated degradation of PER2	SIGNOR-277419
P46108	Q13905	1	binding	up-regulates	0.901	The endogenous c3g could be coprecipitated with crk from cell lysates of cells expressing high levels of c-crk or v-crk, suggesting high binding affinity and a possible interaction in vivo.	SIGNOR-33732
Q9NW38	Q9NPD8	2	ubiquitination	down-regulates quantity	0.901	Monoubiquitination of UBE2T was enhanced by FANCL introduction, suggesting that FANCL feeds back to UBE2T and can downregulate its activity.Although the FA pathway has been extensively studied, the E2 enzyme cooperating with the FA core complex for monoubiquitination of FANCD2 has not been discovered.\|This monoubiquitination is stimulated by the presence of the FANCL protein and inactivates UBE2T.	SIGNOR-278809
Q12770	Q12772	1	relocalization	up-regulates activity	0.901	SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function	SIGNOR-267502
P49336	Q9UHV7	1	phosphorylation	down-regulates quantity by destabilization	0.901	Here, cyclin C-Cdk8 phosphorylation of Med13 most likely primes the phosphodegron for destruction.	SIGNOR-279687
Q15596	P10275	1	binding	up-regulates activity	0.901	The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis	SIGNOR-251531
Q9HBE4	Q9HBE5	1	binding	up-regulates	0.901	Il-21 mediates its biological effects via the il-21r in conjunction with the common receptor gamma-chain that is also shared by members of the il-2 family	SIGNOR-143849
Q9NPD8	Q9NW38	2	ubiquitination	up-regulates activity	0.901	Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex\|Our structural and biochemical analyses suggest that, in a cellular environment with multiple E2s present, FANCL will preferentially select Ube2T.	SIGNOR-263263
Q9Y4K3	P14778	1	ubiquitination	down-regulates quantity by destabilization	0.9	We found that of all TRAFs and E3 ligases examined, TRAF6 preferentially ubiquitinated IL-1R1.	SIGNOR-278576

P25054

P35222

1

binding

down-regulates quantity

0.921

Apc binds to both b-catenin and axin, and could shuttle b-catenin from the plasma membrane and nucleus to the cytoplasmic axin complex. APC cooperates with Axin to promote the phosphorylation of _-catenin by GSK3 [which requires priming phosphorylation by casein kinase 1, _-isoform (CK1_)].

SIGNOR-177230

Q08AM6

Q92562

1

binding

up-regulates quantity by stabilization

0.921

Our data indentify a novel regulatory mechanism whereby ArPIKfyve enhances Sac3 abundance by attenuating Sac3 proteasome-dependent degradation and suggest that a failure of this mechanism could be the primary molecular defect in the pathogenesis of CMT4J. our data are consistent with the notion that when associated with ArPIKfyve, Sac3 is stabilized and protected from degradation, whereas in the absence of associated ArPIKfyve, Sac3 remains unfolded and, hence, prone to rapid destruction.

SIGNOR-253534

P49841

O15169

1

phosphorylation

up-regulates activity

0.92

Axin residues T609 and S614 are physiological GSK3beta targets. Axin phosphorylation in the regulation of b-catenin stability. When active (left), GSK3b phosphorylates Axin as well as APC and b-catenin. The phosphorylated form of Axin binds strongly to b-catenin and promotes the phosphorylation of b-catenin by GSK3b, leading to strong interaction with b-TrCP

SIGNOR-251221

P15498

P43405

2

binding

up-regulates

0.92

Vav interacts with the tyrosine kinase syk

SIGNOR-107049

P43405

P15498

2

phosphorylation

up-regulates

0.92

Vav interacts with the tyrosine kinase syk. inhibition of syk kinase activity prevents tyrosine phosphorylation of vav and its interaction with pi 3-k.

SIGNOR-107046

P08603

P05156

1

binding

up-regulates activity

0.92

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-263490

O75381

Q92968

1

binding

up-regulates activity

0.92

Pex14 interacts via its proline-rich motif with the SH3 domain of Pex13. We conclude that the association of Pex13 with Pex14 is an essential step in peroxisomal protein import

SIGNOR-253029

P60953

O00401

1

binding

up-regulates activity

0.919

In the presence of Cdc42 and PI(4,5)P2, the potency of N-WASP was increased to a level approaching that of GST-VCA, suggesting that N-WASP was fully activated by the two molecules.

SIGNOR-261868

O75143

Q8TDY2

1

binding

up-regulates

0.919

Atg13 directly binds fip200.

SIGNOR-184120

P25942

Q13114

1

binding

up-regulates activity

0.918

Cd40, a tumor necrosis factor receptor (tnfr) family member, forms a complex containing adaptor molecules traf2 and traf3.

SIGNOR-250560

P08603

P01024

1

binding

down-regulates activity

0.918

As a regulator of the alternative pathway, FH binds to C3b and inhibits the binding of factor B to C3b, acts as a cofactor for the factor I-mediated cleavage of C3b to iC3b (cofactor activity), and accelerates the decay of C3bBb, the alternative pathway C3 convertase (decay-accelerating activity)

SIGNOR-252141

P05231

P08887

1

binding

up-regulates

0.918

We show that the augmentation of the il6 signal by recombinant il6 receptors (ril6r) delivery allows the functional recovery of phagocytes in a peritonitis mouse model.

SIGNOR-137236

Q9GZT9

Q16665

1

hydroxylation

down-regulates quantity by destabilization

0.918

Hypoxia-inducible factor-1 (HIF-1) is a key regulator of erythropoiesis. In this article, we report 3 novel mutations, P378S, A385T, and G206C, on the EGLN1 gene encoding the negative HIF-1α regulator prolyl hydroxylase domain-2 (PHD2) in 3 patients with isolated erythrocytosis. These mutations impair PHD2 protein stability and partially reduce PHD2 activity, leading to increased HIF-1α protein levels in cultured cells.|Oxygen-dependent hydroxylation by the prolyl hydroxylase domain-2 (PHD2) protein marks HIF-1alpha for ubiquitination by the von Hippel Lindau (VHL) tumor suppressor protein, leading to proteasomal degradation

SIGNOR-261994

P06850

Q13324

1

binding

up-regulates activity

0.917

The actions of CRH are transduced through CRH receptors, which belong to the class II/secretin-like family of the G-protein coupled receptor (GPCR) superfamily (Martin et al. 2005). There are three types of CRH receptors – type 1 (CRHR1), type 2 (CRHR2) and type 3 (CRHR3). Among these, CRHR3 has not been identified in mammals. |CRH is a high-affinity ligand of CRHR1. It also binds to CRHR2, but with lower affinity

SIGNOR-268611

O75385

O75143

1

phosphorylation

up-regulates

0.917

Ulks directly phosphorylate atg13

SIGNOR-183957

P35222

Q9UJU2

1

binding

up-regulates activity

0.917

Activated dvl binds and inhibits the phosphorylation of beta catenin by gsk3beta/alfa, blocking beta catenin degradation), so that beta catenin accumulates and translocates to the nucleus, where it interacts with the t cell specific factor (tcf)/lymphoid enhancer binding factor 1 (lef-1) transcription factor and induces the transcription of target genes such as c-jun, c-myc, and cyclin d1

SIGNOR-134219

Q15185

P07900

1

binding

up-regulates activity

0.916

The mutant Hsp90 proteins tested are defective in the binding and ATP hydrolysis-dependent cycling of the co-chaperone p23, which is thought to regulate the binding and release of substrate polypeptide from Hsp90.

SIGNOR-262831

P46019

P15735

1

binding

down-regulates activity

0.916

Phk is among the most complex of the protein kinases so far elucidated. It has one catalytic (gamma) subunit and three different regulatory (alpha, beta, and delta) subunits, a molecular mass of 1.3 X 106 daltons, and each holoenzyme molecule is presumed to contain four molecules of each subunit. The three regulatory subunits inhibit the phosphotransferase activity of the gamma subunit.

SIGNOR-267406

P49767

P35968

1

binding

up-regulates

0.916

Vegf-c is also a ligand for vegfr-2 (12), but the functional significance of this potential interaction in vivo is unknown

SIGNOR-55208

Q13546

Q9Y6K9

1

binding

up-regulates activity

0.915

Interestingly, polyubiquitinated rip1 recruits ikk through the binding between the polyubiquitin chains and nemo, a regulatory subunit of the ikk complex. Mutations of nemo that disrupt its polyubiquitin binding also abolish ikk activation.

SIGNOR-145858

P20810

P07384

1

binding

down-regulates activity

0.915

In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain

SIGNOR-251582

Q07817

Q14457

1

binding

down-regulates

0.915

The anti-apoptotic proteins bcl-2 and bcl-x(l) bind and inhibit beclin-1, an essential mediator of autophagy.

SIGNOR-154480

Q05397

P49023

1

binding

up-regulates activity

0.914

Focal adhesion kinase (FAK) is activated by growth factors and integrins during migration, and functions as a receptor-proximal regulator of cell motility. At contacts between cells and the extracellular matrix, FAK functions as an adaptor protein to recruit other focal contact proteins or their regulators, which affects the assembly or disassembly of focal contacts. Whereas it was first hypothesized that FAK might bind directly to the cytoplasmic tails of integrins, accumulated evidence supports an indirect association of FAK with integrins through binding to integrin-associated proteins such as paxillin and talin.

SIGNOR-257732

P06213

P35568

1

phosphorylation

up-regulates activity

0.914

All known IRS proteins contain multiple YXXM motifs that upon phosphorylation by activated insulin receptors A previous study using phosphopeptides suggested that tyrosine-phosphorylated YXXM motifs at positions 608 and 939 in rat IRS-1 bind with high affinity to SH2 domains of p85, and motifs at positions 460 and 987 bind with lower affinity (10).

SIGNOR-235975

P05230

P11362

1

binding

up-regulates activity

0.914

Together these data highlight the unique nature of the role of FGF-1 during the earliest stages of adipogenesis and establish a role for FGFR1 in human adipogenesis, identifying FGFR1 as a potential therapeutic target to reduce obesity.

SIGNOR-236936

P22301

Q13651

1

binding

up-regulates

0.914

Functionally active il-10 receptors are composed of two distinct subunits. The il-10 receptor ? Chain is a 110-kda polypeptide that plays the dominant role in mediating high affinity ligand binding and signal transduction. The il-10 receptor ? Subunit (also known as crf2_4) is predicted to be a 40-kda polypeptide that is largely required only for signaling

SIGNOR-67964

Q9P2K8

P05198

1

phosphorylation

down-regulates activity

0.914

Translation initiation factor 2α [eukaryotic translation initiation factor 2α (eIF2α)] kinase phosphorylates serine51 (Ser51) of eIF2α and downregulates cellular protein synthesis.

SIGNOR-246157

P13232

P16871

1

binding

up-regulates

0.914

This receptor (il-7r) is a heterodimer consisting of the il-7r chain and the common cytokine ? -chain.

SIGNOR-163548

P98170

Q9NR28

2

ubiquitination

down-regulates quantity by destabilization

0.914

Xiap functions as ubiquitin ligase toward smac to inhibit apoptosis.

SIGNOR-134504

Q9NR28

P98170

2

binding

down-regulates activity

0.914

Smac/diablo, an inhibitor of xiap, is released from mitochondria upon receiving apoptotic stimuli and binds to the bir2 and bir3 domains of xiap, thereby inhibiting its caspase-inhibitory activity

SIGNOR-110831

P06400

Q14209

1

binding

down-regulates

0.914

Cyclin-dependent kinase (cdk) phosphorylation of the retinoblastoma protein (rb) drives cell proliferation through rb complexes with e2f transcription factors and other regulatory proteins.

SIGNOR-197328

Q7Z434

Q9UHD2

1

binding

up-regulates activity

0.913

After ligand binding, cGAS and RIG-I signal through respective adaptor proteins STING and MAVS to recruit the kinases IKK and TBK1, which then activate the transcription factors NF-κB and interferon regulatory factor 3 (IRF3), respectively.

SIGNOR-260145

P51617

Q9Y4K3

2

binding

up-regulates activity

0.913

Il-1 treatment of 293 cells induces the association of traf6 with irak.

SIGNOR-44234

Q14563

O14786

1

binding

up-regulates activity

0.913

Further examination of the composition of the functional Sema3B receptor revealed that, unlike Sema3A, which signals exclusively using the NP1 receptor, Sema3B utilizes both NP1 and NP2 for signal transduction.

SIGNOR-261815

O75326

O60486

1

binding

up-regulates

0.913

Plexin-c1 is a receptor for the gpi-anchored semaphorin sema7a. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro.

SIGNOR-71260

O75385

Q8TDY2

1

phosphorylation

up-regulates

0.913

Ulk1 and ulk2 are the kinase phosphorylating their binding proteins atg13 and fip200. Atg13 directly binds fip200 and mediates the interaction between fip200 and ulks.

SIGNOR-186992

P00533

P29353

1

binding

up-regulates activity

0.913

Adaptors such as Shc, Grb2, Crk or the recently characterised Dok-R protein (Jones Dumont 1999) show a modular structure containing protein protein interaction domains and putative phosphorylation sites and act as signalling platforms which extend the receptors repertoire of activated intracellular pathways.

SIGNOR-107712

Q9Y4K3

P51617

2

ubiquitination

up-regulates activity

0.913

K63-linked polyubiquitination of proximal signaling proteins is a common mechanism used by diverse innate immune receptors for recruiting IKK and activating NF-_B

SIGNOR-252252

Q92793

P04637

1

acetylation

up-regulates activity

0.912

C-terminal acetylation of p53 by p300/CBP and PCAF promotes an open conformation of p53 by preventing the occlusion of the DNA binding domain by the C-terminal tail. This enhances p53 transcriptional activity, leading to growth arrest and/or apoptosis

SIGNOR-261495

Q09472

P04637

1

polyubiquitination

down-regulates quantity by destabilization

0.912

P53 is stabilized by the binding of p300 to the oncoprotein E1A, suggesting that p300 regulates p53 degradation. Purified p300 exhibited intrinsic ubiquitin ligase activity that was inhibited by E1A. In vitro, p300 with MDM2 catalyzed p53 polyubiquitination, whereas MDM2 catalyzed p53 monoubiquitination. E1A expression caused a decrease in polyubiquitinated but not monoubiquitinated p53 in cells. Thus, generation of the polyubiquitinated forms of p53 that are targeted for proteasome degradation requires the intrinsic ubiquitin ligase activities of MDM2 and p300.

SIGNOR-271418

Q6ZMJ4

P07333

1

binding

up-regulates activity

0.912

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

SIGNOR-277714

P62993

Q07889

1

relocalization

up-regulates activity

0.912

Interaction domains of sos1/grb2 are finely tuned for cooperative control of embryonic stem cell fate.

SIGNOR-235773

P63151

P67775

1

binding

down-regulates activity

0.912

Since B_ suppresses the association of the catalytic C and regulatory A subunits of protein phosphatase 2A [94], the B_ interaction with the receptor is expected to result in enhanced protein phosphatase 2A activity

SIGNOR-217875

Q53ET0

P16220

1

binding

up-regulates activity

0.912

The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting

SIGNOR-256102

P62993

Q9UQC2

1

binding

up-regulates

0.911

The signaling mechanism utilizes an adaptor protein, shc, which binds to a phosphotyrosine residue on the il-2/15r?, Resulting in activation of grb2 and onto akt via the shc-grb2-gab2-pi3k-akt signaling pathway to increase cell proliferation and/or survival

SIGNOR-204969

P51531

Q92922

1

binding

up-regulates

0.911

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

SIGNOR-65432

Q96EB6

O43524

1

deacetylation

up-regulates activity

0.911

Sirt1 increased foxo3's ability to induce cell cycle arrest and resistance to oxidative stress

SIGNOR-122405

Q92574

Q15382

1

binding

down-regulates activity

0.911

Tsc1 and tsc2 proteins, which together inhibit rheb through the gap activity of tsc2.

SIGNOR-162096

Q8WW43

P49768

1

binding

up-regulates

0.911

Biochemical and genetic studies have recently identified nicastrin, aph-1, and pen-2 as essential cofactors that physically interact with ps1 and are necessary for the gamma-secretase activity.

SIGNOR-97107

Q9UN37

O43633

1

cleavage

up-regulates activity

0.911

Here, we show, using high-speed atomic force microscopy and electron microscopy, that the AAA-type adenosine triphosphatase VPS4 constricts and cleaves ESCRT-III CHMP2A-CHMP3 helical filaments in vitro. Our results demonstrate that VPS4 actively constricts ESCRT-III filaments and cleaves them before their complete disassembly. We propose that the formation of ESCRT-III dome-like end caps by VPS4 within a membrane neck structure constricts the membrane to set the stage for membrane fission.

SIGNOR-260846

P29597

P17181

1

phosphorylation

up-regulates activity

0.91

We demonstrate that, in vitro, p135tyk2 phosphorylates two tyrosines on IFNaR1. A phosphopeptide corresponding to the major phosphorylation site (Tyr466) binds STAT2, but not STAT1, in an SH-2-dependent manner. Furthermore, only latent, non-phosphorylated STAT2 interacts with this phosphopeptide. When this phosphopeptide is introduced into permeabilized cells, the IFN alpha-dependent tyrosine phosphorylation of both STATs is blocked. Finally, mutant versions of IFNaR1, in which Tyr466 is changed to phenylalanine, can act in a dominant negative manner to inhibit phosphorylation of STAT2.

SIGNOR-246934

P39905

P07949

1

binding

up-regulates

0.91

A receptor complex comprised of trnr1 (gdnfr alpha) and ret was recently identified and found to be capable of mediating both gdnf and ntn signaling

SIGNOR-49094

P31749

O43524

1

phosphorylation

down-regulates activity

0.91

Akt-dependent phosphorylation of foxo3a (thr32, ser253, and ser315 for human foxo3) enhances foxo3a/14?3?3 Interaction and promotes foxo3a nuclear export to the cytoplasm, resulting in the repression of foxo3a transcriptional function

SIGNOR-252523

O95631

P43146

1

binding

up-regulates activity

0.91

DCC (Deleted in Colorectal Cancer) is a single-pass transmembrane protein that belongs to the immunoglobulin superfamily. It was originally identified as a prognostic tumor marker and then subsequently found to be a receptor for netrin-1. DCC plays a key role in axon guidance and also in a number of other important cellular processes.

SIGNOR-268162

P01116

P42336

1

binding

up-regulates

0.91

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k phosphatidylinositol 3-kinase (pi3k) is one of the main effector pathways of ras, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism.

SIGNOR-175204

P25445

Q13158

1

binding

up-regulates activity

0.91

Aggregation-induced conformational changes in fas lead to the formation of the death-inducing signalling complex (disc) which involves recruitment of the adaptor protein fadd/mort1 through a homotypic interaction of death domains, present in both the intracellular region of fas and the c-terminus of fadd.

SIGNOR-176651

Q96RL1

P38398

1

binding

up-regulates

0.91

Rap80 specifically recruits brca1 to dna damage sites and functions with brca1 in g2/m checkpoint control

SIGNOR-155201

Q8WW43

P49810

1

binding

up-regulates

0.909

By using co-immunoprecipitation and nickel affinity pull-down approaches, we now show that mammalian aph-1 (maph-1), a conserved multipass membrane protein, physically associates with nicastrin and the heterodimers of the presenilin amino- and carboxyl-terminal fragments in human cell lines and in rat brain.

SIGNOR-93310

Q14790

Q13546

2

cleavage

down-regulates activity

0.909

These results suggested that the aspartic acid at position 324 is the cleavage site of ripk1. In this study we found that receptor-interacting protein (ripk1) is cleaved by casp8 when cells undergo tnf-induced apoptosis. The cleavage of ripk1 abolished its nf-kb inducing ability.

SIGNOR-71265

Q15628

Q14790

1

binding

up-regulates activity

0.909

Tradd recruits caspase-8

SIGNOR-118591

Q9UMX1

P10070

1

relocalization

down-regulates activity

0.909

We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms

SIGNOR-129065

P05230

P21802

1

binding

up-regulates

0.909

We have crystallized a complex between human FGF1 and a two-domain extracellular fragment of human FGFR2.

SIGNOR-73811

Q13546

Q14790

2

binding

up-regulates activity

0.909

Tradd and rip1 associate with fadd and caspase-8, forming a cytoplasmic complex

SIGNOR-104255

Q9UIC8

P67775

1

methylation

up-regulates activity

0.908

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |The PP2A core enzyme was methylated by a PP2A-specific leucine carboxyl methyltransferase (LCMT1)

SIGNOR-265749

O15273

Q8WZ42

1

binding

up-regulates activity

0.908

TCAP, a core sarcomeric component capping the titin proteins, was identified as a positive hit (Figure 1A). TCAP is a small (19 kDa), highly abundant cytoplasmic protein expressed exclusively in skeletal muscle and the heart (Valle et al., 1997). TCAP interacts with titin through its N-terminal beta sheet to anchor titin to the Z-disc

SIGNOR-264854

O95405

Q15796

1

relocalization

up-regulates activity

0.908

Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor.

SIGNOR-165786

P45983

P05412

1

phosphorylation

up-regulates activity

0.907

JNK1 binds to the c-Jun transactivation domain and phosphorylates it on Ser-63 and Ser-73. The effect on AP-1 transcriptional activity results, in part, from enhanced phosphorylation of the c-Jun NH2-terminal activation domain.

SIGNOR-250122

Q9UK05

P37023

1

binding

up-regulates

0.907

Finally, we demonstrate that bmp9 and bmp10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of alk1. Taken together, our results suggest that bmp9 and bmp10 are two specific alk1 ligands that may physiologically trigger the effects of alk1 on angiogenesis.

SIGNOR-150260

P78527

Q13426

1

phosphorylation

up-regulates activity

0.907

In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair.

SIGNOR-277198

O00512

Q9Y3Y4

1

binding

up-regulates

0.907

Here we report the identification of two segment polarity genes in drosophila, legless (lgs), and pygopus (pygo), and we show that their products are required for wnt signal transduction at the level of nuclear beta-catenin. Lgs encodes the homolog of human bcl9, and we provide genetic and molecular evidence that these proteins exert their function by physically linking pygo to beta-catenin.

SIGNOR-116577

P01584

P14778

1

binding

up-regulates activity

0.906

Pro-IL-1beta, mIL-1beta and mIL-beta all bind to IL-1RI, which recruits the IL-1 receptor accessory protein (IL-1RAcP) as a co-receptor.

SIGNOR-249511

P01127

P09619

1

binding

up-regulates

0.906

Pdgf-b activates both pdgfr-alpha and pdgfr-beta

SIGNOR-107400

Q14393

P30530

1

binding

up-regulates

0.905

Receptor tyrosine kinases of the axl family are activated by the vitamin k-dependent protein gas6. We report the identification of ligands for tyro 3 (alternatively called sky, rse, brt, or tif) and axl (alternatively, ark or ufo), members of a previously orphan family of receptor-like tyrosine kinases. These ligands correspond to protein s, a protease regulator that is a potent anticoagulant, and gas6, a protein related to protein s but lacking any known function.

SIGNOR-34339

Q9Y570

P67775

1

demethylation

down-regulates activity

0.905

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the C subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits |Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans.

SIGNOR-265748

P46937

P28347

1

binding

up-regulates

0.905

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

SIGNOR-201465

Q9NZN5

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.905

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-260539

Q07960

P60953

1

gtpase-activating protein

down-regulates activity

0.905

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-260459

P42771

P11802

1

binding

down-regulates

0.905

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

SIGNOR-44554

Q9NQL2

Q8N122

1

binding

up-regulates

0.905

Active rag and gtr heterodimers are able to bind and activate torc1, through direct interactions with raptor

SIGNOR-162093

O95352

P60520

1

binding

up-regulates activity

0.905

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-142002

P20810

P17655

1

binding

down-regulates activity

0.904

In addition to Ca2+, calpastatin has a key role in the regulation of calpain. Calpastatin, a heat-stable protein ranging from ~70 to ~140 kDa of apparent molecular weight depending on the cell type, is considered a specific endogenous inhibitor of calpains|The calpastatin molecule contains four inhibitory units [75–77]. Each of these units binds to one calpain molecule [75–77]. Therefore, the ratio calpain/calpastatin plays a key role in the regulation of calpain activity [78–80]. The inhibitory effect of calpastatin requires Ca2+-dependent high-affinity binding to three sites of calpain

SIGNOR-251609

P42345

Q96B36

1

phosphorylation

down-regulates activity

0.904

We propose that after mtorc1 kinase activation by upstream regulators, pras40 is phosphorylated directly by mtor, thus contributing to the relief of pras40-mediated substrate competitionwe also find that mutation of ser-221 to ala increases the inhibitory activity of pras40 toward mtorc1.

SIGNOR-178128

Q02297

Q15303

1

binding

up-regulates

0.904

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-122053

Q16828

P28482

2

dephosphorylation

down-regulates activity

0.904

Dual-specificity phosphatase six (DUSP6, MKP3, or PYST1) dephosphorylates phosphotyrosine and phosphothreonine residues on ERK-2 (MAPK1) to inactivate the ERK-2 kinase.

SIGNOR-277006

P28482

Q16828

2

phosphorylation

down-regulates quantity by destabilization

0.904

In vitro phosphorylation assays using glutathione S-transferase (GST)-MKP-3 fusion proteins indicated that ERK2 could phosphorylate MKP-3 on serines 159 and 197Double serine mutants of MKP-3 or MKP-3-GFP were more efficiently protected from degradation than single mutants or wild-type MKP-3, indicating that phosphorylation of either serine by ERK1/2 enhances proteasomal degradation of MKP-3.

SIGNOR-132971

P62993

P22681

1

relocalization

up-regulates

0.904

The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization.

SIGNOR-114704

O94907

O75581

1

binding

down-regulates

0.904

We report that dkk-1 is a high-affinity ligand for lrp6 and inhibits wnt signaling by preventing fz-lrp6 complex formation induced by wnt. Dkk1 has been shown to inhibit wnt by binding to and antagonizing lrp5/6.

SIGNOR-109247

P48023

P25445

1

binding

up-regulates activity

0.903

The death-inducing receptor fas is activated when cross-linked by the type ii membrane protein faslg (fasl)

SIGNOR-49688

P37231

Q9UBK2

1

transcriptional regulation

up-regulates quantity by expression

0.903

NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,

SIGNOR-263984

O15085

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.903

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-260538

Q13114

Q9UHD2

1

binding

up-regulates activity

0.903

MAVS also interacts with STING that locates at the ER (endoplasmic reticulum), and induces the ubiquitination and dimerization of STING. The activated STING recruits TBK1 and IRF3 and contributes to the phosphorylation of IRF3 mediated by TBK1.

SIGNOR-260156

P49674

O15055

1

phosphorylation

down-regulates quantity by destabilization

0.902

Priming-independent clusters located in the C-terminal portion of PER2’s PAS domains are targeted by CK1ε/δ and are required for ubiquitin ligase–mediated degradation of PER2

SIGNOR-277419

P46108

Q13905

1

binding

up-regulates

0.901

The endogenous c3g could be coprecipitated with crk from cell lysates of cells expressing high levels of c-crk or v-crk, suggesting high binding affinity and a possible interaction in vivo.

SIGNOR-33732

Q9NW38

Q9NPD8

2

ubiquitination

down-regulates quantity

0.901

Monoubiquitination of UBE2T was enhanced by FANCL introduction, suggesting that FANCL feeds back to UBE2T and can downregulate its activity.Although the FA pathway has been extensively studied, the E2 enzyme cooperating with the FA core complex for monoubiquitination of FANCD2 has not been discovered.|This monoubiquitination is stimulated by the presence of the FANCL protein and inactivates UBE2T.

SIGNOR-278809

Q12770

Q12772

1

relocalization

up-regulates activity

0.901

SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function

SIGNOR-267502

P49336

Q9UHV7

1

phosphorylation

down-regulates quantity by destabilization

0.901

Here, cyclin C-Cdk8 phosphorylation of Med13 most likely primes the phosphodegron for destruction.

SIGNOR-279687

Q15596

P10275

1

binding

up-regulates activity

0.901

The NCOA2 gene encodes a transcriptional coactivator (SRC-2) that modulates gene expression by hormone receptors, including AR. NCOA2 is both amplified and rarely mutated in prostate cancers, with higher NCOA2 levels resulting in increased androgen signaling readout. Furthermore, as mentioned previously, SRC-3, a close homolog encoded by NCOA3, is a substrate of SPOP whose protein levels are increased by SPOP mutation, potentially linking these common point mutations to the androgen axis

SIGNOR-251531

Q9HBE4

Q9HBE5

1

binding

up-regulates

0.901

Il-21 mediates its biological effects via the il-21r in conjunction with the common receptor gamma-chain that is also shared by members of the il-2 family

SIGNOR-143849

Q9NPD8

Q9NW38

2

ubiquitination

up-regulates activity

0.901

Using the Fanconi Anemia pathway exclusive E3-E2 pair, FANCL-Ube2T, we report the atomic structure of the FANCL RING-Ube2T complex|Our structural and biochemical analyses suggest that, in a cellular environment with multiple E2s present, FANCL will preferentially select Ube2T.

SIGNOR-263263

Q9Y4K3

P14778

1

ubiquitination

down-regulates quantity by destabilization

0.9

We found that of all TRAFs and E3 ligases examined, TRAF6 preferentially ubiquitinated IL-1R1.

SIGNOR-278576