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
Q01105	P15531	1	binding	down-regulates	0.728	Tumor suppressor nm23-h1 is a granzyme a-activated dnase during ctl-mediated apoptosis, and the nucleosome assembly protein set is its inhibitor. / nm23-h1 binds to set and is released from inhibition by gzma cleavage of set.	SIGNOR-99205
P13385	P36896	1	binding	up-regulates activity	0.728	Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.	SIGNOR-251938
O15530	P23443	2	phosphorylation	up-regulates	0.727	A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. Phosphorylation and activation of p70s6k by pdk1.	SIGNOR-188907
P10721	P27986	1	binding	up-regulates activity	0.727	Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells	SIGNOR-255948
P01344	P11717	1	binding	up-regulates	0.727	Insulin-like growth factor ii receptor (igf2r) is a multifunctional cell surface receptor implicated in tumour suppression. Its growth inhibitory activity has been associated with an ability to bind igf-ii.	SIGNOR-115250
P23443	O15530	2	phosphorylation	down-regulates activity	0.727	Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT.	SIGNOR-273844
P28482	P49407	1	phosphorylation	down-regulates	0.727	Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation	SIGNOR-67630
P53355	Q14457	1	phosphorylation	up-regulates	0.727	The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy.	SIGNOR-183548
Q96GD4	Q02241	1	phosphorylation	down-regulates quantity	0.727	Furthermore, reduced turnover of regulatory phosphorylation on another Aurora B substrate MKlp1 was observed, suggesting that PP2A-B56\u03b3 and -\u03b5 play a general role opposing Aurora B at the central spindle.\|In anaphase, the KIF4A-targeted pool of B56\u03b3 and -\u03b5 is ideally placed to counteract Aurora B phosphorylations on other central spindle proteins such as MKlp1.	SIGNOR-280192
O43683	Q9Y6D9	1	relocalization	up-regulates activity	0.727	Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity	SIGNOR-252017
Q00978	P48551	1	binding	up-regulates activity	0.727	By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2.	SIGNOR-217779
P22362	P51685	1	binding	up-regulates	0.726	Ccl1 activates the mapk pathway in ccr8-transfected cho cells.	SIGNOR-99401
O60603	P58753	1	binding	up-regulates activity	0.726	To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group	SIGNOR-266745
Q14790	P42574	1	cleavage	up-regulates activity	0.726	Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction.	SIGNOR-171767
P19883	O14793	1	binding	down-regulates activity	0.726	Follistatin (FST) is a member of the tissue growth factor beta family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. FST315-deltaHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function.	SIGNOR-251717
P51812	P16220	1	phosphorylation	up-regulates activity	0.726	MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression	SIGNOR-248951
P13725	P42702	1	binding	up-regulates	0.726	Oncostatin m binds the high-affinity leukemia inhibitory factor receptor	SIGNOR-19873
P00738	P02647	1	binding	up-regulates quantity by stabilization	0.726	Haptoglobin binding to apolipoprotein A-I prevents damage from hydroxyl radicals on its stimulatory activity of the enzyme lecithin-cholesterol acyl-transferase. haptoglobin, when circulating at enhanced levels with free Hb during the acute phase of inflammation, might protect ApoA-I structure and function against hydroxyl radicals.	SIGNOR-252106
P11021	Q9NZJ5	1	binding	down-regulates activity	0.726	In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation.	SIGNOR-260164
O00255	Q03164	1	binding	up-regulates activity	0.726	However, menin dramatically increases the amount of MLL bound at the p27Kip1 and p18Ink4c loci, suggesting that it either directly or indirectly promotes MLL recruitment to these targets. Once recruited, MLL could enhance transcription by a number of mechanisms.Overall, the data suggest that transcriptional regulation by menin involves increasing MLL protein association with target loci.	SIGNOR-255890
P10276	P19793	2	binding	up-regulates	0.725	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16433
P07948	Q9NWQ8	1	phosphorylation	up-regulates activity	0.725	Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.	SIGNOR-262898
P04628	Q9H461	1	binding	up-regulates	0.725	Wnt signaling is mediated by the frizzled (fz) family of seven-pass transmembrane receptors that bind wnt via the conserved amino-terminal cysteine-rich domain (crd)	SIGNOR-109250
Q06124	Q14289	1	dephosphorylation	down-regulates activity	0.725	We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. \|We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. Moreover, overexpression of dominant negative SHP2 blocked the protective effect of IL-6 against Dex-induced apoptosis. These findings demonstrate that SHP2 mediates the anti-apoptotic effect of IL-6 and suggest SHP2 as a novel therapeutic target in MM..... 1) RAFTK is a substrate of SHP2 in vitro and 2) dephosphorylation of RAFTK by SHP2 inhibits its kinase activity.	SIGNOR-277084
P31749	P63000	1	phosphorylation	down-regulates activity	0.725	Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1	SIGNOR-252576
Q9HAU4	Q15797	1	polyubiquitination	down-regulates quantity by destabilization	0.725	Here, we report the identification of Smurf2, a new member of the Hect family of E3 ubiquitin ligases. Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation. At higher expression levels, Smurf2 also decreases the protein levels of Smad2, but not Smad3.	SIGNOR-272936
P19793	P10276	2	binding	up-regulates	0.725	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16665
P10721	P42224	1	phosphorylation	up-regulates activity	0.725	KIT is responsible for the permanent phosphorylation of all three STAT proteins. STAT1, -3, and -5 were phosphorylated on their activation-specific Tyr701, Tyr704, and Tyr694, respectively, following KIT stimulation.	SIGNOR-251365
O60664	P11717	1	relocalization	up-regulates activity	0.725	TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi.	SIGNOR-253092
Q7Z460	P30622	1	binding	up-regulates activity	0.725	CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.\|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. \| Both EB1- and cortex-binding domains of CLASP are required to promote MT stability.	SIGNOR-265091
Q9NRY4	P63000	1	gtpase-activating protein	down-regulates activity	0.724	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-260493
Q13882	Q9UGK3	1	phosphorylation	up-regulates activity	0.724	Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates the signaling pathways downstream of them. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by Brk, using a series of STAP-2 YF mutants and anti-phospho-STAP-2 Tyr250 antibody. Furthermore, overexpression of the STAP-2 Y250F mutant protein affected Brk-mediated STAT3 activation.	SIGNOR-247067
P49841	Q16555	1	phosphorylation	down-regulates activity	0.724	Here, we showed that glycogen synthase kinase-3beta (gsk-3beta) phosphorylated crmp-2 at thr-514 and inactivated it	SIGNOR-133255
P32121	P07550	1	binding	down-regulates activity	0.724	The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors	SIGNOR-256501
P16298	O95644	1	relocalization	up-regulates	0.724	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-84047
P55212	P05067	1	cleavage	up-regulates activity	0.724	Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Ab. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Ab-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons	SIGNOR-261762
Q13535	P33991	1	phosphorylation	up-regulates	0.724	Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6.	SIGNOR-169412
P15391	P15498	1	binding	up-regulates activity	0.724	CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades.	SIGNOR-242897
Q6ZNA4	P12757	1	polyubiquitination	down-regulates quantity by destabilization	0.723	Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.	SIGNOR-272885
Q13233	O14733	1	phosphorylation	up-regulates	0.723	Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1	SIGNOR-51207
P19876	P25025	1	binding	up-regulates activity	0.723	CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively	SIGNOR-277719
Q8WY64	P01130	1	ubiquitination	down-regulates quantity by destabilization	0.723	The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells.	SIGNOR-271485
P35568	P42338	1	binding	up-regulates activity	0.723	To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1	SIGNOR-235487
P27986	P48736	1	binding	up-regulates activity	0.723	Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival	SIGNOR-242646
P53350	O43663	1	phosphorylation	down-regulates activity	0.723	Plk1 negatively regulates PRC1 to prevent premature midzone formation before cytokinesis.\|Plk1, but not Cdk1, phosphorylates PRC1 on Thr-602 to prevent premature midzone assembly in metaphase.	SIGNOR-279645
O96017	O15151	1	phosphorylation	down-regulates	0.723	Phosphorylation of s342 and s367 in vivo require the chk2 kinase. Chk2 also stimulates mdmx ubiquitination and degradation by mdm2	SIGNOR-140417
P35070	Q15303	1	binding	up-regulates	0.723	For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4	SIGNOR-195347
Q05513	P35568	1	phosphorylation	down-regulates activity	0.723	Extensive studies have provided evidence that phosphorylation of Ser307 in IRS-1 inhibits IR/IRS-1 complex formation and IRS-1 tyrosine phosphorylation after prolonged insulin-stimulation similar to our results.	SIGNOR-236760
Q9NTX7	O95271	1	ubiquitination	down-regulates quantity	0.723	We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.	SIGNOR-260004
Q15058	O14578	2	binding	up-regulates activity	0.723	We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase.	SIGNOR-266422
O14578	Q15058	2	binding	up-regulates activity	0.723	We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase.	SIGNOR-266424
P45983	Q9UPT6	2	phosphorylation	up-regulates	0.722	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134545
P37173	P36897	1	phosphorylation	up-regulates activity	0.722	Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta	SIGNOR-246728
P08069	P46108	1	phosphorylation	down-regulates activity	0.722	On activation of the IGF-I receptor, Crk-II binds to phosphorylated tyrosine residues, especially in the juxtamembrane region. As a result of this binding, the IGF-I receptor kinase phosphorylates Tyr-221 of Crk-II, resulting in a change in intramolecular folding and binding of the SH2 domain to the phosphorylated Tyr-221, which causes rapid disassociation of the Crk-II-IGF-I receptor complex.	SIGNOR-251273
P28482	Q15796	1	phosphorylation	up-regulates	0.722	We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity.	SIGNOR-91714
P01111	P48736	1	binding	up-regulates	0.722	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.llysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-175228
Q9UQF2	O14733	1	binding	up-regulates	0.722	Both jip1 and jip2 selectively bind the mapkk isoform mkk7.	SIGNOR-70848
Q9UPT6	P45983	2	binding	up-regulates	0.722	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-134558
P46459	P60880	1	binding	down-regulates activity	0.722	NSF is an important regulator of SNARE assembly/disassembly. NSF binds to SNAP-25, while in complex with other SNAREs, and hydrolyzes adenosine triphosphate to disassemble the SNARE complex down to monomers	SIGNOR-263974
Q9UBU3	Q92847	1	binding	up-regulates	0.722	In contrast to wild-type mice, acute treatment of ghsr- mice with ghrelin stimulated neither gh release nor food intake, showing that the ghsr is a biologically relevant ghrelin receptor.	SIGNOR-123948
O14965	P30305	1	phosphorylation	up-regulates	0.722	We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353	SIGNOR-139396
P01222	P16473	1	binding	up-regulates	0.722	Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners.	SIGNOR-88653
P35568	P42336	1	binding	up-regulates activity	0.722	Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin.	SIGNOR-168985
Q96EB6	Q04206	1	deacetylation	down-regulates activity	0.722	SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310.	SIGNOR-238817
P28702	P10276	1	binding	up-regulates	0.722	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16674
O15146	Q18PE1	2	phosphorylation	up-regulates activity	0.721	Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes.	SIGNOR-273845
P06241	Q03135	1	phosphorylation	down-regulates activity	0.721	Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn.Therefore,	SIGNOR-118003
O96017	Q08050	1	phosphorylation	up-regulates	0.721	Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of dna repair genesthis phosphorylation of foxm1 on serine residue 361 caused increased stability of the foxm1 protein	SIGNOR-150746
Q92823	Q12955	1	relocalization	up-regulates quantity	0.721	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266720
P07947	P46937	1	phosphorylation	up-regulates activity	0.721	Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C).	SIGNOR-277653
Q8WUP2	O75369	1	binding	up-regulates activity	0.721	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-266106
Q18PE1	O15146	2	binding	up-regulates	0.721	In addition, dok7, a cytoplasmic adaptor protein, is also required for musk activation in vivo. This review focuses on the physical interplay between these proteins and musk for activation and downstream signaling, which culminates in nmj formation.	SIGNOR-192264
P53350	Q99640	1	phosphorylation	down-regulates activity	0.721	Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site.	SIGNOR-263096
P21359	P01116	1	binding	down-regulates activity	0.721	Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS.	SIGNOR-273661
Q9UHD2	O00571	1	phosphorylation	up-regulates activity	0.721	Coexpression of TBK1 strongly increased the activity of DDX3X.\|This suggests that DDX3X is rather specifically phosphorylated by TBK1 and IKK-i.	SIGNOR-278997
Q9HD26	P13569	1	binding	down-regulates	0.721	Cal binds to cftr / cal affects insertion of cftr to the plasma membrane as well as its half-life in the plasma membrane.	SIGNOR-111671
Q15796	Q13485	1	binding	up-regulates activity	0.721	the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4	SIGNOR-235183
P19793	P10828	1	binding	up-regulates	0.721	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr	SIGNOR-81449
P27361	P40763	1	phosphorylation	up-regulates	0.72	The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1	SIGNOR-118596
P67775	P23443	1	dephosphorylation	down-regulates	0.72	Protein phosphatase 2a inactivates the mitogen-stimulated s6 kinase from swiss mouse 3t3 cells	SIGNOR-23575
O00587	P46531	1	binding	up-regulates	0.72	Manic fringe elongates the o-linked fucose saccharides on full-length notch1 and notch1 egf repeats 1923.	SIGNOR-80555
O00634	Q92859	1	binding	up-regulates activity	0.72	Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins.	SIGNOR-268171
Q96GD4	Q08J23	1	phosphorylation	down-regulates	0.72	Aurora-b phosphorylated nsun2 at ser139. Aurora-b-phosphorylation and the phosphorylation-mimic mutation (s139e) suppressed methyltransferase activities of nsun2.	SIGNOR-152001
P43146	Q05397	1	binding	up-regulates activity	0.72	Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.	SIGNOR-268371
P49841	P01106	1	phosphorylation	down-regulates quantity by destabilization	0.72	Phosphorylation of Thr 58, likely mediated by GSK-3 but dependent on the prior phosphorylation of Ser 62, is associated with degradation of Myc.	SIGNOR-252080
Q15746	P10916	1	phosphorylation	up-regulates activity	0.72	MLCK directly phosphorylates MLC2 and is a substrate for ERK1/2 ( ), thus providing a direct link between the Raf-MEK1/2-ERK1/2 module and MLC2.\|These findings strongly suggest that the phosphorylation of MLC2 stimulated by MLCK and ROCK1/2 is an integral component of the biochemical signal transduction program that promotes noninvasive motility.	SIGNOR-279233
Q99759	Q13163	1	phosphorylation	up-regulates	0.72	Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.	SIGNOR-104637
Q16539	P42224	1	phosphorylation	up-regulates activity	0.72	All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).	SIGNOR-154779
P48061	P25106	1	binding	up-regulates	0.72	Here we show that cxcl12, the only known natural ligand for cxcr4, binds to and signals through rdc1.	SIGNOR-139709
P16591	P35222	1	phosphorylation	down-regulates activity	0.72	Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases. Transfection of these kinases to epithelial cells disrupted the association between both catenins.	SIGNOR-251131
P20333	Q13077	1	binding	up-regulates	0.72	Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.	SIGNOR-33133
P17706	P12931	1	dephosphorylation	down-regulates	0.72	We found that tcptp dephosphorylates and inactivates src family kinases to regulate t cell responses._	SIGNOR-177116
Q02790	P10275	1	binding	up-regulates activity	0.72	We noted that FK506 altered nuclear localization of the GR and inhibited expression of GR-responsive genes. Furthermore, si-RNA knockdown of FKBP4 gene, coding for the immunophilin FKBP52, inhibited cortisol-activated GR nuclear translocation	SIGNOR-252034
Q15746	P14649	1	phosphorylation	up-regulates	0.72	Cytoskeletal dynamics are primarily modulated by interactions of actin and myosin ii that are regulated by myosin light chain kinase (mlck)-mediated phosphorylation of the regulatory myosin light chain (mlc).	SIGNOR-65865
Q8N474	P56705	1	binding	down-regulates	0.72	Sfrp-1 binds wnt-4 with considerable avidity and inhibits the dna-binding activity of tcf, an effector of wnt signaling,	SIGNOR-106556
Q9GZM8	Q14204	1	binding	up-regulates activity	0.72	LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex	SIGNOR-252159
Q96GD4	P04637	1	phosphorylation	down-regulates	0.719	We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma).	SIGNOR-197598
Q8TCU6	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.719	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-260569
P45983	P17275	1	phosphorylation	up-regulates activity	0.719	JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation.	SIGNOR-250120
Q9UHD0	Q6UXL0	1	binding	up-regulates	0.719	Il-19 signals only through the type i il-20r complex.	SIGNOR-151820

Q01105

P15531

1

binding

down-regulates

0.728

Tumor suppressor nm23-h1 is a granzyme a-activated dnase during ctl-mediated apoptosis, and the nucleosome assembly protein set is its inhibitor. / nm23-h1 binds to set and is released from inhibition by gzma cleavage of set.

SIGNOR-99205

P13385

P36896

1

binding

up-regulates activity

0.728

Nodal effects are dependent upon interactions with Cripto, a small cysteine-rich extracellular protein that is attached to the plasma membrane through a glycosyl phosphatidyl inositol linkage. Cripto interacts with Nodal and ALK4, independently, and promotes the formation of a stable high affinity complex with activin type II receptors.

SIGNOR-251938

O15530

P23443

2

phosphorylation

up-regulates

0.727

A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. Phosphorylation and activation of p70s6k by pdk1.

SIGNOR-188907

P10721

P27986

1

binding

up-regulates activity

0.727

Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells

SIGNOR-255948

P01344

P11717

1

binding

up-regulates

0.727

Insulin-like growth factor ii receptor (igf2r) is a multifunctional cell surface receptor implicated in tumour suppression. Its growth inhibitory activity has been associated with an ability to bind igf-ii.

SIGNOR-115250

P23443

O15530

2

phosphorylation

down-regulates activity

0.727

Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT.

SIGNOR-273844

P28482

P49407

1

phosphorylation

down-regulates

0.727

Erk1 and erk2 phosphorylate beta-arrestin1 at ser-412 in vitro. . in the resting state, cytosolic arrestin1 proteins are constitutively phosphorylated by extracellular signal-regulated kinase (erk) at ser412, located within their distal c terminus. erk-phosphorylated arrestin1 is unable to associate with clathrin cages, whereas this constraint is removed upon its dephosphorylation

SIGNOR-67630

P53355

Q14457

1

phosphorylation

up-regulates

0.727

The activated form of DAPK triggers autophagy in a beclin-1-dependent manner. DAPK phosphorylates beclin 1 on Thr 119 located at a crucial position within its BH3 domain, and thus promotes the dissociation of beclin 1 from Bcl-XL and the induction of autophagy.

SIGNOR-183548

Q96GD4

Q02241

1

phosphorylation

down-regulates quantity

0.727

Furthermore, reduced turnover of regulatory phosphorylation on another Aurora B substrate MKlp1 was observed, suggesting that PP2A-B56\u03b3 and -\u03b5 play a general role opposing Aurora B at the central spindle.|In anaphase, the KIF4A-targeted pool of B56\u03b3 and -\u03b5 is ideally placed to counteract Aurora B phosphorylations on other central spindle proteins such as MKlp1.

SIGNOR-280192

O43683

Q9Y6D9

1

relocalization

up-regulates activity

0.727

Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity

SIGNOR-252017

Q00978

P48551

1

binding

up-regulates activity

0.727

By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2.

SIGNOR-217779

P22362

P51685

1

binding

up-regulates

0.726

Ccl1 activates the mapk pathway in ccr8-transfected cho cells.

SIGNOR-99401

O60603

P58753

1

binding

up-regulates activity

0.726

To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group

SIGNOR-266745

Q14790

P42574

1

cleavage

up-regulates activity

0.726

Triggering of the DISC leads to caspase-8 activation. Active caspase-8 cleaves caspase-3 which, in type I cells, leads to cell death induction.

SIGNOR-171767

P19883

O14793

1

binding

down-regulates activity

0.726

Follistatin (FST) is a member of the tissue growth factor beta family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. FST315-deltaHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function.

SIGNOR-251717

P51812

P16220

1

phosphorylation

up-regulates activity

0.726

MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression

SIGNOR-248951

P13725

P42702

1

binding

up-regulates

0.726

Oncostatin m binds the high-affinity leukemia inhibitory factor receptor

SIGNOR-19873

P00738

P02647

1

binding

up-regulates quantity by stabilization

0.726

Haptoglobin binding to apolipoprotein A-I prevents damage from hydroxyl radicals on its stimulatory activity of the enzyme lecithin-cholesterol acyl-transferase. haptoglobin, when circulating at enhanced levels with free Hb during the acute phase of inflammation, might protect ApoA-I structure and function against hydroxyl radicals.

SIGNOR-252106

P11021

Q9NZJ5

1

binding

down-regulates activity

0.726

In the stressed ER, protein chaperone GRP78 binds to unfolded proteins and dissociates from the luminal domain of PERK, leading to oligomerization and activation of PERK by autophosphorylation.

SIGNOR-260164

O00255

Q03164

1

binding

up-regulates activity

0.726

However, menin dramatically increases the amount of MLL bound at the p27Kip1 and p18Ink4c loci, suggesting that it either directly or indirectly promotes MLL recruitment to these targets. Once recruited, MLL could enhance transcription by a number of mechanisms.Overall, the data suggest that transcriptional regulation by menin involves increasing MLL protein association with target loci.

SIGNOR-255890

P10276

P19793

2

binding

up-regulates

0.725

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins

SIGNOR-16433

P07948

Q9NWQ8

1

phosphorylation

up-regulates activity

0.725

Here we show that Lyn interacts with C-terminal Src kinase-binding protein (Cbp), an adaptor protein that recruits negative regulators C-terminal Src kinase (Csk)/Csk-like protein-tyrosine kinase (Ctk). Lyn phosphorylated Cbp on several tyrosine residues, including Tyr314, which recruited Csk/Ctk to suppress Lyn kinase activity.Thus, a single phosphotyrosine residue on Cbp coordinates a two-phase process involving distinct negative regulatory pathways to inactivate, then degrade, Lyn.

SIGNOR-262898

P04628

Q9H461

1

binding

up-regulates

0.725

Wnt signaling is mediated by the frizzled (fz) family of seven-pass transmembrane receptors that bind wnt via the conserved amino-terminal cysteine-rich domain (crd)

SIGNOR-109250

Q06124

Q14289

1

dephosphorylation

down-regulates activity

0.725

We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. |We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. Moreover, overexpression of dominant negative SHP2 blocked the protective effect of IL-6 against Dex-induced apoptosis. These findings demonstrate that SHP2 mediates the anti-apoptotic effect of IL-6 and suggest SHP2 as a novel therapeutic target in MM..... 1) RAFTK is a substrate of SHP2 in vitro and 2) dephosphorylation of RAFTK by SHP2 inhibits its kinase activity.

SIGNOR-277084

P31749

P63000

1

phosphorylation

down-regulates activity

0.725

Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1

SIGNOR-252576

Q9HAU4

Q15797

1

polyubiquitination

down-regulates quantity by destabilization

0.725

Here, we report the identification of Smurf2, a new member of the Hect family of E3 ubiquitin ligases. Smurf2 selectively interacts with receptor-regulated Smads and preferentially targets Smad1 for ubiquitination and proteasome-mediated degradation. At higher expression levels, Smurf2 also decreases the protein levels of Smad2, but not Smad3.

SIGNOR-272936

P19793

P10276

2

binding

up-regulates

0.725

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins

SIGNOR-16665

P10721

P42224

1

phosphorylation

up-regulates activity

0.725

KIT is responsible for the permanent phosphorylation of all three STAT proteins. STAT1, -3, and -5 were phosphorylated on their activation-specific Tyr701, Tyr704, and Tyr694, respectively, following KIT stimulation.

SIGNOR-251365

O60664

P11717

1

relocalization

up-regulates activity

0.725

TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi.

SIGNOR-253092

Q7Z460

P30622

1

binding

up-regulates activity

0.725

CLIP-associating protein (CLASP) 1 and CLASP2 are mammalian microtubule (MT) plus-end binding proteins, which associate with CLIP-170 and CLIP-115.|We demonstrate that the middle part of CLASPs binds directly to EB1 and to MTs. | Both EB1- and cortex-binding domains of CLASP are required to promote MT stability.

SIGNOR-265091

Q9NRY4

P63000

1

gtpase-activating protein

down-regulates activity

0.724

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-260493

Q13882

Q9UGK3

1

phosphorylation

up-regulates activity

0.724

Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates the signaling pathways downstream of them. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by Brk, using a series of STAP-2 YF mutants and anti-phospho-STAP-2 Tyr250 antibody. Furthermore, overexpression of the STAP-2 Y250F mutant protein affected Brk-mediated STAT3 activation.

SIGNOR-247067

P49841

Q16555

1

phosphorylation

down-regulates activity

0.724

Here, we showed that glycogen synthase kinase-3beta (gsk-3beta) phosphorylated crmp-2 at thr-514 and inactivated it

SIGNOR-133255

P32121

P07550

1

binding

down-regulates activity

0.724

The protein, termed beta-arrestin, was expressed and partially purified. It inhibited the signaling function of beta ARK-phosphorylated beta-adrenergic receptors by more than 75 percent, but not that of rhodopsin. It is proposed that beta-arrestin in concert with beta ARK effects homologous desensitization of beta-adrenergic receptors

SIGNOR-256501

P16298

O95644

1

relocalization

up-regulates

0.724

The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.

SIGNOR-84047

P55212

P05067

1

cleavage

up-regulates activity

0.724

Inhibition of caspase-6 activity prevents serum deprivation-mediated increase of Ab. Caspase-6 directly cleaves APP at the C terminus and generates a C-terminal fragment of 3 kDa (Capp3) and an Ab-containing 6.5-kDa fragment, Capp6.5, that increases in serum-deprived neurons

SIGNOR-261762

Q13535

P33991

1

phosphorylation

up-regulates

0.724

Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6.

SIGNOR-169412

P15391

P15498

1

binding

up-regulates activity

0.724

CD19 has an extracellular region containing two C2-type Ig-like domains and a cytoplasmic region of ~240 amino acids with 9 conserved tyrosine residues24. Lyn, a Src-family protein tyrosine kinase member, is the dominant kinase that phosphorylates CD19 upon stimulation. Once tyrosyl-phosphorylated, CD19 serves as a membrane-bound adaptor protein for Src homology 2-containing signaling molecules such as Lyn, Vav, and phosphatidylinositol 3-kinase, which further mediate downstream activation cascades.

SIGNOR-242897

Q6ZNA4

P12757

1

polyubiquitination

down-regulates quantity by destabilization

0.723

Upon TGF-β induction, interaction of Arkadia with phosphorylated Smad2 triggers degradation of SnoN, whereas upon arsenic treatment, interaction of Arkadia with poly-SUMO in PML nuclear bodies induces degradation of polysumoylated PML together with RNF4.

SIGNOR-272885

Q13233

O14733

1

phosphorylation

up-regulates

0.723

Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1

SIGNOR-51207

P19876

P25025

1

binding

up-regulates activity

0.723

CXCL2/3, also known as macrophage inflammatory protein-2α/2β (MIP-2α/MIP-2β), share the same receptor CXCR2 with CXCL1 and are able to activate neutrophils effectively

SIGNOR-277719

Q8WY64

P01130

1

ubiquitination

down-regulates quantity by destabilization

0.723

The RING E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL, also known as MYLIP) promotes ubiquitylation and subsequent lysosomal degradation of the LDL receptor (LDLR), thus acting to limit uptake of lipoprotein-derived cholesterol into cells.

SIGNOR-271485

P35568

P42338

1

binding

up-regulates activity

0.723

To examine contributions of specific YXXM motifs in human insulin receptor substrate-1 (IRS-1) to mediating the metabolic actions of insulin, we studied IRS-1 mutants containing various substitutions of Phe for Tyr. In transfected NIH-3T3(IR) cells, insulin stimulation caused a 5-fold increase in phosphatidylinositol 3-kinase (PI3K) activity coimmunoprecipitated with wild-type IRS-1

SIGNOR-235487

P27986

P48736

1

binding

up-regulates activity

0.723

Signal transduction pathways triggered by Tie2 have been extensively examined. Tyr-1101of Tie2 directly associates in a phosphotyrosine (pTyr)-dependent manner with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase, which in turn activate PI 3-kinase, leading to cell motility and survival

SIGNOR-242646

P53350

O43663

1

phosphorylation

down-regulates activity

0.723

Plk1 negatively regulates PRC1 to prevent premature midzone formation before cytokinesis.|Plk1, but not Cdk1, phosphorylates PRC1 on Thr-602 to prevent premature midzone assembly in metaphase.

SIGNOR-279645

O96017

O15151

1

phosphorylation

down-regulates

0.723

Phosphorylation of s342 and s367 in vivo require the chk2 kinase. Chk2 also stimulates mdmx ubiquitination and degradation by mdm2

SIGNOR-140417

P35070

Q15303

1

binding

up-regulates

0.723

For example, betacellulin binds to and activates both erbb1 and erbb4, whereas epiregulin binds to erbb1, erbb3 and erbb4

SIGNOR-195347

Q05513

P35568

1

phosphorylation

down-regulates activity

0.723

Extensive studies have provided evidence that phosphorylation of Ser307 in IRS-1 inhibits IR/IRS-1 complex formation and IRS-1 tyrosine phosphorylation after prolonged insulin-stimulation similar to our results.

SIGNOR-236760

Q9NTX7

O95271

1

ubiquitination

down-regulates quantity

0.723

We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all three proteins to target them for proteasomal degradation.

SIGNOR-260004

Q15058

O14578

2

binding

up-regulates activity

0.723

We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase.

SIGNOR-266422

O14578

Q15058

2

binding

up-regulates activity

0.723

We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase.

SIGNOR-266424

P45983

Q9UPT6

2

phosphorylation

up-regulates

0.722

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

SIGNOR-134545

P37173

P36897

1

phosphorylation

up-regulates activity

0.722

Recent studies have revealed that upon TGF-beta binding several serine and threonine residues in the GS domain of TGF-beta type I receptor (T beta R-I) are phosphorylated by TGF-beta type II receptor (T beta R-II) and that the phosphorylation of GS domain is essential for TGF-beta signalingThese observations indicate that serine 172 and threonine 176 of T beta R-I are dispensable for extracellular matrix protein production but essential to the growth inhibition by TGF-beta

SIGNOR-246728

P08069

P46108

1

phosphorylation

down-regulates activity

0.722

On activation of the IGF-I receptor, Crk-II binds to phosphorylated tyrosine residues, especially in the juxtamembrane region. As a result of this binding, the IGF-I receptor kinase phosphorylates Tyr-221 of Crk-II, resulting in a change in intramolecular folding and binding of the SH2 domain to the phosphorylated Tyr-221, which causes rapid disassociation of the Crk-II-IGF-I receptor complex.

SIGNOR-251273

P28482

Q15796

1

phosphorylation

up-regulates

0.722

We show that phosphorylation of smad2, a mediator of the activin/transforming growth factor-beta signal, by activated extracellular signal-regulated kinase 1 (erk1) increases the amount of smad2 protein and leads to enhanced transcriptional activity.

SIGNOR-91714

P01111

P48736

1

binding

up-regulates

0.722

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.llysine residue 227 is essential for the interaction of ras with pi3k

SIGNOR-175228

Q9UQF2

O14733

1

binding

up-regulates

0.722

Both jip1 and jip2 selectively bind the mapkk isoform mkk7.

SIGNOR-70848

Q9UPT6

P45983

2

binding

up-regulates

0.722

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

SIGNOR-134558

P46459

P60880

1

binding

down-regulates activity

0.722

NSF is an important regulator of SNARE assembly/disassembly. NSF binds to SNAP-25, while in complex with other SNAREs, and hydrolyzes adenosine triphosphate to disassemble the SNARE complex down to monomers

SIGNOR-263974

Q9UBU3

Q92847

1

binding

up-regulates

0.722

In contrast to wild-type mice, acute treatment of ghsr- mice with ghrelin stimulated neither gh release nor food intake, showing that the ghsr is a biologically relevant ghrelin receptor.

SIGNOR-123948

O14965

P30305

1

phosphorylation

up-regulates

0.722

We show that bypass of the g2/m checkpoint by the chk1 kinase inhibitor ucn-01 results in the activation of aurora-a and phosphorylation of cdc25b on s353

SIGNOR-139396

P01222

P16473

1

binding

up-regulates

0.722

Two novel human glycoprotein hormonelike genes, alpha2 (a2) and beta5 (b5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners.

SIGNOR-88653

P35568

P42336

1

binding

up-regulates activity

0.722

Irs proteins are capable of both regulating and activating pi3k, depending on the cell of origin.

SIGNOR-168985

Q96EB6

Q04206

1

deacetylation

down-regulates activity

0.722

SIRT1 physically interacts with the RelA/p65 subunit of NF-kappaB and inhibits transcription by deacetylating RelA/p65 at lysine 310.

SIGNOR-238817

P28702

P10276

1

binding

up-regulates

0.722

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins

SIGNOR-16674

O15146

Q18PE1

2

phosphorylation

up-regulates activity

0.721

Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes.

SIGNOR-273845

P06241

Q03135

1

phosphorylation

down-regulates activity

0.721

Caveolin-1 is phosphorylated on tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the src family kinase fyn.Therefore,

SIGNOR-118003

O96017

Q08050

1

phosphorylation

up-regulates

0.721

Chk2 mediates stabilization of the foxm1 transcription factor to stimulate expression of dna repair genesthis phosphorylation of foxm1 on serine residue 361 caused increased stability of the foxm1 protein

SIGNOR-150746

Q92823

Q12955

1

relocalization

up-regulates quantity

0.721

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

SIGNOR-266720

P07947

P46937

1

phosphorylation

up-regulates activity

0.721

Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C).

SIGNOR-277653

Q8WUP2

O75369

1

binding

up-regulates activity

0.721

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-266106

Q18PE1

O15146

2

binding

up-regulates

0.721

In addition, dok7, a cytoplasmic adaptor protein, is also required for musk activation in vivo. This review focuses on the physical interplay between these proteins and musk for activation and downstream signaling, which culminates in nmj formation.

SIGNOR-192264

P53350

Q99640

1

phosphorylation

down-regulates activity

0.721

Here, we have shown that Plk1 is responsible for part of the phosphorylation of Myt1 during M phase. The kinase activity of human Myt1 is reported to be decreased during M phase, and the decreased activity correlates with hyperphosphorylated forms of Myt1 (35, 37). We then tested the ability of these mutant forms of Myt1 (GST fusion proteins), to serve as a substrate for Plk1 in vitro. Quantification of the result (Fig. 5C) showed that Ser-426 is the major phosphorylation site by Plk1 in vitro and Thr-495 the second major site.

SIGNOR-263096

P21359

P01116

1

binding

down-regulates activity

0.721

Sprouty-related, EVH1 domain-containing (SPRED) proteins negatively regulate RAS/mitogen-activated protein kinase (MAPK) signaling following growth factor stimulation. This inhibition of RAS is thought to occur primarily through SPRED1 binding and recruitment of neurofibromin, a RasGAP, to the plasma membrane. Here, we report the structure of neurofibromin (GTPase-activating protein [GAP]-related domain) complexed with SPRED1 (EVH1 domain) and KRAS. The structure provides insight into how the membrane targeting of neurofibromin by SPRED1 allows simultaneous interaction with activated KRAS.

SIGNOR-273661

Q9UHD2

O00571

1

phosphorylation

up-regulates activity

0.721

Coexpression of TBK1 strongly increased the activity of DDX3X.|This suggests that DDX3X is rather specifically phosphorylated by TBK1 and IKK-i.

SIGNOR-278997

Q9HD26

P13569

1

binding

down-regulates

0.721

Cal binds to cftr / cal affects insertion of cftr to the plasma membrane as well as its half-life in the plasma membrane.

SIGNOR-111671

Q15796

Q13485

1

binding

up-regulates activity

0.721

the receptor-regulated Smad, such as Smad2, forms a heterocomplex with the co-mediator Smad, Smad4

SIGNOR-235183

P19793

P10828

1

binding

up-regulates

0.721

Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr

SIGNOR-81449

P27361

P40763

1

phosphorylation

up-regulates

0.72

The activation of stat-3 is regulated by phosphorylation of tyrosine 705 by receptor and nonreceptor protein tyrosine kinases these include epidermal growth factor receptor (egfr) kinase,92 src,5 janus-activated kinases (jak), and extracellular signal-regulated kinase (erk)a constitutively active galpha16 mutant, galpha16ql, stimulated stat3-dependent luciferase activity as well as the phosphorylation of stat3 at both tyr705 and ser727. Galpha16ql-induced stat3 activation was enhanced by overexpression of extracellular signal-regulated kinase 1 (erk1

SIGNOR-118596

P67775

P23443

1

dephosphorylation

down-regulates

0.72

Protein phosphatase 2a inactivates the mitogen-stimulated s6 kinase from swiss mouse 3t3 cells

SIGNOR-23575

O00587

P46531

1

binding

up-regulates

0.72

Manic fringe elongates the o-linked fucose saccharides on full-length notch1 and notch1 egf repeats 1923.

SIGNOR-80555

O00634

Q92859

1

binding

up-regulates activity

0.72

Experiments have demonstrated that Neogenin also mediates Netrin-1 attractive functions. Both DCC and Neogenin are type I transmembrane receptors that belong to the immunoglobulin superfamily proteins.

SIGNOR-268171

Q96GD4

Q08J23

1

phosphorylation

down-regulates

0.72

Aurora-b phosphorylated nsun2 at ser139. Aurora-b-phosphorylation and the phosphorylation-mimic mutation (s139e) suppressed methyltransferase activities of nsun2.

SIGNOR-152001

P43146

Q05397

1

binding

up-regulates activity

0.72

Here we show that different regions of the intracellular domain of DCC directly interacted with the tyrosine kinases Src and focal adhesion kinase (FAK). Netrin activated both FAK and Src and stimulated tyrosine phosphorylation of DCC. Inhibition of Src family kinases reduced DCC tyrosine phosphorylation and blocked both axon attraction and outgrowth of neurons in response to netrin. Mutation of the tyrosine phosphorylation residue in DCC abolished its function of mediating netrin-induced axon attraction. On the basis of our observations, we suggest a model in which DCC functions as a kinase-coupled receptor, and FAK and Src act immediately downstream of DCC in netrin signaling.

SIGNOR-268371

P49841

P01106

1

phosphorylation

down-regulates quantity by destabilization

0.72

Phosphorylation of Thr 58, likely mediated by GSK-3 but dependent on the prior phosphorylation of Ser 62, is associated with degradation of Myc.

SIGNOR-252080

Q15746

P10916

1

phosphorylation

up-regulates activity

0.72

MLCK directly phosphorylates MLC2 and is a substrate for ERK1/2 ( ), thus providing a direct link between the Raf-MEK1/2-ERK1/2 module and MLC2.|These findings strongly suggest that the phosphorylation of MLC2 stimulated by MLCK and ROCK1/2 is an integral component of the biochemical signal transduction program that promotes noninvasive motility.

SIGNOR-279233

Q99759

Q13163

1

phosphorylation

up-regulates

0.72

Mekk2 and mekk3 are mapk kinase kinases that bind, phosphorylate and activate mek5.

SIGNOR-104637

Q16539

P42224

1

phosphorylation

up-regulates activity

0.72

All stats are phosphorylated on at least one serine residue in their tad specifically, ser727 in stats 1 and 3 and ser721 in stat4. Stat serine kinases have been identified through the use of inhibitors, dominant-negative alleles, and in vitro kinase assays. They include mapk (p38mapk: stats 1, 3, 4;erk: stat3, 5;jnk: stat3), pkc_ (stat1, stat3), mtor (stat3), nlk (stat3 (42)), and camkii and ikk_ (stat1 (39, 40, 43)).STAT Serine phosphorylation regulates transcriptional activity (see below).

SIGNOR-154779

P48061

P25106

1

binding

up-regulates

0.72

Here we show that cxcl12, the only known natural ligand for cxcr4, binds to and signals through rdc1.

SIGNOR-139709

P16591

P35222

1

phosphorylation

down-regulates activity

0.72

Interaction of beta-catenin with alpha-catenin is regulated by the phosphorylation of beta-catenin Tyr-142. This residue can be phosphorylated in vitro by Fer or Fyn tyrosine kinases. Transfection of these kinases to epithelial cells disrupted the association between both catenins.

SIGNOR-251131

P20333

Q13077

1

binding

up-regulates

0.72

Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.

SIGNOR-33133

P17706

P12931

1

dephosphorylation

down-regulates

0.72

We found that tcptp dephosphorylates and inactivates src family kinases to regulate t cell responses._

SIGNOR-177116

Q02790

P10275

1

binding

up-regulates activity

0.72

We noted that FK506 altered nuclear localization of the GR and inhibited expression of GR-responsive genes. Furthermore, si-RNA knockdown of FKBP4 gene, coding for the immunophilin FKBP52, inhibited cortisol-activated GR nuclear translocation

SIGNOR-252034

Q15746

P14649

1

phosphorylation

up-regulates

0.72

Cytoskeletal dynamics are primarily modulated by interactions of actin and myosin ii that are regulated by myosin light chain kinase (mlck)-mediated phosphorylation of the regulatory myosin light chain (mlc).

SIGNOR-65865

Q8N474

P56705

1

binding

down-regulates

0.72

Sfrp-1 binds wnt-4 with considerable avidity and inhibits the dna-binding activity of tcf, an effector of wnt signaling,

SIGNOR-106556

Q9GZM8

Q14204

1

binding

up-regulates activity

0.72

LIS1 specifically binds the P1 loop domain of CDHC, while NUDEL binds the C-terminal region as well as a distinct binding site in the P1 loop domain. LIS1 and NUDEL regulate CDHC localization and motor function. Reduction of LIS1 leads to mislocalization of NUDEL, CDHC, β-tubulin, and the Golgi complex

SIGNOR-252159

Q96GD4

P04637

1

phosphorylation

down-regulates

0.719

We show that aurora b phosphorylates p53 at s183, t211, and s215 to accelerate the degradation of p53 through the polyubiquitination-proteasome pathway, thus functionally suppressing the expression of p53 target genes involved in cell cycle inhibition and apoptosis (e.g., p21 and puma).

SIGNOR-197598

Q8TCU6

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.719

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-260569

P45983

P17275

1

phosphorylation

up-regulates activity

0.719

JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation.

SIGNOR-250120

Q9UHD0

Q6UXL0

1

binding

up-regulates

0.719

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

SIGNOR-151820