GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P10071	O43791	ubiquitination	down-regulates quantity	0.704	RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins	SIGNOR-268861
P01375	P78536	cleavage	up-regulates quantity	0.704	We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified.	SIGNOR-46754
O14641	Q13467	binding	up-regulates activity	0.704	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.	SIGNOR-258960
Q00534	P30304	dephosphorylation	up-regulates activity	0.704	Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs.	SIGNOR-267569
O75197	Q9ULV1	binding	up-regulates activity	0.704	Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain.	SIGNOR-258967
Q15797	Q04771	phosphorylation	up-regulates activity	0.703	ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif	SIGNOR-251439
Q9NWQ8	P06241	phosphorylation	up-regulates activity	0.703	Thus, Fyn mediates Csk-binding protein-Csk interaction and recruits Csk to rafts by phosphorylating Csk-binding protein.	SIGNOR-279987
Q08945	P68400	phosphorylation	down-regulates activity	0.703	CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. \| we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity.	SIGNOR-250961
P30622	P53350	phosphorylation	up-regulates	0.703	Furthermore, we provide evidence that plk1 phosphorylation of clip-170 at s195 enhances its association with ck2	SIGNOR-167172
Q92466	Q9UPU5	deubiquitination	up-regulates	0.703	Usp24-mediated ddb2 deubiquitination prevents ddb2 degradation	SIGNOR-199731
Q9BPZ7	P31749	phosphorylation	up-regulates activity	0.703	Akt phosphorylates SIN1 at T86, enhancing mTORC2 kinase activity, which leads to phosphorylation of Akt S473 by mTORC2, thereby catalyzing full activation of Akt.	SIGNOR-276932
Q9Y281	P53667	phosphorylation	down-regulates activity	0.703	Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3;. Here we show that lim-kinase 1 (limk-1), a serine/threonine kinase containing lim and pdz domains, phosphorylates cofilin at ser 3, both in vitro and in vivo	SIGNOR-58596
P01106	Q96RU2	deubiquitination	up-regulates	0.703	Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc.	SIGNOR-155590
O43914	A8K4G0	binding	up-regulates activity	0.703	The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2.	SIGNOR-264834
Q06330	Q96T58	binding	down-regulates	0.703	We identified sharp as an rbp-jkappa/cbf-1-interacting corepressor in a yeast two-hybrid screen.	SIGNOR-94201
Q92945	P31749	phosphorylation	down-regulates activity	0.703	Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome.	SIGNOR-252497
P25445	Q9UER7	binding	down-regulates	0.703	A c-terminal portion of daxx interacts with the fas death domain. The fas-binding domain of daxx is a dominant-negative inhibitor of both fas-induced apoptosis and jnk activation.	SIGNOR-49473
P04637	P17844	binding	up-regulates	0.702	The dead box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor	SIGNOR-133341
Q9Y4K3	P21580	deubiquitination	down-regulates activity	0.702	A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6	SIGNOR-160223
P51668	Q9HAU4	ubiquitination	up-regulates activity	0.702	Our data further show that SMURF2 monoubiquitinates UBCH5 at lysine 144 to form an active complex required for efficient degradation of a RAS family E3, beta transducing repeat containing protein 1 (beta-TrCP1).	SIGNOR-278718
Q15759	P52564	phosphorylation	up-regulates	0.702	The p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms.	SIGNOR-54947
P62993	P10747	binding	up-regulates	0.702	Binding of the py site in cd28 (py-m-n-m) by pi3k and grb2 through their sh2 domains is a key step that triggers the cd28 signal transduction for t cell activation and differentiation	SIGNOR-202706
P61764	Q02410	binding	up-regulates activity	0.702	Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1.	SIGNOR-264035
P48058	P05129	phosphorylation	up-regulates	0.702	We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.	SIGNOR-97558
P21802	P12034	binding	up-regulates	0.702	Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2	SIGNOR-38995
Q13285	P51843	binding	down-regulates activity	0.702	The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes.	SIGNOR-271784
P26992	Q9UBD9	binding	up-regulates	0.702	Striking phenotypic differences between cntf- and cntfr-deficient mice suggest that cntfr serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (clc) and the soluble receptor cytokine-like factor-1 (clf).	SIGNOR-81376
Q9UP38	P04628	binding	up-regulates activity	0.701	Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6)	SIGNOR-217827
Q96RT7	O00444	phosphorylation	up-regulates activity	0.701	Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.	SIGNOR-262902
P61764	Q99767	binding	up-regulates activity	0.701	Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1.	SIGNOR-264037
Q16539	Q99956	dephosphorylation	down-regulates	0.701	These properties define the ability of this enzyme to dephosphorylate and inactivate erk1/2 and p38a, but not jnk (c-jun n-terminal kinase) in vivo.	SIGNOR-87150
O60674	Q5VWK5	binding	up-regulates	0.701	Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12.	SIGNOR-87808
Q9Y2I6	P53350	phosphorylation	down-regulates activity	0.7	Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction	SIGNOR-103356
P13591	P39905	binding	up-regulates activity	0.7	Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable.	SIGNOR-252189
Q01094	P06493	phosphorylation	up-regulates	0.7	Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro.	SIGNOR-36026
P49190	P01270	binding	up-regulates	0.7	Pth was shown to efficiently activate the human type 2 pth receptor (pth2 receptor)	SIGNOR-115104
Q9BQA1	P11802	phosphorylation	up-regulates activity	0.7	Phosphorylation of MEP50 on Thr 5 by D1T286A and CDK4 is necessary and sufficient to increase the intrinsic methyltransferase activity of PRMT5, resulting in increased H4R3 and H3R8 methylation and repression of the CUL4A/B expression.	SIGNOR-279019
P11362	P12034	binding	up-regulates	0.7	Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2.	SIGNOR-38704
Q13085	Q13131	phosphorylation	down-regulates activity	0.7	We have isolated and purified from rat livers a novel kinase that phosphorylates and inactivates the carboxylase Ser1200 isphosphorylated by both CAMP-dependent protein kinase and AMP-activated protein kinase	SIGNOR-250400
P04049	P31749	phosphorylation	down-regulates	0.7	Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity.	SIGNOR-147963
Q86Y01	Q96J02	ubiquitination	down-regulates	0.7	Itch/aip4 mediates deltex degradation through the formation of k29-linked polyubiquitin chains.	SIGNOR-150002
Q13224	Q9UQM7	phosphorylation	up-regulates activity	0.7	By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons.	SIGNOR-250630
O14733	Q9UPT6	binding	up-regulates	0.7	These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3	SIGNOR-73906
P56704	Q9H237	palmitoylation	up-regulates activity	0.7	And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane.	SIGNOR-256598
P45983	O14733	phosphorylation	up-regulates	0.699	Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues.	SIGNOR-51199
Q99594	Q9GZV5	binding	up-regulates	0.699	When dephosphorylated, yap/taz enter nuclei and induce gene transcription by interacting with transcription factors tead14.	SIGNOR-201415
P35968	Q12913	dephosphorylation	down-regulates	0.699	The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2.	SIGNOR-181672
P26651	P49137	phosphorylation	down-regulates activity	0.699	We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.	SIGNOR-250153
P40763	P06239	phosphorylation	up-regulates activity	0.699	Lck was able to induce tyrosine phosphorylation of STAT3 to a level equal to or greater than that induced by Jak2.\|This finding, along with the previous data, gives strong evidence that Lck can directly and positively affect STAT3 activity.Our data provide strong evidence that Lck can activate STAT3 via phosphorylation in baculovirus infected insect cells.	SIGNOR-279201
Q96SD1	P78527	phosphorylation	up-regulates	0.699	Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin	SIGNOR-148327
P51149	P20339	binding	down-regulates activity	0.699	The absence of active Rab7 prolongs ALS2presence and Rab5 activation on macropinosomes, indicating that activeRab7 is necessary for Rab5 inactivation through ALS2 dissociation and playskey roles in the Rab switch on macropinosomes. Taken together, active Rab7is necessary for Rab5 down-regulation through ALS2dissociation, thereby acting as a central component inthe Rab5-to-Rab7 switch in macropinocytosis	SIGNOR-277780
P28482	Q99956	binding	down-regulates	0.699	Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein.	SIGNOR-176583
Q02763	Q9Y264	binding	up-regulates	0.699	In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2.	SIGNOR-127351
O75197	P56704	binding	up-regulates activity	0.699	Ligands such as wnt1, wnt3a, and wnt8 couple the seventransmembrane domain receptor frizzled (fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (lrp5/6) to activate wnt?Beta-catenin signaling.All the frizzled genes studied have	SIGNOR-169657
P31749	Q5T1C6	binding	down-regulates	0.699	Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308.	SIGNOR-111003
Q9Y4K3	Q13404	binding	up-regulates activity	0.699	We find that traf6, a ring domain protein, functions together with ubc13/uev1a to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (k63) of ubiquitin	SIGNOR-83603
Q00613	O75506	binding	down-regulates activity	0.699	HSBP1 is nuclear-localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock. During attenuation of HSF1 to the inert monomer, HSBP1 associates with Hsp70. HSBP1 negatively affects HSF1 DNA-binding activity, and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. HSF1 interacts with HSBP1 in vivo and is a nuclear localized protein.	SIGNOR-261181
P62995	P09651	transcriptional regulation	up-regulates quantity by expression	0.699	HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells.	SIGNOR-262280
P99999	Q07812	relocalization	up-regulates	0.699	The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease	SIGNOR-73898
Q15797	P12755	binding	down-regulates	0.699	Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad5.	SIGNOR-195630
P52333	O14543	binding	down-regulates activity	0.699	SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR).	SIGNOR-238645
Q9UQC2	P31749	phosphorylation	down-regulates	0.699	Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation.	SIGNOR-252468
P15336	P45984	phosphorylation	up-regulates	0.698	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163266
O60353	P41221	binding	up-regulates activity	0.698	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141437
Q9GZV5	Q9NRM7	phosphorylation	down-regulates	0.698	Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators	SIGNOR-175787
P41091	Q9UI10	guanine nucleotide exchange factor	up-regulates activity	0.698	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269137
Q9Y6W5	P00519	phosphorylation	up-regulates activity	0.698	Furthermore, Abl phosphorylates WAVE2 on tyrosine 150, and WAVE2 deficient cells rescued with a Y150F mutant fail to regain their ability to ruffle and form microspikes, unlike cells rescued with wild-type WAVE2.\|Together, these data show that c-Abl activates WAVE2 via tyrosine phosphorylation to promote actin remodeling in vivo and that Abi-1 forms the crucial link between these two factors.	SIGNOR-279390
P36873	O75807	binding	up-regulates activity	0.698	Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning 15. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival	SIGNOR-260174
P41208	O43303	binding	up-regulates activity	0.698	We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.	SIGNOR-265967
P58012	P63279	sumoylation	up-regulates	0.698	Foxl2 is sumoylated by ubc9, and this ubc9-mediated sumoylation is essential to the transcriptional activity of foxl2 on the star promoter. / the sumoylation site was identified at lysine 25 of foxl2	SIGNOR-187901
Q13490	Q15628	binding	up-regulates activity	0.698	The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD. N-terminal domain of tradd may become accessible to traf2, thereby permitting recruitment of the traf2/ciap1 heterocomplex.	SIGNOR-45134
P98155	Q8WY64	ubiquitination	down-regulates quantity by destabilization	0.698	Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation.	SIGNOR-271487
Q08334	Q8IZJ0	binding	up-regulates	0.697	Il-28 and il-29 interacted with a heterodimeric class ii cytokine receptor that consisted of il-10 receptor beta (il-10rbeta) and an orphan class ii receptor chain, designated il-28ralpha.	SIGNOR-96209
Q04721	Q8NES3	binding	up-regulates	0.697	These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch. It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2.	SIGNOR-107702
P24385	Q13547	binding	up-regulates	0.697	Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.	SIGNOR-134059
Q96RI0	P00734	binding	up-regulates	0.697	Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4).	SIGNOR-196003
P01106	P11309	phosphorylation	up-regulates activity	0.697	FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells	SIGNOR-261557
Q13085	P54646	phosphorylation	down-regulates	0.697	Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed.	SIGNOR-87583
Q09472	P31749	phosphorylation	up-regulates	0.697	We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity	SIGNOR-148983
Q13393	P61586	binding	up-regulates	0.697	Our results demonstrate that direct stimulation of pld1 in vivo by rhoa	SIGNOR-84953
Q9Y2T1	Q9H2K2	ADP-ribosylation	down-regulates quantity by destabilization	0.697	Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin.	SIGNOR-263380
P14778	O43187	binding	up-regulates activity	0.697	Two additional proximal mediators were identified that are required for IL-1R–induced NF-κB activation: IRAK-2, a Pelle family member, and MyD88, a death domain–containing adapter molecule. IRAK-2 preferentially bound IL-1RI. A truncated version of IRAK-2 that lacked the first 96 amino acids [IRAK-2(97-590)] did not associate with IL-1RI, which suggests that the NH2-terminal segment docks with the cytoplasmic domain of IL-1RI.	SIGNOR-273854
Q13188	Q9NS23	binding	up-regulates	0.697	Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization.	SIGNOR-175790
Q99717	P12755	binding	down-regulates	0.697	Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad6	SIGNOR-95468
P52333	P17706	dephosphorylation	down-regulates activity	0.697	Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.	SIGNOR-133078
P08294	Q04656	null	up-regulates activity	0.696	Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide.	SIGNOR-272267
Q06413	Q16539	phosphorylation	up-regulates activity	0.696	We found that in monocytic cells, lps increases the transactivation activity of mef2c through p38-catalysed phosphorylation.	SIGNOR-47136
Q16816	P46019	binding	down-regulates activity	0.696	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-267404
P25054	O14640	binding	down-regulates activity	0.696	Dvl-1 inhibits Axin-promoted GSK-3_-dependent phosphorylation of _-catenin and APC, leading to beta-catenin stabilization.	SIGNOR-167951
P43405	Q13191	ubiquitination	down-regulates quantity	0.696	In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.\|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling.	SIGNOR-278754
Q15303	Q8WWG1	binding	up-regulates	0.696	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-122062
Q9BX63	P27694	binding	up-regulates activity	0.696	Our data are consistent with a model in which FANCJ associates with RPA in a DNA damage-inducible manner and through the protein interaction RPA stimulates FANCJ helicase to better unwind duplex DNA substrates. These findings identify RPA as the first regulatory partner of FANCJ.	SIGNOR-259187
Q01968	P20339	binding	up-regulates activity	0.696	We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis	SIGNOR-277771
Q08334	Q9GZX6	binding	up-regulates	0.696	See table 2	SIGNOR-151880
Q9Y566	Q9Y2H0	relocalization	up-regulates activity	0.696	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264595
P16298	P0DP23	binding	up-regulates	0.696	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-114101
P41091	P49770	guanine nucleotide exchange factor	up-regulates activity	0.696	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269135
Q06413	Q9UQL6	binding	down-regulates	0.696	The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.	SIGNOR-84026
Q92835	P29353	binding	up-regulates	0.696	The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation.	SIGNOR-66949
P55055	P28702	binding	up-regulates	0.696	We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.	SIGNOR-123094

P10071

O43791

0

ubiquitination

down-regulates quantity

0.704

RNAi knockdown of Spop (a substrate-binding adaptor for the cullin3-based ubiquitin E3 ligase) in Sufu mutant mouse embryonic fibroblasts (MEFs) can restore the levels of Gli2 and Gli3 full-length proteins

SIGNOR-268861

P01375

P78536

0

cleavage

up-regulates quantity

0.704

We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. [...]This enzyme (called the tnf-alpha-converting enzyme, or tace) is a new member of the family of mammalian adamalysins (or adams), for which no physiological catalytic function has previously been identified.

SIGNOR-46754

O14641

Q13467

0

binding

up-regulates activity

0.704

Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.

SIGNOR-258960

Q00534

P30304

0

dephosphorylation

up-regulates activity

0.704

Invalidation of CDK4 has no impact by itself on the cell proliferation, but invalidation of CDC25A prevents the dephosphorylation of CDK6 (Y24) and CDK4 (Y17) residues, and impedes their association with CCNDs.

SIGNOR-267569

O75197

Q9ULV1

0

binding

up-regulates activity

0.704

Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain.

SIGNOR-258967

Q15797

Q04771

0

phosphorylation

up-regulates activity

0.703

ALK2 receptor specifically interacts with and phosphorylates Smad1 protein. ALK2 Activates Smad1 and Induces BMP-specific Signals. Biochemical analysis revealed that constitutively active ALK2 associated with and phosphorylated Smad1 on the COOH-terminal SSXS motif

SIGNOR-251439

Q9NWQ8

P06241

0

phosphorylation

up-regulates activity

0.703

Thus, Fyn mediates Csk-binding protein-Csk interaction and recruits Csk to rafts by phosphorylating Csk-binding protein.

SIGNOR-279987

Q08945

P68400

0

phosphorylation

down-regulates activity

0.703

CK2 phosphorylates SSRP1 and inhibits its DNA-binding activity. | we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity.

SIGNOR-250961

P30622

P53350

0

phosphorylation

up-regulates

0.703

Furthermore, we provide evidence that plk1 phosphorylation of clip-170 at s195 enhances its association with ck2

SIGNOR-167172

Q92466

Q9UPU5

0

deubiquitination

up-regulates

0.703

Usp24-mediated ddb2 deubiquitination prevents ddb2 degradation

SIGNOR-199731

Q9BPZ7

P31749

0

phosphorylation

up-regulates activity

0.703

Akt phosphorylates SIN1 at T86, enhancing mTORC2 kinase activity, which leads to phosphorylation of Akt S473 by mTORC2, thereby catalyzing full activation of Akt.

SIGNOR-276932

Q9Y281

P53667

0

phosphorylation

down-regulates activity

0.703

Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3;. Here we show that lim-kinase 1 (limk-1), a serine/threonine kinase containing lim and pdz domains, phosphorylates cofilin at ser 3, both in vitro and in vivo

SIGNOR-58596

P01106

Q96RU2

0

deubiquitination

up-regulates

0.703

Usp28, an ubiquitin-specific protease, binds to myc through an interaction with fbw7alpha, an f-box protein that is part of an scf-type ubiquitin ligase. Therefore, it stabilizes myc.

SIGNOR-155590

O43914

A8K4G0

0

binding

up-regulates activity

0.703

The CD300b receptor is a non-classical activating receptor able to deliver signals by associating with the transmembrane adaptor protein DAP-12 and the intracellular mediator Grb-2.

SIGNOR-264834

Q06330

Q96T58

0

binding

down-regulates

0.703

We identified sharp as an rbp-jkappa/cbf-1-interacting corepressor in a yeast two-hybrid screen.

SIGNOR-94201

Q92945

P31749

0

phosphorylation

down-regulates activity

0.703

Beta-catenin transcript can be stabilized by either wnt or pi3k-akt signaling activation. Akt phosphorylates ksrp at a unique serine residue akt phosphorylates the mrna decay-promoting factor ksrp at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents ksrp interaction with the exoribonucleolytic complex exosome.

SIGNOR-252497

P25445

Q9UER7

0

binding

down-regulates

0.703

A c-terminal portion of daxx interacts with the fas death domain. The fas-binding domain of daxx is a dominant-negative inhibitor of both fas-induced apoptosis and jnk activation.

SIGNOR-49473

P04637

P17844

0

binding

up-regulates

0.702

The dead box protein p68: a novel transcriptional coactivator of the p53 tumour suppressor

SIGNOR-133341

Q9Y4K3

P21580

0

deubiquitination

down-regulates activity

0.702

A20 is a deubiquitinating enzyme (dub) for lys63-linked polyubiquitinated signaling mediators such as traf6

SIGNOR-160223

P51668

Q9HAU4

0

ubiquitination

up-regulates activity

0.702

Our data further show that SMURF2 monoubiquitinates UBCH5 at lysine 144 to form an active complex required for efficient degradation of a RAS family E3, beta transducing repeat containing protein 1 (beta-TrCP1).

SIGNOR-278718

Q15759

P52564

0

phosphorylation

up-regulates

0.702

The p38 mapkinasekinasemkk6 is identified as a common activator of p38 alpha, p38 beta 2, and p38 gamma mapkinaseisoforms.

SIGNOR-54947

P62993

P10747

0

binding

up-regulates

0.702

Binding of the py site in cd28 (py-m-n-m) by pi3k and grb2 through their sh2 domains is a key step that triggers the cd28 signal transduction for t cell activation and differentiation

SIGNOR-202706

P61764

Q02410

0

binding

up-regulates activity

0.702

Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1.

SIGNOR-264035

P48058

P05129

0

phosphorylation

up-regulates

0.702

We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.

SIGNOR-97558

P21802

P12034

0

binding

up-regulates

0.702

Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2

SIGNOR-38995

Q13285

P51843

0

binding

down-regulates activity

0.702

The in vivo existence of an SF-1 corepressor complex consisting of DAX-1, RNF31, and SMRT at the steroidogenic promoters of the human StAR and CYP19 genes. We demonstrate that RNF31 is necessary for the stable association of the DAX-1 corepressor complex with chromatin-bound SF-1, thereby inhibiting the recruitment of coactivators and Pol II and controlling basal transcription levels of SF-1 target genes.

SIGNOR-271784

P26992

Q9UBD9

0

binding

up-regulates

0.702

Striking phenotypic differences between cntf- and cntfr-deficient mice suggest that cntfr serves as a receptor for a second, developmentally important ligand. We have identified this factor as a stable secreted complex of cardiotrophin-like cytokine (clc) and the soluble receptor cytokine-like factor-1 (clf).

SIGNOR-81376

Q9UP38

P04628

0

binding

up-regulates activity

0.701

Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6)

SIGNOR-217827

Q96RT7

O00444

0

phosphorylation

up-regulates activity

0.701

Plk4 interacts with and phosphorylates GCP6. we show that GCP6 is an integral component of the centriole and required for centriole duplication. Moreover, we find that GCP6 interacts in vitro and in vivo with Plk4. We show that phosphorylation of GCP6 by Plk4 is required for Plk4-induced centriole overduplication.

SIGNOR-262902

P61764

Q99767

0

binding

up-regulates activity

0.701

Munc18-1 is a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis. We have now identified two Munc18-1-interacting proteins called Mint1 and Mint2 that may mediate the function of Munc18-1.

SIGNOR-264037

Q16539

Q99956

0

dephosphorylation

down-regulates

0.701

These properties define the ability of this enzyme to dephosphorylate and inactivate erk1/2 and p38a, but not jnk (c-jun n-terminal kinase) in vivo.

SIGNOR-87150

O60674

Q5VWK5

0

binding

up-regulates

0.701

Il-23 activates the same jak-stat signaling molecules as il-12: jak2, tyk2, and stat1, -3, -4, and -5, but stat4 activation is substantially weaker and different dna-binding stat complexes form in response to il-23 compared with il-12.

SIGNOR-87808

Q9Y2I6

P53350

0

phosphorylation

down-regulates activity

0.7

Here, we identify a centrosomal plk1 substrate, termed nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates nlp and disrupts both its centrosome association and its gamma-tubulin interaction

SIGNOR-103356

P13591

P39905

0

binding

up-regulates activity

0.7

Recently, NCAM was identified as an alternative receptor for GDNF. These new results may explain the findings that, in several regions, the GDNF receptor (GFRa1) is highly expressed, while RET is undetectable.

SIGNOR-252189

Q01094

P06493

0

phosphorylation

up-regulates

0.7

Association of e2f with rb inhibits its transactivation potential. phosphorylation of e2f-1 on serine residues 332 and 337 prevented its interaction with rbthese residues were phosphorylated in vivo and by p34cdc2 kinase in vitro.

SIGNOR-36026

P49190

P01270

0

binding

up-regulates

0.7

Pth was shown to efficiently activate the human type 2 pth receptor (pth2 receptor)

SIGNOR-115104

Q9BQA1

P11802

0

phosphorylation

up-regulates activity

0.7

Phosphorylation of MEP50 on Thr 5 by D1T286A and CDK4 is necessary and sufficient to increase the intrinsic methyltransferase activity of PRMT5, resulting in increased H4R3 and H3R8 methylation and repression of the CUL4A/B expression.

SIGNOR-279019

P11362

P12034

0

binding

up-regulates

0.7

Fgf-5 can bind and induce autophosphorylation of human fgf receptors (fgfr) 1 and 2.

SIGNOR-38704

Q13085

Q13131

0

phosphorylation

down-regulates activity

0.7

We have isolated and purified from rat livers a novel kinase that phosphorylates and inactivates the carboxylase Ser1200 isphosphorylated by both CAMP-dependent protein kinase and AMP-activated protein kinase

SIGNOR-250400

P04049

P31749

0

phosphorylation

down-regulates

0.7

Akt and protein kinase a (pka) phosphorylate s259 on raf-1 and inhibit its activity.

SIGNOR-147963

Q86Y01

Q96J02

0

ubiquitination

down-regulates

0.7

Itch/aip4 mediates deltex degradation through the formation of k29-linked polyubiquitin chains.

SIGNOR-150002

Q13224

Q9UQM7

0

phosphorylation

up-regulates activity

0.7

By peptide mapping, automated sequencing, and mass spectrometry, we identified the major site of phosphorylation on the fusion protein as Ser-383, corresponding to Ser-1303 of full-length NR2B. The Km for phosphorylation of this site in the fusion protein was approximately 50 nM, much lower than that of other known substrates for CaM kinase II, suggesting that the receptor is a high affinity substrate. We show that serine 1303 in the full-length NR2B and/or the cognate site in NR2A is a major site of phosphorylation of the receptor both in the postsynaptic density fraction and in living hippocampal neurons.

SIGNOR-250630

O14733

Q9UPT6

0

binding

up-regulates

0.7

These data demonstrate that jip3 interacts with proteins that can form a mapk signaling module, including jnk, mkk7, and mlk3

SIGNOR-73906

P56704

Q9H237

0

palmitoylation

up-regulates activity

0.7

And WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane.

SIGNOR-256598

P45983

O14733

0

phosphorylation

up-regulates

0.699

Jnk is activated by jnk-activating kinase 1 (jnkk1), a dual specificity protein kinase that phosphorylates jnk on threonine 183 and tyrosine 185 residues.

SIGNOR-51199

Q99594

Q9GZV5

0

binding

up-regulates

0.699

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

SIGNOR-201415

P35968

Q12913

0

dephosphorylation

down-regulates

0.699

The autoactivation residues y1054 and y1059 are targeted by dep-1 and this results in the inhibition of kinase activity and the consequent general dephosphorylation of vegfr2.

SIGNOR-181672

P26651

P49137

0

phosphorylation

down-regulates activity

0.699

We confirm phosphorylation of TTP by MK2 and identify specific phosphorylation sites at Ser52, Ser105, Ser58, Ser176, Ser178, and Ser316. If MK2 regulates translation in part by TTP phosphorylation, TTP should be a repressor of translation when dephosphorylated and an activator of (or neutral to) translation when phosphorylated.

SIGNOR-250153

P40763

P06239

0

phosphorylation

up-regulates activity

0.699

Lck was able to induce tyrosine phosphorylation of STAT3 to a level equal to or greater than that induced by Jak2.|This finding, along with the previous data, gives strong evidence that Lck can directly and positively affect STAT3 activity.Our data provide strong evidence that Lck can activate STAT3 via phosphorylation in baculovirus infected insect cells.

SIGNOR-279201

Q96SD1

P78527

0

phosphorylation

up-regulates

0.699

Artemis is a nuclear phosphoprotein required for genomic integrity whose phosphorylation is increased subsequent to dna damage. Artemis phosphorylation by the dna-dependent protein kinase (dna-pk). However, regardless of its association with dna-pkcs, phosphorylation of artemis at both s516 and s645 was stimulated in response to the double-stranded dna-damaging agent bleomycin

SIGNOR-148327

P51149

P20339

0

binding

down-regulates activity

0.699

The absence of active Rab7 prolongs ALS2presence and Rab5 activation on macropinosomes, indicating that activeRab7 is necessary for Rab5 inactivation through ALS2 dissociation and playskey roles in the Rab switch on macropinosomes. Taken together, active Rab7is necessary for Rab5 down-regulation through ALS2dissociation, thereby acting as a central component inthe Rab5-to-Rab7 switch in macropinocytosis

SIGNOR-277780

P28482

Q99956

0

binding

down-regulates

0.699

Here we demonstrate that inactivation of both erk1/2 and p38_ by dusp9/mkp-4 is mediated by a conserved arginine-rich kinase interaction motif located within the amino-terminal non-catalytic domain of the protein.

SIGNOR-176583

Q02763

Q9Y264

0

binding

up-regulates

0.699

In experiments with human endothelial cell lines, ang3 was identified as an antagonist of tie2 and ang4 was identified as an agonist of tie2.

SIGNOR-127351

O75197

P56704

0

binding

up-regulates activity

0.699

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

SIGNOR-169657

P31749

Q5T1C6

0

binding

down-regulates

0.699

Here, we describe a protein partner for pkbalpha termed ctmp, or carboxyl-terminal modulator protein, that binds specifically to the carboxyl-terminal regulatory domain of pkbalpha at the plasma membrane. Binding of ctmp reduces the activity of pkbalpha by inhibiting phosphorylation on serine 473 and threonine 308.

SIGNOR-111003

Q9Y4K3

Q13404

0

binding

up-regulates activity

0.699

We find that traf6, a ring domain protein, functions together with ubc13/uev1a to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (k63) of ubiquitin

SIGNOR-83603

Q00613

O75506

0

binding

down-regulates activity

0.699

HSBP1 is nuclear-localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock. During attenuation of HSF1 to the inert monomer, HSBP1 associates with Hsp70. HSBP1 negatively affects HSF1 DNA-binding activity, and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. HSF1 interacts with HSBP1 in vivo and is a nuclear localized protein.

SIGNOR-261181

P62995

P09651

0

transcriptional regulation

up-regulates quantity by expression

0.699

HnRNPA1 interacts with G-quadruplex in the TRA2B promoter and stimulates its transcription in human colon cancer cells.

SIGNOR-262280

P99999

Q07812

0

relocalization

up-regulates

0.699

The integration of bax oligomers in the outer mitochondrial membrane is followed by cytochrome crelease

SIGNOR-73898

Q15797

P12755

0

binding

down-regulates

0.699

Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad5.

SIGNOR-195630

P52333

O14543

0

binding

down-regulates activity

0.699

SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity.Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity directly through their kinase inhibitory regions (KIR).

SIGNOR-238645

Q9UQC2

P31749

0

phosphorylation

down-regulates

0.699

Pkb constitutively associates with gab2, phosphorylates gab2 on a consensus phosphorylation site, ser159, in vitro and inhibits gab2 tyrosine phosphorylation.

SIGNOR-252468

P15336

P45984

0

phosphorylation

up-regulates

0.698

Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.

SIGNOR-163266

O60353

P41221

0

binding

up-regulates activity

0.698

Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.

SIGNOR-141437

Q9GZV5

Q9NRM7

0

phosphorylation

down-regulates

0.698

Activated lats1/2 in turn phosphorylate and inhibit yap/taz transcription co-activators

SIGNOR-175787

P41091

Q9UI10

0

guanine nucleotide exchange factor

up-regulates activity

0.698

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269137

Q9Y6W5

P00519

0

phosphorylation

up-regulates activity

0.698

Furthermore, Abl phosphorylates WAVE2 on tyrosine 150, and WAVE2 deficient cells rescued with a Y150F mutant fail to regain their ability to ruffle and form microspikes, unlike cells rescued with wild-type WAVE2.|Together, these data show that c-Abl activates WAVE2 via tyrosine phosphorylation to promote actin remodeling in vivo and that Abi-1 forms the crucial link between these two factors.

SIGNOR-279390

P36873

O75807

0

binding

up-regulates activity

0.698

Dephosphorylation of eIF2α is central to ISR signal termination to restore protein synthesis and normal cell functioning 15. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damage‐inducible protein, GADD34), which is induced as part of the ISR. the GADD34–PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival

SIGNOR-260174

P41208

O43303

0

binding

up-regulates activity

0.698

We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.

SIGNOR-265967

P58012

P63279

0

sumoylation

up-regulates

0.698

Foxl2 is sumoylated by ubc9, and this ubc9-mediated sumoylation is essential to the transcriptional activity of foxl2 on the star promoter. / the sumoylation site was identified at lysine 25 of foxl2

SIGNOR-187901

Q13490

Q15628

0

binding

up-regulates activity

0.698

The recruitment of TRAF2 and c-IAP1 to TNF-R1 is TNF-dependent, is mediated by TRADD. N-terminal domain of tradd may become accessible to traf2, thereby permitting recruitment of the traf2/ciap1 heterocomplex.

SIGNOR-45134

P98155

Q8WY64

0

ubiquitination

down-regulates quantity by destabilization

0.698

Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation.

SIGNOR-271487

Q08334

Q8IZJ0

0

binding

up-regulates

0.697

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

SIGNOR-96209

Q04721

Q8NES3

0

binding

up-regulates

0.697

These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch. It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2.

SIGNOR-107702

P24385

Q13547

0

binding

up-regulates

0.697

Cyclin d1 bound hdac in vivo and preferentially physically associated with hdac1, hdac2, hdac3, and hdac5.

SIGNOR-134059

Q96RI0

P00734

0

binding

up-regulates

0.697

Thrombin activates platelets by binding and cleaving protease-activated receptors 1 and 4 (par1 and par4).

SIGNOR-196003

P01106

P11309

0

phosphorylation

up-regulates activity

0.697

FLT3-ITD kinase may regulate c-MYC through STAT5-induced enhancement of PIM kinases (Choudhary et al., 2009), which can modulate c-MYC stability and activity via phosphorylation (van der Lugt et al., 1995s). This is supported by the observation that FLT3-ITD CD34+ cells showed higher PIM activity compared to cells expressing FLT3-WT, indicated by increased expression of the PIM targets including p-BAD (Ser112), p-4EBP1 (Thr37/46), and p-c-MYC (Ser62) (Figure 6C); and by the observation that siRNA-mediated inhibition of PIM1, but not PIM2, expression resulted in significantly decreased p-c-MYC (Ser62), c-MYC, and SIRT1 expression in MV4-11 cells

SIGNOR-261557

Q13085

P54646

0

phosphorylation

down-regulates

0.697

Significant negative linear correlations between phospho-acc and acc activity were observed in all models (p < 0.01). The decline in acc activity was related to the decrease in pcr and the rise in amp. A relationship between phospho-ampk (threonine 172) and activity of ampk immunoprecipitated with anti-alpha(2) subunit antibody preparation was also observed.

SIGNOR-87583

Q09472

P31749

0

phosphorylation

up-regulates

0.697

We find that suberoylanilide hydroxamic acid stimulates akt activity, which is required to phosphorylate p300 at ser(1834). Akt-mediated phosphorylation of p300 dramatically increases its acetyltransferase activity

SIGNOR-148983

Q13393

P61586

0

binding

up-regulates

0.697

Our results demonstrate that direct stimulation of pld1 in vivo by rhoa

SIGNOR-84953

Q9Y2T1

Q9H2K2

0

ADP-ribosylation

down-regulates quantity by destabilization

0.697

Together, these findings are consistent with the hypothesis that TNKS promotes the ubiquitination and degradation of axin, which may be mediated, at least in part, through the direct PARsylation of axin.

SIGNOR-263380

P14778

O43187

0

binding

up-regulates activity

0.697

Two additional proximal mediators were identified that are required for IL-1R–induced NF-κB activation: IRAK-2, a Pelle family member, and MyD88, a death domain–containing adapter molecule. IRAK-2 preferentially bound IL-1RI. A truncated version of IRAK-2 that lacked the first 96 amino acids [IRAK-2(97-590)] did not associate with IL-1RI, which suggests that the NH2-terminal segment docks with the cytoplasmic domain of IL-1RI.

SIGNOR-273854

Q13188

Q9NS23

0

binding

up-regulates

0.697

Mst1/2 is also activated by binding to Ras association domain family (RASSF) proteins, possibly owing to alteration of Mst1/2 subcellular localization.

SIGNOR-175790

Q99717

P12755

0

binding

down-regulates

0.697

Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad6

SIGNOR-95468

P52333

P17706

0

dephosphorylation

down-regulates activity

0.697

Upon ligand binding, IL-2R , IL-6R or LeptinR , IFN-_R , IFN-_R and PRLR or growth hormone (GH) receptor associated JAKs become activated. These JAKs mediate phosphorylation of specific tyrosine residues and recruit STATs. Activated STATs are released from the receptor and translocate to the nucleus. PTP1B dephosphorylates JAK2, TYK2 and STAT5 . The 45-kDa form of TC-PTP was shown to dephosphorylate JAK1 and JAK3 as well as STAT1, STAT3 and STAT5.

SIGNOR-133078

P08294

Q04656

0

null

up-regulates activity

0.696

Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide.

SIGNOR-272267

Q06413

Q16539

0

phosphorylation

up-regulates activity

0.696

We found that in monocytic cells, lps increases the transactivation activity of mef2c through p38-catalysed phosphorylation.

SIGNOR-47136

Q16816

P46019

0

binding

down-regulates activity

0.696

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-267404

P25054

O14640

0

binding

down-regulates activity

0.696

Dvl-1 inhibits Axin-promoted GSK-3_-dependent phosphorylation of _-catenin and APC, leading to beta-catenin stabilization.

SIGNOR-167951

P43405

Q13191

0

ubiquitination

down-regulates quantity

0.696

In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling.

SIGNOR-278754

Q15303

Q8WWG1

0

binding

up-regulates

0.696

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-122062

Q9BX63

P27694

0

binding

up-regulates activity

0.696

Our data are consistent with a model in which FANCJ associates with RPA in a DNA damage-inducible manner and through the protein interaction RPA stimulates FANCJ helicase to better unwind duplex DNA substrates. These findings identify RPA as the first regulatory partner of FANCJ.

SIGNOR-259187

Q01968

P20339

0

binding

up-regulates activity

0.696

We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis

SIGNOR-277771

Q08334

Q9GZX6

0

binding

up-regulates

0.696

See table 2

SIGNOR-151880

Q9Y566

Q9Y2H0

0

relocalization

up-regulates activity

0.696

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

SIGNOR-264595

P16298

P0DP23

0

binding

up-regulates

0.696

Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.

SIGNOR-114101

P41091

P49770

0

guanine nucleotide exchange factor

up-regulates activity

0.696

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269135

Q06413

Q9UQL6

0

binding

down-regulates

0.696

The histone deacetylase hdac-5, upon dephosphorylation and translocation to the nucleus, directly inactivates mef2, preventing myogenesis.

SIGNOR-84026

Q92835

P29353

0

binding

up-regulates

0.696

The results indicate that ship, shc, and grb2 form a ternary complex in stimulated b cells, with grb2 stabilizing the interaction between shc and ship. The interactions between shc, grb2, and ship are therefore analogous to the interactions between shc, grb2, and sos. Shc and grb2 may help to localize ship to the cell membrane, regulating ship's inhibitory function following bcr stimulation.

SIGNOR-66949

P55055

P28702

0

binding

up-regulates

0.696

We provide genetic and molecular evidence that cholesterol homeostasis in scs does not require pparalpha and beta, but depends upon the tif2 coactivator and rxrbeta/lxrbeta heterodimers, in which rxrbeta af-2 is transcriptionally active.

SIGNOR-123094