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
P27361	Q13480	1	phosphorylation	up-regulates activity	0.633	Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. \|serine and threonine phosphorylation are capable of modulating the initial signal	SIGNOR-249464
P52306	P61586	1	binding	up-regulates	0.633	Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc	SIGNOR-171347
P01116	O00329	1	binding	up-regulates	0.633	Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k	SIGNOR-175210
P53805	Q08209	1	binding	down-regulates activity	0.633	MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure	SIGNOR-252025
Q9H1J5	O75197	1	binding	up-regulates	0.633	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131987
P0DMV8	P04150	1	binding	down-regulates	0.633	Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex	SIGNOR-251668
P16220	O75030	1	transcriptional regulation	up-regulates quantity by expression	0.633	Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription.	SIGNOR-249619
P51812	P18848	1	phosphorylation	up-regulates	0.633	Here, we show that rsk2 is required for osteoblast differentiation and function. We identify the transcription factor atf4 as a critical substrate of rsk2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression	SIGNOR-124436
P28482	P04049	1	phosphorylation	down-regulates activity	0.632	Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. \| Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.\|FLAG-Raf-1 phosphorylated by activated ERK2	SIGNOR-249441
Q86UR1	Q9HBY0	1	binding	up-regulates activity	0.632	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner\|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein\|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264711
O75122	Q15691	1	binding	up-regulates activity	0.632	GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.\| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells	SIGNOR-264829
P56703	Q9NPG1	1	binding	up-regulates	0.632	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131820
Q13464	P53671	1	phosphorylation	up-regulates	0.632	Specific activation of lim kinase 2 via phosphorylation of threonine 505 by rock, a rho-dependent protein kinase	SIGNOR-82755
Q16828	P45983	1	dephosphorylation	down-regulates activity	0.632	Our data demonstrate MKP-3 has differential substrate preference in astrocytes compared to other cells types, since it preferentially dephosphorylated p-JNK over p-ERK.\|The main findings of our studies are (1) MKP-3 preferentially reduces p-JNK over p-ERK and p-p38 in primary astrocytes; (2) This MAPK modulation pattern in primary astrocytes significantly reduced NO and completely abolished IL-6 and TNF accumulation; and (3) These effects are specifically induced by MKP-3 since block-age of MKP-3 mRNA expression reversed its action on MAPKs and pro-inflammatory mediators in BV-2 microglia cells.	SIGNOR-277150
O95393	P36894	1	binding	up-regulates	0.632	We showed that three orphan ligands known to be important for joint and cartilage formation (gdf6) (10), interneuron, sensory neurons, and seminal vesicle formation (gdf7) (11_13), and heart development (bmp10) (14) used the type i receptors alk3 or alk6 and the type ii receptors bmprii or actriia to activate the smad1/5/8 proteins.	SIGNOR-139052
P49840	O75581	1	phosphorylation	up-regulates activity	0.632	Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493	SIGNOR-275398
P12931	P46937-3	1	phosphorylation	up-regulates activity	0.632	We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation.	SIGNOR-274025
P48736	O15530	1	binding	up-regulates	0.632	Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (pdk-1), which binds with high affinity to the pi 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (ptdins-3,4,5-p), phosphorylates and potently activates two other pi 3-kinase targets, the protein kinases akt/pkb and p70s6k.	SIGNOR-60567
P41743	Q15334	1	phosphorylation	up-regulates activity	0.632	This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner.	SIGNOR-263179
O00308	P60484	1	ubiquitination	down-regulates quantity by destabilization	0.632	We have shown that WWP2 interacts with and ubiquitylates PTEN, promoting its degradation.	SIGNOR-278650
Q99835	Q2M1P5	1	relocalization	up-regulates activity	0.632	Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins.	SIGNOR-209605
O15327	P60484	1	dephosphorylation	down-regulates activity	0.632	In support, the increase in PTEN caused by INPP4B knockdown was associated with increased phosphorylation of the Ser380, Thr382, Thr383 and Ser385 cluster of the protein (XREF_FIG), which is known to increase PTEN half-life, in colon cancer cells.\|Exogenous INPP4B could pull down and dephosphorylate endogenous PTEN, suggesting that effect of INPP4B on PTEN in colon cancer cells is not due to cell-type-specific characteristics of INPP4B per se.\|INPP4B downregulates PTEN in colon cancer cells.	SIGNOR-277018
Q13873	P36894	2	phosphorylation	up-regulates	0.631	Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1.	SIGNOR-180545
P14784	P23458	2	binding	up-regulates	0.631	In lymphocytes, binding of il-15 to the il-2/15rbg heterodimer induces jak1 activation that subsequently phosphorylates stat3 via the b-chain and jak3/stat5 activation via its g-chain	SIGNOR-204972
P04637	Q9UI32	1	transcriptional regulation	up-regulates quantity by expression	0.631	Glutaminase 2 (GLS2) can be directly transactivated by p53 and can therefore mediate p53-dependent regulation of cellular energy metabolism. G	SIGNOR-268041
P18031	Q9H1D0	1	dephosphorylation	down-regulates activity	0.631	In HEK293 cells, transfected with the Ca2+ channel protein TRPV6, Ca2+ influx is increased and TRPV6 is tyrosine phosphorylated following addition of the tyrosine phosphatase inhibitor\|PTP1B interacts with the N-terminal domain of TRPV6 within a region of amino acids 1-191 as shown by co-immunoprecipitation, bimolecular fluorescence complementation and the yeast 2-hybrid system. Point mutation of both tyrosines 161 and 162 in the TRPV6 protein abolishes the DMHV-effect on Ca2+ influx and tyrosine phosphorylation by Src. Single mutations of Y161 or Y162 shows that each of both tyrosines alone is sufficient for the DMHV-effect. We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of Ca2+ influx through TRPV6 Ca2+ channels in HEK293 cells.	SIGNOR-248433
Q99683	P45985	1	phosphorylation	up-regulates activity	0.631	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)	SIGNOR-45373
Q7Z5L9	P14316	1	binding	up-regulates activity	0.631	We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation.	SIGNOR-224073
P27361	Q00613	1	phosphorylation	down-regulates	0.631	Sequential phosphorylation of hsf1 by mitogen-activated protein kinase and glycogen synthase kinase 3 at ser-303 and ser-307 represses transcriptional activation by heat shock factor-1.	SIGNOR-44999
Q9Y4K3	Q99558	1	binding	up-regulates activity	0.631	RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. TRAF6 has been demonstrated to interact with NIK.	SIGNOR-253048
Q5H8A3	Q9GZQ4	1	binding	up-regulates	0.631	Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus.	SIGNOR-133131
P23458	P14784	2	phosphorylation	up-regulates activity	0.631	In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc.	SIGNOR-251340
P22607	P40763	1	phosphorylation	up-regulates activity	0.631	Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.	SIGNOR-251139
Q15596	P10276	1	binding	up-regulates	0.631	Transcriptional coactivator for steroid receptors and nuclear receptors.nteracts with casp8ap2 and ttll5/stamp. Interacts with esr1, rara and rxra.	SIGNOR-96827
Q15831	Q13485	1	phosphorylation	down-regulates activity	0.631	LKB1 inhibits the DNA binding and the transcriptional activity of Smad4.\|We further demonstrate that LKB1 is capable of phosphorylating Smad4 on Thr 77 of its DNA-binding domain.	SIGNOR-278193
Q9Y618	P41182	1	binding	up-regulates activity	0.631	The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT.	SIGNOR-252240
P36897	O95405	1	binding	up-regulates activity	0.631	Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex	SIGNOR-62868
Q03113	O15085	1	binding	up-regulates activity	0.631	This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho	SIGNOR-256516
P36894	Q13873	2	binding	up-regulates	0.631	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors	SIGNOR-75652
Q02930	P15336	1	binding	up-regulates activity	0.631	CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription	SIGNOR-219655
P17693	P26715	1	binding	up-regulates	0.631	Current models of nk cell function have supposed that the cd94/nkg2a heterodimer is interacting with an epitope common to classical hla class i	SIGNOR-56714
P20393	Q99743	1	transcriptional regulation	down-regulates quantity by repression	0.631	In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.	SIGNOR-267981
Q13882	P49023	1	phosphorylation	up-regulates activity	0.63	It was also observed that the attenuation of BRK phosphorylation in turn inhibits BRK mediated activation of its direct targets, STAT3, SAM68, and Paxillin.\|The EGF pathway also stimulates BRK 's phosphorylation of paxillin to promote migratory and invasive characteristics in breast cancer cells.	SIGNOR-280102
P61106	Q96T51	1	relocalization	up-regulates activity	0.63	Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.	SIGNOR-261279
Q93097	Q9NPG1	1	binding	up-regulates	0.63	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131777
Q8IVT5	P15056	1	binding	up-regulates activity	0.63	In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.	SIGNOR-273878
Q04206	P08047	1	binding	up-regulates	0.63	Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1.	SIGNOR-75004
P31152	Q8IW41	2	phosphorylation	up-regulates activity	0.63	ERK3, ERK4 and p38 MAPK can all phosphorylate MK5 at Thr 182 , , , - ], but it is not known whether these enzymes also can phosphorylate Ser 115 and whether this modification contributes to ERK3-, ERK4-, or p38 MAPK -regulated subcellular localization of MK5.	SIGNOR-279072
O60641	P63027	1	binding	up-regulates quantity	0.63	the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval.	SIGNOR-264112
Q9Y6Y9	P09429	1	binding	up-regulates activity	0.63	Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling.	SIGNOR-252058
O15530	Q15418	1	phosphorylation	up-regulates activity	0.63	Full-length RSK1, RSK2, and RSK3 Are Activated when Coexpressed with PDK1 in COS7 Cells. Ser221 phosphorylation is increased 2–3-fold during ERK-mediated activation of RSK1 in COS1 cells	SIGNOR-250270
Q8IW41	P31152	2	phosphorylation	up-regulates	0.63	This is due to mk5-dependent phosphorylation and only this retarded erk4 species is both phosphorylated on ser(186) and co-immunoprecipitates with wild-type mk5. We conclude that binding between erk4 and mk5 facilitates phosphorylation of ser(186) and stabilization of the erk4-mk5 complex.	SIGNOR-17069
Q13555	P42261	1	phosphorylation	up-regulates activity	0.63	In this study, CaM-kinase II enhanced kainate currents of expressed glutamate receptor 6 in 293 cells and of wild-type glutamate receptor 1, but not the Ser-627 to Ala mutant, in Xenopus oocytes. \| This CaM-kinase II regulatory phosphorylation site is conserved in all AMPA/kainate-type glutamate receptors, and its phosphorylation may be important in enhancing postsynaptic responsiveness as occurs during synaptic plasticity.	SIGNOR-250697
O00548	Q9UM47	1	binding	up-regulates	0.63	These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors.	SIGNOR-82398
Q00987	P98177	1	ubiquitination	down-regulates activity	0.63	Mdm2 Induces Mono-Ubiquitination of FOXO4.\|higher amounts of Mdm2 transfected resulted in reduced FOXO4 transcriptional activity.	SIGNOR-278656
Q8N2H9	Q9Y4K3	1	ubiquitination	down-regulates quantity	0.63	Finally, we used coexpression studies to directly demonstrate that Pellino3 inhibits the ability of wild-type TRAF6 to stabilize HIF-1alpha but not the stabilizing effects of the K124A TRAF6 mutant that is resistant to ubiquitination.\|In the present study, Pellino3 ubiquitinates TRAF6 with lysine 63-linked polyubiquitin chains to block the interaction of TRAF6 with HIF-1\u03b1.	SIGNOR-278707
Q08209	Q13469	1	dephosphorylation	up-regulates activity	0.629	NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity	SIGNOR-248690
Q96GD4	Q96FF9	1	phosphorylation	down-regulates activity	0.629	Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.	SIGNOR-276116
Q9UPT6	P45985	1	binding	up-regulates	0.629	Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct.	SIGNOR-71468
Q9UNA1	P61586	1	gtpase-activating protein	down-regulates activity	0.629	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-260481
Q9UQB8	Q92558	1	binding	up-regulates	0.629	Here we demonstrate that irsp53, a substrate forinsulinreceptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex.	SIGNOR-85299
Q15833	O75558	1	binding	up-regulates activity	0.629	Strikingly, addition of Munc18-2 substantially and selectively facilitates complete fusion mediated by lipid-anchored STX11 by promoting and stabilizing the assembly of SNARE complexes.	SIGNOR-261898
P22681	P09619	1	polyubiquitination	down-regulates quantity by destabilization	0.629	Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as observed with PDGFRalpha.	SIGNOR-272549
Q05086	P49815	1	ubiquitination	down-regulates quantity by destabilization	0.629	An in vivo ubiquitination assay was done to reveal that E6AP promoted the ubiquitination of TSC2 independent of HPV16 E6. We further found that TSC2 bound E6AP in the presence as well as in the absence of HPV16 E6. The binding regions on E6AP and TSC2 have been identified as amino acid (aa) 260-316, aa 428-500 and aa 1-175, aa 1251-1807, respectively. Taken together, degradation of TSC2 is mediated by E6AP ubiquitin ligase.	SIGNOR-271396
P63092	O60503	1	binding	up-regulates activity	0.628	Adenylyl cyclase 9 (AC9) is a membrane-bound enzyme that converts ATP into cAMP. The enzyme is weakly activated by forskolin, fully activated by the G protein Gαs subunit and is autoinhibited by the AC9 C-terminus.	SIGNOR-278883
P42574	Q9UKV3	1	cleavage	up-regulates	0.628	Induces apoptotic chromatin condensation after activation by casp3	SIGNOR-70800
P41134	P15884	1	binding	down-regulates activity	0.628	All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.	SIGNOR-241385
P98170	O43353	1	ubiquitination	up-regulates activity	0.628	XIAP is the essential E3 for RIPK2 ubiquitination and interacts with RIPK2 through its baculoviral IAP-repeat (BIR).	SIGNOR-280449
O00571	P06730	1	binding	down-regulates activity	0.628	DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G.	SIGNOR-269193
P28482	P17655	1	phosphorylation	up-regulates	0.628	Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo.	SIGNOR-123079
P28482	P15056	1	phosphorylation	down-regulates activity	0.628	Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.	SIGNOR-236388
Q9Y6F9	Q9NPG1	1	binding	up-regulates	0.628	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131891
P15514	P04626	1	phosphorylation	up-regulates	0.628	Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor	SIGNOR-31199
Q9HBE5	P23458	1	binding	up-regulates	0.628	Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5	SIGNOR-90266
P53779	P04637	1	phosphorylation	up-regulates	0.628	The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53	SIGNOR-120552
P03372	P27986	1	binding	up-regulates	0.628	Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k.	SIGNOR-140470
P04628	Q9NPG1	1	binding	up-regulates activity	0.628	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131571
Q5T5U3	P61586	1	gtpase-activating protein	down-regulates activity	0.628	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-260475
Q15831	P54646	1	phosphorylation	up-regulates	0.627	We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli	SIGNOR-122725
Q12778	P46527	1	transcriptional regulation	up-regulates quantity by expression	0.627	To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter.	SIGNOR-277739
O00548	P46531	1	binding	up-regulates activity	0.627	Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.	SIGNOR-209732
Q9UNE7	P04626	1	ubiquitination	down-regulates quantity by destabilization	0.627	The ErbB2 kinase domain is required for GA-induced and CHIP-dependent ErbB2 ubiquitination and degradation .	SIGNOR-278645
Q16539	P61244	1	phosphorylation	down-regulates	0.627	Mxi2 phosphorylates max both in vitro and in vivo. Phosphorylation by mxi2 may affect the ability of max to oligomerize with itself and its partners, bind dna, or regulate gene expression.	SIGNOR-26511
P01106	P30304	1	transcriptional regulation	up-regulates quantity by expression	0.627	Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen	SIGNOR-245465
Q16619	P40189	1	binding	up-regulates	0.627	In the cos-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for ct-1 signaling	SIGNOR-46509
P63092	Q08828	1	binding	up-regulates activity	0.627	Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR	SIGNOR-156958
Q96HS1	Q8IVP5	1	dephosphorylation	up-regulates activity	0.627	Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation.	SIGNOR-273654
Q6ZNA4	P61956	1	polyubiquitination	down-regulates quantity by destabilization	0.626	Arkadia ubiquitinates poly-SUMO2 chains in a SIM- and RING-dependent manner.	SIGNOR-272882
Q6ZUJ8	P27986	1	binding	up-regulates	0.626	Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling	SIGNOR-191673
P29320	P46108	1	binding	up-regulates	0.626	Our results suggest that recruitment of crkii and activation of rho signalling are responsible for epha3-mediated cell rounding, blebbing and de-adhesion, and that ephrin-a5-mediated receptor clustering and epha3 tyrosine kinase activity are essential for this response	SIGNOR-115335
P48730	P35222	1	phosphorylation	down-regulates	0.626	However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo.	SIGNOR-87441
O94813	Q96MS0	1	binding	up-regulates activity	0.626	This observation suggests that Slit2 may require the Robo2 and Robo3 receptors in this process . Slit2 causes the miRNA miR-182 to release cofilin1 mRNA, potentiating cofilin1 local translation and resulting in growth cone collapse. The use of morpholinos or RNAi to knockdown robo2 and robo3 in X. laevis RGCs, would be useful to further confirm that Robo2 and Robo3 are the receptors involved in Slit2-dependent cofilin1 translation.	SIGNOR-268381
O00623	P51668	1	binding	up-regulates activity	0.626	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.	SIGNOR-253024
P0DP25	Q08209	1	binding	up-regulates	0.626	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266343
O00566	P46782	1	binding	up-regulates activity	0.626	Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome.	SIGNOR-261175
P14598	Q9HBY0	1	binding	up-regulates activity	0.626	Stimulus-induced phosphorylation of p47phox causes a conformational change, by which both PX and SH3 domains become accessible to their membranous targets, phosphoinositides and p22phox, respectively. Cooperation of these two interactions, each being indispensable, enables p47phox to form a stable complex with cytochrome b558 (composed of the two subunit gp91phox and p22phox), leading to activation of the phagocyte NADPH oxidase.	SIGNOR-276624
P63279	Q13485	1	sumoylation	up-regulates	0.626	The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses	SIGNOR-98997
Q16584	P45985	1	phosphorylation	up-regulates	0.625	These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo.	SIGNOR-75836
P49137	P63104	1	phosphorylation	down-regulates activity	0.625	We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. Mutation analysis showed that MAPKAPK2 phosphorylated 14-3-3zeta at Ser-58. S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1.	SIGNOR-250151
P12931	P00533	1	phosphorylation	up-regulates activity	0.625	Revealed that peptides derived from egfr residues y992, y1086, y1101, and y1148 bound directly to the sh2 domain of c-src (figure 8c). These experiments demonstrate that a specific subset of egfr receptor c-src phosphorylation sites are also ligands for the sh2 domain of c-src.Cellular src functions as a co-transducer of transmembrane signals emanating from a variety of growth factor receptors, including egfr	SIGNOR-44251

P27361

Q13480

1

phosphorylation

up-regulates activity

0.633

Our results demonstrate that ERK1/2 phosphorylate Gab1 at six serine/threonine residues (T312, S381, S454, T476, S581, S597) in consensus motifs for MAP kinase phosphorylation. |serine and threonine phosphorylation are capable of modulating the initial signal

SIGNOR-249464

P52306

P61586

1

binding

up-regulates

0.633

Smggds is a guanine nucleotide exchange factor that specifically activates rhoa and rhoc

SIGNOR-171347

P01116

O00329

1

binding

up-regulates

0.633

Grb2 binds and activates sos, which then activates ras, and this activates p110 independently of p85./it was also described that ras interacts with pi3k in a direct manner./lysine residue 227 is essential for the interaction of ras with pi3k

SIGNOR-175210

P53805

Q08209

1

binding

down-regulates activity

0.633

MCIP proteins can bind to and inhibit calcineurin, a calcium/calmodulin-regulated serine/threonine protein phosphatase that is activated during cardiac hypertrophy and failure

SIGNOR-252025

Q9H1J5

O75197

1

binding

up-regulates

0.633

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131987

P0DMV8

P04150

1

binding

down-regulates

0.633

Interestingly, FKBP51 forms complexes in mitochondria with the glucocorticoid receptor and the Hsp90/Hsp70-based chaperone heterocomplex

SIGNOR-251668

P16220

O75030

1

transcriptional regulation

up-regulates quantity by expression

0.633

Therefore, the molecular steps linking cAMPto melanogenesis up-regulation appear currently better elucidated. cAMP activates PKA, and PKA phosphorylates and activates CREB which, when activated, binds to the CRE domain present in the microphthalmia promoter,thereby up-regulating its transcription.

SIGNOR-249619

P51812

P18848

1

phosphorylation

up-regulates

0.633

Here, we show that rsk2 is required for osteoblast differentiation and function. We identify the transcription factor atf4 as a critical substrate of rsk2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression

SIGNOR-124436

P28482

P04049

1

phosphorylation

down-regulates activity

0.632

Here, we identify six residues of Raf-1 (S29, S43, S289, S296, S301, and S642) that become hyperphosphorylated in a manner coincident with Raf-1 inactivation. | Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli.|FLAG-Raf-1 phosphorylated by activated ERK2

SIGNOR-249441

Q86UR1

Q9HBY0

1

binding

up-regulates activity

0.632

Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation

SIGNOR-264711

O75122

Q15691

1

binding

up-regulates activity

0.632

GSK-3beta directly phosphorylates CLASP2 at Ser533 and Ser537 within the region responsible for the IQGAP1 binding. Phosphorylation of CLASP2 results in the dissociation of CLASP2 from IQGAP1, EB1 and microtubules.| CLASPs were originally identified as CLIP-170-interacting proteins and later found to be required for microtubule stabilisation at the cortical regions of epithelial cells

SIGNOR-264829

P56703

Q9NPG1

1

binding

up-regulates

0.632

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131820

Q13464

P53671

1

phosphorylation

up-regulates

0.632

Specific activation of lim kinase 2 via phosphorylation of threonine 505 by rock, a rho-dependent protein kinase

SIGNOR-82755

Q16828

P45983

1

dephosphorylation

down-regulates activity

0.632

Our data demonstrate MKP-3 has differential substrate preference in astrocytes compared to other cells types, since it preferentially dephosphorylated p-JNK over p-ERK.|The main findings of our studies are (1) MKP-3 preferentially reduces p-JNK over p-ERK and p-p38 in primary astrocytes; (2) This MAPK modulation pattern in primary astrocytes significantly reduced NO and completely abolished IL-6 and TNF accumulation; and (3) These effects are specifically induced by MKP-3 since block-age of MKP-3 mRNA expression reversed its action on MAPKs and pro-inflammatory mediators in BV-2 microglia cells.

SIGNOR-277150

O95393

P36894

1

binding

up-regulates

0.632

We showed that three orphan ligands known to be important for joint and cartilage formation (gdf6) (10), interneuron, sensory neurons, and seminal vesicle formation (gdf7) (11_13), and heart development (bmp10) (14) used the type i receptors alk3 or alk6 and the type ii receptors bmprii or actriia to activate the smad1/5/8 proteins.

SIGNOR-139052

P49840

O75581

1

phosphorylation

up-regulates activity

0.632

Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493

SIGNOR-275398

P12931

P46937-3

1

phosphorylation

up-regulates activity

0.632

We found that YAP1, the pivotal effector of the Hippo signaling pathway, is a direct SRC phosphorylation target, and YAP1 phosphorylation at three sites in its transcription activation domain is necessary for SRC-YAP1-mediated transformation.

SIGNOR-274025

P48736

O15530

1

binding

up-regulates

0.632

Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (pdk-1), which binds with high affinity to the pi 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (ptdins-3,4,5-p), phosphorylates and potently activates two other pi 3-kinase targets, the protein kinases akt/pkb and p70s6k.

SIGNOR-60567

P41743

Q15334

1

phosphorylation

up-regulates activity

0.632

This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner.

SIGNOR-263179

O00308

P60484

1

ubiquitination

down-regulates quantity by destabilization

0.632

We have shown that WWP2 interacts with and ubiquitylates PTEN, promoting its degradation.

SIGNOR-278650

Q99835

Q2M1P5

1

relocalization

up-regulates activity

0.632

Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins.

SIGNOR-209605

O15327

P60484

1

dephosphorylation

down-regulates activity

0.632

In support, the increase in PTEN caused by INPP4B knockdown was associated with increased phosphorylation of the Ser380, Thr382, Thr383 and Ser385 cluster of the protein (XREF_FIG), which is known to increase PTEN half-life, in colon cancer cells.|Exogenous INPP4B could pull down and dephosphorylate endogenous PTEN, suggesting that effect of INPP4B on PTEN in colon cancer cells is not due to cell-type-specific characteristics of INPP4B per se.|INPP4B downregulates PTEN in colon cancer cells.

SIGNOR-277018

Q13873

P36894

2

phosphorylation

up-regulates

0.631

Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1.

SIGNOR-180545

P14784

P23458

2

binding

up-regulates

0.631

In lymphocytes, binding of il-15 to the il-2/15rbg heterodimer induces jak1 activation that subsequently phosphorylates stat3 via the b-chain and jak3/stat5 activation via its g-chain

SIGNOR-204972

P04637

Q9UI32

1

transcriptional regulation

up-regulates quantity by expression

0.631

Glutaminase 2 (GLS2) can be directly transactivated by p53 and can therefore mediate p53-dependent regulation of cellular energy metabolism. G

SIGNOR-268041

P18031

Q9H1D0

1

dephosphorylation

down-regulates activity

0.631

In HEK293 cells, transfected with the Ca2+ channel protein TRPV6, Ca2+ influx is increased and TRPV6 is tyrosine phosphorylated following addition of the tyrosine phosphatase inhibitor|PTP1B interacts with the N-terminal domain of TRPV6 within a region of amino acids 1-191 as shown by co-immunoprecipitation, bimolecular fluorescence complementation and the yeast 2-hybrid system. Point mutation of both tyrosines 161 and 162 in the TRPV6 protein abolishes the DMHV-effect on Ca2+ influx and tyrosine phosphorylation by Src. Single mutations of Y161 or Y162 shows that each of both tyrosines alone is sufficient for the DMHV-effect. We conclude that phosphorylation/dephosphorylation of tyrosines in position 161 and 162 is essential for regulation of Ca2+ influx through TRPV6 Ca2+ channels in HEK293 cells.

SIGNOR-248433

Q99683

P45985

1

phosphorylation

up-regulates activity

0.631

A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)

SIGNOR-45373

Q7Z5L9

P14316

1

binding

up-regulates activity

0.631

We have identified two novel proteins that interact specifically with the C-terminal repression domain of Interferon Regulatory Factor-2 (IRF-2). These proteins, which we term IRF-2 binding proteins 1 and 2 (IRF-2BP1 and IRF-2BP2, the latter having two splicing isoforms, A and B), are nuclear proteins, and have the properties of IRF-2-dependent transcriptional co-repressors that can inhibit both enhancer-activated and basal transcription in a manner that is not dependent upon histone deacetylation.

SIGNOR-224073

P27361

Q00613

1

phosphorylation

down-regulates

0.631

Sequential phosphorylation of hsf1 by mitogen-activated protein kinase and glycogen synthase kinase 3 at ser-303 and ser-307 represses transcriptional activation by heat shock factor-1.

SIGNOR-44999

Q9Y4K3

Q99558

1

binding

up-regulates activity

0.631

RANK activates NF-κB by interacting with TRAF6 via a novel TRAF6 interaction motif and TRAF6 potentially activates NIK, leading to NF-κB activation. TRAF6 has been demonstrated to interact with NIK.

SIGNOR-253048

Q5H8A3

Q9GZQ4

1

binding

up-regulates

0.631

Here we identify a novel neuropeptide of 36 amino-acid residues in rat brain as an endogenous ligand for the orphan g protein-coupled receptor fm-4/tgr-1, which was identified to date as the neuromedin u (nmu) receptor, and designate this peptide 'neuromedin s (nms)' because it is specifically expressed in the suprachiasmatic nuclei (scn) of the hypothalamus.

SIGNOR-133131

P23458

P14784

2

phosphorylation

up-regulates activity

0.631

In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc.

SIGNOR-251340

P22607

P40763

1

phosphorylation

up-regulates activity

0.631

Activation of Stat1 and Stat3 by FGFR derivatives. Lysates of 293T cells transfected as indicated were analysed by Western blotting using Phospho-Stat1 (Y701) antisera (top) or Stat1 antisera (bottom). (b) The same lysates in (a) were re-examined for phosphorylated Stat3 by Western blotting with Phospho-Stat3 (Y705) (top). all three FGFR family members examined here are able to lead to Stat activation. Expression of the 'TDII-like' derivatives of FGFR1, FGFR3, and FGFR4, as well as myrR1-WT, led to phosphorylation of both Stat1 and Stat3.

SIGNOR-251139

Q15596

P10276

1

binding

up-regulates

0.631

Transcriptional coactivator for steroid receptors and nuclear receptors.nteracts with casp8ap2 and ttll5/stamp. Interacts with esr1, rara and rxra.

SIGNOR-96827

Q15831

Q13485

1

phosphorylation

down-regulates activity

0.631

LKB1 inhibits the DNA binding and the transcriptional activity of Smad4.|We further demonstrate that LKB1 is capable of phosphorylating Smad4 on Thr 77 of its DNA-binding domain.

SIGNOR-278193

Q9Y618

P41182

1

binding

up-regulates activity

0.631

The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT.

SIGNOR-252240

P36897

O95405

1

binding

up-regulates activity

0.631

Sara functions to recruit smad2 to the tgfbeta receptor by controlling the subcellular localization of smad2 and by interacting with the tgfbeta receptor complex

SIGNOR-62868

Q03113

O15085

1

binding

up-regulates activity

0.631

This RGS-like (RGL) domain provides a structural motif by which heterotrimeric G protein alpha subunits of the Galpha(12) family can bind and regulate the activity of RhoGEFs. Hence, these newly discovered RGL domain-containing RhoGEFs provide a direct link from Galpha(12) and Galpha(13) to Rho

SIGNOR-256516

P36894

Q13873

2

binding

up-regulates

0.631

Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors

SIGNOR-75652

Q02930

P15336

1

binding

up-regulates activity

0.631

CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription

SIGNOR-219655

P17693

P26715

1

binding

up-regulates

0.631

Current models of nk cell function have supposed that the cd94/nkg2a heterodimer is interacting with an epitope common to classical hla class i

SIGNOR-56714

P20393

Q99743

1

transcriptional regulation

down-regulates quantity by repression

0.631

In this study, we found that NPAS2, like BMAL1, is a direct target gene of RORα and REV-ERBα. it appears in the context of the NPAS2 promoter RORα functions as a transcriptional activator, but REV-ERBα may only function as an inhibitor of RORα activity by blocking binding.

SIGNOR-267981

Q13882

P49023

1

phosphorylation

up-regulates activity

0.63

It was also observed that the attenuation of BRK phosphorylation in turn inhibits BRK mediated activation of its direct targets, STAT3, SAM68, and Paxillin.|The EGF pathway also stimulates BRK 's phosphorylation of paxillin to promote migratory and invasive characteristics in breast cancer cells.

SIGNOR-280102

P61106

Q96T51

1

relocalization

up-regulates activity

0.63

Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.

SIGNOR-261279

Q93097

Q9NPG1

1

binding

up-regulates

0.63

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131777

Q8IVT5

P15056

1

binding

up-regulates activity

0.63

In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.

SIGNOR-273878

Q04206

P08047

1

binding

up-regulates

0.63

Rela (p65) nf-kappab subunit interacts with the zinc finger dna-binding domain of sp1.

SIGNOR-75004

P31152

Q8IW41

2

phosphorylation

up-regulates activity

0.63

ERK3, ERK4 and p38 MAPK can all phosphorylate MK5 at Thr 182 , , , - ], but it is not known whether these enzymes also can phosphorylate Ser 115 and whether this modification contributes to ERK3-, ERK4-, or p38 MAPK -regulated subcellular localization of MK5.

SIGNOR-279072

O60641

P63027

1

binding

up-regulates quantity

0.63

the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval.

SIGNOR-264112

Q9Y6Y9

P09429

1

binding

up-regulates activity

0.63

Here we demonstrate that the extracellular TLR4 adaptor, myeloid differentiation factor 2 (MD-2), binds specifically to the cytokine-inducing disulfide isoform of HMGB1, to the exclusion of other isoforms. Using MD-2-deficient mice, as well as MD-2 silencing in macrophages, we show a requirement for HMGB1-dependent TLR4 signaling.

SIGNOR-252058

O15530

Q15418

1

phosphorylation

up-regulates activity

0.63

Full-length RSK1, RSK2, and RSK3 Are Activated when Coexpressed with PDK1 in COS7 Cells. Ser221 phosphorylation is increased 2–3-fold during ERK-mediated activation of RSK1 in COS1 cells

SIGNOR-250270

Q8IW41

P31152

2

phosphorylation

up-regulates

0.63

This is due to mk5-dependent phosphorylation and only this retarded erk4 species is both phosphorylated on ser(186) and co-immunoprecipitates with wild-type mk5. We conclude that binding between erk4 and mk5 facilitates phosphorylation of ser(186) and stabilization of the erk4-mk5 complex.

SIGNOR-17069

Q13555

P42261

1

phosphorylation

up-regulates activity

0.63

In this study, CaM-kinase II enhanced kainate currents of expressed glutamate receptor 6 in 293 cells and of wild-type glutamate receptor 1, but not the Ser-627 to Ala mutant, in Xenopus oocytes. | This CaM-kinase II regulatory phosphorylation site is conserved in all AMPA/kainate-type glutamate receptors, and its phosphorylation may be important in enhancing postsynaptic responsiveness as occurs during synaptic plasticity.

SIGNOR-250697

O00548

Q9UM47

1

binding

up-regulates

0.63

These results suggest that delta1, jagged1, and jagged2 are ligands for notch1 and notch3 receptors.

SIGNOR-82398

Q00987

P98177

1

ubiquitination

down-regulates activity

0.63

Mdm2 Induces Mono-Ubiquitination of FOXO4.|higher amounts of Mdm2 transfected resulted in reduced FOXO4 transcriptional activity.

SIGNOR-278656

Q8N2H9

Q9Y4K3

1

ubiquitination

down-regulates quantity

0.63

Finally, we used coexpression studies to directly demonstrate that Pellino3 inhibits the ability of wild-type TRAF6 to stabilize HIF-1alpha but not the stabilizing effects of the K124A TRAF6 mutant that is resistant to ubiquitination.|In the present study, Pellino3 ubiquitinates TRAF6 with lysine 63-linked polyubiquitin chains to block the interaction of TRAF6 with HIF-1\u03b1.

SIGNOR-278707

Q08209

Q13469

1

dephosphorylation

up-regulates activity

0.629

NFAT1 is phosphorylated on fourteen conserved phosphoserine residues in its regulatory domain, thirteen of which are dephosphorylated upon stimulation. Dephosphorylation of all thirteen residues is required to mask a nuclear export signal (NES), cause full exposure of a nuclear localization signal (NLS), and promote transcriptional activity

SIGNOR-248690

Q96GD4

Q96FF9

1

phosphorylation

down-regulates activity

0.629

Here we show that the mitotic kinases Aurora B and Cyclin-dependent kinase 1 (Cdk1) destabilize interactions between Sororin and the cohesin subunit precocious dissociation of sisters protein 5 (Pds5) by phosphorylating Sororin, leading to release of acetylated cohesin from chromosome arms and loss of cohesion.

SIGNOR-276116

Q9UPT6

P45985

1

binding

up-regulates

0.629

Overexpression of full-length jsap1 in cos-7 cells led to a considerable enhancement of jnk3 activation, and modest enhancement of jnk1 and jnk2 activation, by the mekk1-sek1 pathwaythe regions of jsap1 that bound jnk, sek1, and mekk1 were distinct from one another. Jnk and mekk1 also bound jsap1 in vitro, suggesting that these interactions are direct.

SIGNOR-71468

Q9UNA1

P61586

1

gtpase-activating protein

down-regulates activity

0.629

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-260481

Q9UQB8

Q92558

1

binding

up-regulates

0.629

Here we demonstrate that irsp53, a substrate forinsulinreceptor with unknown function, is the 'missing link' between rac and wave. Activated rac binds to the amino terminus of irsp53, and carboxy-terminal src-homology-3 domain of irsp53 binds to wave to form a trimolecular complex.

SIGNOR-85299

Q15833

O75558

1

binding

up-regulates activity

0.629

Strikingly, addition of Munc18-2 substantially and selectively facilitates complete fusion mediated by lipid-anchored STX11 by promoting and stabilizing the assembly of SNARE complexes.

SIGNOR-261898

P22681

P09619

1

polyubiquitination

down-regulates quantity by destabilization

0.629

Overexpression of wild type Cbl in NIH3T3 cells led to an enhancement of the ligand-dependent ubiquitination and subsequent degradation of the PDGFRbeta, as observed with PDGFRalpha.

SIGNOR-272549

Q05086

P49815

1

ubiquitination

down-regulates quantity by destabilization

0.629

An in vivo ubiquitination assay was done to reveal that E6AP promoted the ubiquitination of TSC2 independent of HPV16 E6. We further found that TSC2 bound E6AP in the presence as well as in the absence of HPV16 E6. The binding regions on E6AP and TSC2 have been identified as amino acid (aa) 260-316, aa 428-500 and aa 1-175, aa 1251-1807, respectively. Taken together, degradation of TSC2 is mediated by E6AP ubiquitin ligase.

SIGNOR-271396

P63092

O60503

1

binding

up-regulates activity

0.628

Adenylyl cyclase 9 (AC9) is a membrane-bound enzyme that converts ATP into cAMP. The enzyme is weakly activated by forskolin, fully activated by the G protein Gαs subunit and is autoinhibited by the AC9 C-terminus.

SIGNOR-278883

P42574

Q9UKV3

1

cleavage

up-regulates

0.628

Induces apoptotic chromatin condensation after activation by casp3

SIGNOR-70800

P41134

P15884

1

binding

down-regulates activity

0.628

All three Ids bound with high affinity to E proteins .Each Id was able to disrupt the ability of E protein-MyoD complexes to transactivate from a muscle creatine kinase reporter construct in vivo.

SIGNOR-241385

P98170

O43353

1

ubiquitination

up-regulates activity

0.628

XIAP is the essential E3 for RIPK2 ubiquitination and interacts with RIPK2 through its baculoviral IAP-repeat (BIR).

SIGNOR-280449

O00571

P06730

1

binding

down-regulates activity

0.628

DDX3 is a human RNA helicase with plethoric functions. we identified translation initiation factor eukaryotic initiation factor 4E (eIF4E) as a DDX3-binding partner. Interestingly, DDX3 utilizes a consensus eIF4E-binding sequence YIPPHLR to interact with the functionally important dorsal surface of eIF4E in a similar manner to other eIF4E-binding proteins. Furthermore, cap affinity chromatography analysis suggests that DDX3 traps eIF4E in a translationally inactive complex by blocking interaction with eIF4G.

SIGNOR-269193

P28482

P17655

1

phosphorylation

up-regulates

0.628

Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo.

SIGNOR-123079

P28482

P15056

1

phosphorylation

down-regulates activity

0.628

Erk-induced phosphorylation of b-raf on t753 promoted the disassembly of raf heterodimers, and the mutation of t753 prolonged growth factor-induced heterodimerization. The b-raf t753a mutant enhanced differentiation of pc12 cells, which was previously shown to be dependent on sustained erk signaling. Site is critical for v-src dependent modulation of slk kinase activity.

SIGNOR-236388

Q9Y6F9

Q9NPG1

1

binding

up-regulates

0.628

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131891

P15514

P04626

1

phosphorylation

up-regulates

0.628

Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor

SIGNOR-31199

Q9HBE5

P23458

1

binding

up-regulates

0.628

Retroviral-mediated transduction of wild-type gamma c into xscid jt cells restored function to the il-21r, as shown by il-21-induced tyrosine phosphorylation of jak1 and jak3, and downstream activation of stat5

SIGNOR-90266

P53779

P04637

1

phosphorylation

up-regulates

0.628

The targets of jnk include the transcription factors p53. P75ntr-mediated apoptosis was shown to be dependent of p53

SIGNOR-120552

P03372

P27986

1

binding

up-regulates

0.628

Recently, it has been known that er activates phosphatidylinositol-3-oh kinase (pi3k) through binding with the p85 regulatory subunit of pi3k.

SIGNOR-140470

P04628

Q9NPG1

1

binding

up-regulates activity

0.628

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131571

Q5T5U3

P61586

1

gtpase-activating protein

down-regulates activity

0.628

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-260475

Q15831

P54646

1

phosphorylation

up-regulates

0.627

We demonstrated that lkb1 phosphorylates ampk on the activation loop threonine (thr172) within the catalytic subunit and activates ampk in vitro. Here, we have investigated whether lkb1 corresponds to the major ampkk activity present in cell extracts. Ampkk purified from rat liver corresponds to lkb1, and blocking lkb1 activity in cells abolishes ampk activation in response to different stimuli

SIGNOR-122725

Q12778

P46527

1

transcriptional regulation

up-regulates quantity by expression

0.627

To date , we have found that TNC regulates the transcriptional activity of FOXO1. And p27Kip1 is one of the transcriptional targets of FOXO1 (Fig. 5A). We speculated that TNC could regulate the binding of FOXO1 to the CDKN1B promoter.

SIGNOR-277739

O00548

P46531

1

binding

up-regulates activity

0.627

Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate.

SIGNOR-209732

Q9UNE7

P04626

1

ubiquitination

down-regulates quantity by destabilization

0.627

The ErbB2 kinase domain is required for GA-induced and CHIP-dependent ErbB2 ubiquitination and degradation .

SIGNOR-278645

Q16539

P61244

1

phosphorylation

down-regulates

0.627

Mxi2 phosphorylates max both in vitro and in vivo. Phosphorylation by mxi2 may affect the ability of max to oligomerize with itself and its partners, bind dna, or regulate gene expression.

SIGNOR-26511

P01106

P30304

1

transcriptional regulation

up-regulates quantity by expression

0.627

Expression of Cdc25A is transcriptionally regulated by Myc and E2F-1 , both of which are expressed in MCF-7 cells in response to estrogen

SIGNOR-245465

Q16619

P40189

1

binding

up-regulates

0.627

In the cos-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for ct-1 signaling

SIGNOR-46509

P63092

Q08828

1

binding

up-regulates activity

0.627

Because adenylyl cyclases are directly activated by G(s)alpha and the carboxyl termini of the various Galpha proteins determine their receptor coupling specificity, we proposed a set of chimeric G(s)alpha where the COOH-terminal five amino acids are replaced by those of other Galpha proteins and used these to dissect the potential Galpha linked to a given GPCR

SIGNOR-156958

Q96HS1

Q8IVP5

1

dephosphorylation

up-regulates activity

0.627

Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation.

SIGNOR-273654

Q6ZNA4

P61956

1

polyubiquitination

down-regulates quantity by destabilization

0.626

Arkadia ubiquitinates poly-SUMO2 chains in a SIM- and RING-dependent manner.

SIGNOR-272882

Q6ZUJ8

P27986

1

binding

up-regulates

0.626

Bcap is constitutively phosphorylated and associated with the p85 subunit of pi3k in macrophages. Tlr signaling causes the phosphorylation of the small amount of bcap that is associated with membranes in the resting state or the translocation of phosphorylated bcap from the cytoplasm to the membrane. This accumulation of tyrosine-phosphorylated bcap at the membrane with its associated pi3k would then allow for the catalysis of ptd ins p2 to ptd ins p3 and downstream pi3k-dependent signals. Bcap is an essential activator of the pi3k pathway downstream of tlr signaling

SIGNOR-191673

P29320

P46108

1

binding

up-regulates

0.626

Our results suggest that recruitment of crkii and activation of rho signalling are responsible for epha3-mediated cell rounding, blebbing and de-adhesion, and that ephrin-a5-mediated receptor clustering and epha3 tyrosine kinase activity are essential for this response

SIGNOR-115335

P48730

P35222

1

phosphorylation

down-regulates

0.626

However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo.

SIGNOR-87441

O94813

Q96MS0

1

binding

up-regulates activity

0.626

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

SIGNOR-268381

O00623

P51668

1

binding

up-regulates activity

0.626

Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.

SIGNOR-253024

P0DP25

Q08209

1

binding

up-regulates

0.626

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

SIGNOR-266343

O00566

P46782

1

binding

up-regulates activity

0.626

Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome.

SIGNOR-261175

P14598

Q9HBY0

1

binding

up-regulates activity

0.626

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

SIGNOR-276624

P63279

Q13485

1

sumoylation

up-regulates

0.626

The mh1 domain of smad4 was shown to associate physically with ubc9, the ubiquitin carrier protein (e2) conjugating enzyme in sumoylation. In cultured cells, smad4 is modified by sumo-1 at the endogenous level. The sumoylation sites were identified as two evolutionarily conserved lysine residues, lys-113 and lys-159, in the mh1 domain. We found that the mutations at lys-113 and lys-159 did not alter the ability of smad4 to form a complex with smad2 and fast on the mix.2 promoter. Importantly, sumo-1 overexpression enhanced tgf-beta-induced transcriptional responses. These findings identify sumoylation as a unique mechanism to modulate smad4-dependent cellular responses

SIGNOR-98997

Q16584

P45985

1

phosphorylation

up-regulates

0.625

These data suggest that mlk-3 phosphorylates sek1 directly and that it does so specifically on those residues known to activate sek1 in vivo.

SIGNOR-75836

P49137

P63104

1

phosphorylation

down-regulates activity

0.625

We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. Mutation analysis showed that MAPKAPK2 phosphorylated 14-3-3zeta at Ser-58. S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1.

SIGNOR-250151

P12931

P00533

1

phosphorylation

up-regulates activity

0.625

Revealed that peptides derived from egfr residues y992, y1086, y1101, and y1148 bound directly to the sh2 domain of c-src (figure 8c). These experiments demonstrate that a specific subset of egfr receptor c-src phosphorylation sites are also ligands for the sh2 domain of c-src.Cellular src functions as a co-transducer of transmembrane signals emanating from a variety of growth factor receptors, including egfr

SIGNOR-44251