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
Q93009	P62987	1	cleavage	up-regulates quantity	0.735	Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.	SIGNOR-270823
P55212	Q14790	2	cleavage	up-regulates	0.735	This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8.	SIGNOR-109411
P17706	P40763	1	dephosphorylation	down-regulates	0.735	The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation.	SIGNOR-90818
P07900	P04150	1	binding	down-regulates	0.735	We report the crucial underlying role of the intranuclear heat shock protein 90 molecular chaperone complex in pulsatile GR regulation. Pharmacological interference of heat shock protein 90 (HSP90) with geldanamycin during the intranuclear chaperone cycle completely ablated GR's cyclical activity, cyclical cAMP response element-binding protein (CREB) binding protein (CBP)/p300 recruitment, and the associated cyclical acetylation at the promoter region.	SIGNOR-251667
P14174	P04233	1	binding	up-regulates	0.735	Mif binds to the extracellular domain of cd74, and cd74 is required for mif-induced activation of the extracellular signal-regulated kinase-1/2 map kinase cascade, cell proliferation, and pge2 production.	SIGNOR-101526
Q13976	P50552	1	phosphorylation	down-regulates activity	0.735	Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts	SIGNOR-268289
P24941	P49736	1	phosphorylation	up-regulates	0.735	In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2	SIGNOR-144000
Q96Q42	P20339	1	binding	up-regulates activity	0.735	ALS2 activates Rab5 on macropinosomes. Rab5 is activated and concurrently recruited to macropinosomes during ruffle closure. ALS2 depletion abolishes transient Rab5 activation on macropinosomes, while ALS2 is recruited to macropinosomes simultaneously with Rab5 activation. Thus, we conclude ALS2 activates Rab5 on macropinosomes.	SIGNOR-277776
Q14790	P55212	2	cleavage	up-regulates	0.735	Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them.	SIGNOR-59857
Q13144	P41091	1	guanine nucleotide exchange factor	up-regulates activity	0.735	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-269133
Q14185	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.735	We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth.	SIGNOR-266822
P28482	P01106	1	phosphorylation	up-regulates activity	0.735	Transactivation of gene expression by myc is inhibited by mutation at the phosphorylation sites thr-58 and ser-62.	SIGNOR-235700
P29350	P07948	2	dephosphorylation	down-regulates activity	0.734	SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation\|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397	SIGNOR-248471
P06241	Q12879	1	phosphorylation	up-regulates activity	0.734	To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain.	SIGNOR-247151
P42574	Q13464	1	cleavage	up-regulates	0.734	Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity.	SIGNOR-106546
Q4VCS5	P46937	1	relocalization	down-regulates	0.734	Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms.	SIGNOR-175779
P17706	P42224	1	dephosphorylation	down-regulates activity	0.734	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-133279
Q92844	Q12933	1	binding	down-regulates activity	0.734	IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex	SIGNOR-262714
P01024	Q16581	1	binding	up-regulates activity	0.734	A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells\|The cDNA clone contained an insert of 4.3 kbp and was able to confer to transfected human HEK-293 cells the capacity to bind specifically iodinated human C3a.	SIGNOR-263451
O95631	O60469	1	binding	up-regulates activity	0.734	Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1.	SIGNOR-268376
O14757	O00311	1	phosphorylation	up-regulates	0.734	Chk1 directly phosphorylates essential s-phase kinases cdc7.	SIGNOR-163161
P07948	P29350	2	phosphorylation	up-regulates activity	0.734	Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity.	SIGNOR-251409
P46108	Q05397	1	phosphorylation	up-regulates activity	0.733	Tyrosine phosphorylation FAK was strictly dependent upon c-Crk II expression \| Crk-inducible FAK tyrosine phosphorylation was completely abrogated by co-expression with R38K Crk (lane 2), and decreased by co-expression with W170K Crk (lane 3), indicating that the SH2 domain of c-Crk is absolutely essential for this effect. In contrast, mutants in the C-terminus of Crk that include Y222F c-Crk, which abrogates the c-Abl phosphorylation site, and W276K Crk, which mutates the C-terminal SH3 domain, modestly increased FAK activation compared to wild-type c-Crk II.	SIGNOR-250777
Q00987	O15151	2	ubiquitination	down-regulates	0.733	The mdm2 homolog mdmx is an important regulator of p53 during mouse embryonic development. Dna damage promotes mdmx phosphorylation, nuclear translocation, and degradation by mdm2.	SIGNOR-144970
Q8IUC6	Q13546	1	binding	up-regulates activity	0.733	TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation.	SIGNOR-216313
P28482	P15336	1	phosphorylation	up-regulates	0.733	Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.	SIGNOR-90517
P17706	P51692	1	dephosphorylation	down-regulates activity	0.733	In the previous study, we demonstrated that the nuclear isoform of T-cell protein-tyrosine phosphatase (TC-PTP) dephosphorylated and deactivated signal transducer and activator of transcription 5a (STAT5a) and STAT5b, thereby negatively regulating prolactin (PRL)-mediated signaling pathway.	SIGNOR-277126
P04049	P36507	1	phosphorylation	up-regulates	0.733	To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1.	SIGNOR-36553
Q9Y4P8	Q676U5	1	binding	up-regulates quantity	0.733	WIPI1 assists WIPI2 in recruiting ATG16L for LC3 lipidation. WIPI1-WIPI2 heterodimer may function more efficiently in ATG16L complex recruitment.	SIGNOR-268478
O15151	Q00987	2	binding	up-regulates quantity by stabilization	0.733	MDM2 has been shown to be degraded by the ubiquitin-proteasome pathway, while MDMX was a stable protein. Interaction of MDMX with MDM2 through the C-terminal RING finger domains resulted in inhibiting degradation of MDM2. These data indicate that MDMX functions as a regulator of MDM2.	SIGNOR-272932
O00206	Q86XR7	1	binding	up-regulates	0.733	Mappit analysis of early toll-like receptor signalling events.	SIGNOR-160424
P17706	P42229	1	dephosphorylation	down-regulates activity	0.733	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-133547
P22681	P08581	1	ubiquitination	down-regulates quantity by destabilization	0.732	Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation	SIGNOR-185680
Q9P0J1	P08559	1	dephosphorylation	up-regulates activity	0.732	Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism	SIGNOR-252055
P31749	O14746	1	phosphorylation	up-regulates	0.732	Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins.	SIGNOR-67313
P36894	Q15797	1	phosphorylation	up-regulates activity	0.732	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255263
O15530	P31751	1	phosphorylation	up-regulates activity	0.732	Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation.	SIGNOR-134485
P06241	P29353	1	phosphorylation	up-regulates	0.732	Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2.	SIGNOR-59623
P05067	Q13564	1	binding	up-regulates activity	0.732	Alzheimer's disease (AD) is the gradual loss of the cognitive function due to neuronal death. Currently no therapy is available to slow down, reverse or prevent the disease. Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis.	SIGNOR-251577
O14713	P05556	1	binding	down-regulates activity	0.732	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257638
Q9Y4K3	Q92985	1	ubiquitination	up-regulates activity	0.732	We have shown that TRAF6 E3 ligase promotes IRF7 K63-linked ubiquitination that is required for EBV LMP1 activation of IRF7 [ xref ]; however, A20, a member with both E3 ligase and deubiquitinase activities in the OTU family, inhibits LMP1-stimulated IRF7 activity by acting as a deubiquitinase [ xref ].	SIGNOR-278788
Q16288	P29353	1	binding	up-regulates	0.732	We demonstrate that the phosphotyrosine binding domain of frs-2 directly binds the trk receptors at the same phosphotyrosine residue that binds the signaling adapter shc, suggesting a model in which competitive binding between frs-2 and shc regulates differentiation versus proliferation.	SIGNOR-65958
Q76I76	P23528	1	dephosphorylation	up-regulates activity	0.732	Differential activities, subcellular distribution and tissue expression patterns of three members of Slingshot family phosphatases that dephosphorylate cofilin.\|Cofilin, a key regulator of actin filament dynamics, is inactivated by phosphorylation at Ser-3 by LIM-kinases and is reactivated by dephosphorylation by a family of protein phosphatases, termed Slingshot (SSH).	SIGNOR-248733
O14543	P23458	1	binding	down-regulates activity	0.732	SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition	SIGNOR-253051
Q00535	P04637	1	phosphorylation	up-regulates	0.732	We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active	SIGNOR-156422
O15524	P23458	1	binding	down-regulates	0.732	Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna.	SIGNOR-202042
P10767	P22455	1	binding	up-regulates	0.732	Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.	SIGNOR-18570
P17252	P31431	1	phosphorylation	up-regulates activity	0.732	The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant.	SIGNOR-249149
Q13464	P15311	1	phosphorylation	up-regulates	0.732	Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. We performed an in vitro kinase assay with 80 selected kinases on an ezrin peptide containing the t567 phosphorylation site (figure 3a). In this screen, we identified the mst and rock kinases as the most potent kinases for the ezrin peptide	SIGNOR-185567
Q96GX5	O43768	1	phosphorylation	up-regulates activity	0.732	We identified cyclic adenosine monophosphateregulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry.	SIGNOR-243690
Q9H0M0	O15105	1	relocalization	up-regulates activity	0.731	We found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor.	SIGNOR-126578
P27361	O43521	1	phosphorylation	down-regulates quantity by destabilization	0.731	In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel	SIGNOR-129878
Q9Y6X2	P40763	1	sumoylation	down-regulates	0.731	Stat3 mediated signaling pathways can be inhibited by pias3 (protein inhibitor of activated stat3), which was recently found to regulate protein stability and function by its sumo (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins.	SIGNOR-124723
Q9H4B4	P30307	1	phosphorylation	up-regulates	0.731	Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation	SIGNOR-122090
P28289	P06753	1	binding	down-regulates activity	0.731	Tropomodulin is a 40.6-kDa protein that binds to one end of the rod-like tropomyosin and inhibits its cooperativity and binding to actin. [.] we demonstrate that it is the N-terminus of tropomyosin that interacts with tropomodulin. Among several tropomyosin isoforms tested, hTM5 encoded by the human gamma-tropomyosin gene has the highest affinity toward human erythrocyte tropomodulin.	SIGNOR-259111
Q06124	Q05397	1	dephosphorylation	down-regulates	0.731	Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner.	SIGNOR-148926
Q96GD4	Q99661	1	phosphorylation	up-regulates	0.731	Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres.	SIGNOR-155890
P84022	P15172	1	binding	down-regulates activity	0.731	We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors.	SIGNOR-252071
P49841	P49815	1	phosphorylation	up-regulates activity	0.731	Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation.	SIGNOR-149380
Q16619	P42702	1	binding	up-regulates	0.731	We conclude that gp130/lif receptor and et(a) receptor activation are essential for cardiac fibroblast growth by ct-1	SIGNOR-114758
O75582	P16220	1	phosphorylation	up-regulates	0.731	Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb.	SIGNOR-59458
P53350	Q9Y266	1	phosphorylation	up-regulates activity	0.73	Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites.	SIGNOR-103403
P17252	P29966	1	phosphorylation	down-regulates activity	0.73	Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin	SIGNOR-249650
Q96CW9	Q9HBW1	1	binding	up-regulates activity	0.73	The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.	SIGNOR-264048
Q96GX5	P56211	1	phosphorylation	up-regulates activity	0.73	We identified cyclic adenosine monophosphateregulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry.	SIGNOR-243611
P08575	P06241	1	dephosphorylation	up-regulates activity	0.73	On the membrane SKAP55, via its phosphorylated Tyr-271, further binds the SH2 domain of Fyn to replace the low-affinity bound inhibitory site of the kinase. Consequently, CD45 may have transiently disassociated with the Tyr-232 residue of SKAP55 through dephosphorylation and simultaneously interacted with the released the phosphorylated inhibitory tyrosine residue of Fyn for dephosphorylation, resulting in activation of the Src family kinase Fyn and initiation of TCR-engaged signal transduction.	SIGNOR-248352
P14778	Q9NPH3	2	binding	up-regulates activity	0.73	Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)	SIGNOR-251981
O60664	P20645	1	relocalization	up-regulates activity	0.73	TIP47 is present in cytosol and on endosomes and is required for MPR transport from endosomes to the trans-Golgi network in vitro and in vivo. TIP47 recognizes a phenylalanine/tryptophan signal in the tail of the cation-dependent MPR that is essential for its proper sorting within the endosomal pathway. These data suggest that TIP47 binds MPR cytoplasmic domains and facilitates their collection into transport vesicles destined for the Golgi.	SIGNOR-253093
O76093	P21802	1	binding	up-regulates	0.73	Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes	SIGNOR-42368
Q9NPH3	P14778	2	binding	up-regulates	0.73	Here we report that the soluble form of the il-1 receptor accessory protein (acp) increases the affinity of binding of human il-1alpha and il-1beta to the soluble human type ii il-1 receptor by approximately 100-fold,	SIGNOR-97396
P27361	P51812	1	phosphorylation	up-regulates	0.73	We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway	SIGNOR-81460
O75096	O15146	1	binding	up-regulates activity	0.73	AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer.	SIGNOR-273850
P51617	Q8N2H9	2	phosphorylation	up-regulates	0.729	Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity.	SIGNOR-103983
P45985	P45984	1	phosphorylation	up-regulates	0.729	Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. 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) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)	SIGNOR-197998
Q9Y4K3	Q9Y6Q6	1	binding	up-regulates activity	0.729	TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation.	SIGNOR-253045
P31751	P49815	1	phosphorylation	down-regulates	0.729	We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex.	SIGNOR-91041
P17676	P37231	1	transcriptional regulation	up-regulates quantity	0.729	Induction of C/EBP beta DNA-binding activity in NIH-3T3 beta 2 cells exposed to dexamethasone in the presence of insulin and fetal bovine serum activates the expression of an adipocyte-specific nuclear hormone receptor, PPAR gamma, that stimulates the conversion of these fibroblasts into committed preadipocytes	SIGNOR-255730
P31749	Q99683	1	phosphorylation	down-regulates activity	0.729	Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1.	SIGNOR-252465
P29350	O60674	1	dephosphorylation	down-regulates activity	0.729	Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1	SIGNOR-248466
Q8N2H9	P51617	2	ubiquitination	up-regulates	0.729	These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4.	SIGNOR-159061
Q6PGQ7	O14965	1	binding	up-regulates	0.729	Both drosophila and human bora can bind to aurora-a and activate the kinase in vitro.	SIGNOR-148661
Q13233	P45985	1	phosphorylation	up-regulates activity	0.729	The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1	SIGNOR-236380
P31749	P22736	1	phosphorylation	down-regulates activity	0.729	We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350	SIGNOR-252466
Q5H8A3	Q9HB89	1	binding	up-regulates	0.729	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-133074
Q13492	P53675	1	binding	up-regulates	0.729	Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro	SIGNOR-144733
P53350	Q9BQQ3	1	phosphorylation	down-regulates quantity	0.729	As GRASP65 is a substrate of cdc2 and polo-like kinase, manipulation of GRASP65 level may affect the localization and activity of these kinases in cell cycle progression, as suggested by a previous study ( ).\|During mitosis, GRASP65 is phosphorylated by two mitotic kinases, cdc2 and polo-like kinase (plk), which leads to GRASP65 deoligomerization and thus Golgi unstacking ( xref , xref ).	SIGNOR-279554
Q96F81	Q15465	1	binding	up-regulates activity	0.729	We show that the vertebrate homologue, dispatched-a (dispa) interacts with human sonic hedgehog (hshh) via its cholesterol anchor, and that this interaction is necessary for hshh secretion. binding to dispa is necessary but not sufficient for hshh secretion	SIGNOR-191888
P42681	Q13094	1	phosphorylation	up-regulates	0.728	Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function	SIGNOR-44669
P28482	P51812	1	phosphorylation	up-regulates	0.728	Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.	SIGNOR-161518
Q9NRM7	Q9Y2J4	2	phosphorylation	down-regulates activity	0.728	The N-terminal regions of Amot proteins contain a conserved HXRXXS consensus site for LATS1/2-mediated phosphorylation.\|Amot family members. Knockdown of LATS1 and LATS2 endogenously reduced the phosphorylation of Amots detected by the phospho-specific antibodies. Mutation of the serine to alanine within this HXRXXS site in Amot and AmotL2 established that this site was essential for Hippo core kinase-mediated phosphorylation. Wild-type and non-phosphorylated Amot (Amot-S175A) were targeted to actin filaments, whereas phospho-mimic Amot (Amot-S175D) failed to be localized with actin.	SIGNOR-272084
P46734	Q16539	1	phosphorylation	up-regulates activity	0.728	Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase.	SIGNOR-232156
Q9UNE7	P11142	1	polyubiquitination	down-regulates quantity by destabilization	0.728	BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association	SIGNOR-272588
P19525	P05198	1	phosphorylation	down-regulates activity	0.728	Besides PERK, eIF2Î± can also be phosphorylated by three other kinases: heme-regulated inhibitor kinase (HRI), general control nonderepressible 2 (GCN2), and PKR. PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. Together, these four eIF2Î± kinases and their convergent downstream signaling pathways are known as the integrated stress response (ISR)	SIGNOR-260168
Q9H461	O75197	1	binding	up-regulates activity	0.728	Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate WntBeta-catenin signaling.	SIGNOR-169635
P61962	Q9Y463	1	binding	up-regulates activity	0.728	Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions.	SIGNOR-260631
Q9Y2J4	Q9NRM7	2	relocalization	up-regulates activity	0.728	Ubiquitinated AMOTL2 then serves as a physical docking site for LATS2, which phosphorylates YAP to promote its cytoplasmic retention and degradation.	SIGNOR-271875
P12755	P84022	1	binding	down-regulates activity	0.728	Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling.	SIGNOR-232123
P05000	P17181	1	binding	up-regulates	0.728	Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.	SIGNOR-105979
Q9UBN6	P50591	1	binding	down-regulates	0.728	One function of trail-r4 may be inhibition of trail cytotoxicy. Dcr2 functions as an inhibitory apo2l receptor.	SIGNOR-53447
P49841	P04637	1	phosphorylation	up-regulates activity	0.728	Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity.	SIGNOR-251258

Q93009

P62987

1

cleavage

up-regulates quantity

0.735

Here we provide data suggesting that two of the four mammalian ubiquitin precursors, UBA52 and UBA80, are processed mostly post-translationally whereas the other two, UBB and UBC, probably undergo a combination of co- and post-translational processing. Using an unbiased biochemical approach we found that UCHL3, USP9X, USP7, USP5 and Otulin/Gumby/FAM105b are by far the most active DUBs acting on these precursors.

SIGNOR-270823

P55212

Q14790

2

cleavage

up-regulates

0.735

This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8.

SIGNOR-109411

P17706

P40763

1

dephosphorylation

down-regulates

0.735

The nuclear isoform of protein-tyrosine phosphatase tc-ptp regulates interleukin-6-mediated signaling pathway through stat3 dephosphorylation.

SIGNOR-90818

P07900

P04150

1

binding

down-regulates

0.735

We report the crucial underlying role of the intranuclear heat shock protein 90 molecular chaperone complex in pulsatile GR regulation. Pharmacological interference of heat shock protein 90 (HSP90) with geldanamycin during the intranuclear chaperone cycle completely ablated GR's cyclical activity, cyclical cAMP response element-binding protein (CREB) binding protein (CBP)/p300 recruitment, and the associated cyclical acetylation at the promoter region.

SIGNOR-251667

P14174

P04233

1

binding

up-regulates

0.735

Mif binds to the extracellular domain of cd74, and cd74 is required for mif-induced activation of the extracellular signal-regulated kinase-1/2 map kinase cascade, cell proliferation, and pge2 production.

SIGNOR-101526

Q13976

P50552

1

phosphorylation

down-regulates activity

0.735

Vertebrate Ena/VASP proteins are phosphorylated by PKA, as well as PKG, and the phosphorylation is required for full function in a number of cellular contexts

SIGNOR-268289

P24941

P49736

1

phosphorylation

up-regulates

0.735

In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2

SIGNOR-144000

Q96Q42

P20339

1

binding

up-regulates activity

0.735

ALS2 activates Rab5 on macropinosomes. Rab5 is activated and concurrently recruited to macropinosomes during ruffle closure. ALS2 depletion abolishes transient Rab5 activation on macropinosomes, while ALS2 is recruited to macropinosomes simultaneously with Rab5 activation. Thus, we conclude ALS2 activates Rab5 on macropinosomes.

SIGNOR-277776

Q14790

P55212

2

cleavage

up-regulates

0.735

Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them.

SIGNOR-59857

Q13144

P41091

1

guanine nucleotide exchange factor

up-regulates activity

0.735

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-269133

Q14185

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.735

We found in this study that AUTS2 is involved in Rac1 activation via P-Rex1 and the Elmo2/Dock180 complex, but not STEF or Tiam1, for the lamellipodia formation in N1E-115 cells. However, the enhancement of neurite elongation in primary neurons by AUTS2 expression is specifically mediated by the Elmo2/Dock180 complex. These results suggested that several Rac-GEFs differentially or cooperatively participate in Rac1 activation to promote neuronal migration and neurite outgrowth.

SIGNOR-266822

P28482

P01106

1

phosphorylation

up-regulates activity

0.735

Transactivation of gene expression by myc is inhibited by mutation at the phosphorylation sites thr-58 and ser-62.

SIGNOR-235700

P29350

P07948

2

dephosphorylation

down-regulates activity

0.734

SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397

SIGNOR-248471

P06241

Q12879

1

phosphorylation

up-regulates activity

0.734

To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain.

SIGNOR-247151

P42574

Q13464

1

cleavage

up-regulates

0.734

Rock i is cleaved by casp3 at a conserved detd1113/g sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity.

SIGNOR-106546

Q4VCS5

P46937

1

relocalization

down-regulates

0.734

Yap/taz and angiomotin (amot) family proteins were shown to interact, resulting in yap/taz localization to tight junctions and inhibition through phosphorylation-dependent and -independent mechanisms.

SIGNOR-175779

P17706

P42224

1

dephosphorylation

down-regulates activity

0.734

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-133279

Q92844

Q12933

1

binding

down-regulates activity

0.734

IKK-i phosphorylates I-TRAF. In vitro kinase assays demonstrate that IKK‐i phosphorylates I‐TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I‐TRAF/TRAF2 complex after I‐TRAF phosphorylation. TRAF2 isdistributed throughout the cytoplasm, in the formof inactive an I-TRAF/TRAF2 complex

SIGNOR-262714

P01024

Q16581

1

binding

up-regulates activity

0.734

A cDNA clone encoding the human C3a anaphylatoxin receptor (C3aR) was isolated from a pcDNAI/Amp expression library prepared from U-937 cells|The cDNA clone contained an insert of 4.3 kbp and was able to confer to transfected human HEK-293 cells the capacity to bind specifically iodinated human C3a.

SIGNOR-263451

O95631

O60469

1

binding

up-regulates activity

0.734

Here, we report that the Down's syndrome Cell Adhesion Molecule (DSCAM), a candidate gene implicated in the mental retardation phenotype of Down's syndrome, is expressed on spinal commissural axons, binds netrin-1, and is necessary for commissural axons to grow toward and across the midline. DSCAM and DCC can each mediate a turning response of these neurons to netrin-1.

SIGNOR-268376

O14757

O00311

1

phosphorylation

up-regulates

0.734

Chk1 directly phosphorylates essential s-phase kinases cdc7.

SIGNOR-163161

P07948

P29350

2

phosphorylation

up-regulates activity

0.734

Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity.

SIGNOR-251409

P46108

Q05397

1

phosphorylation

up-regulates activity

0.733

Tyrosine phosphorylation FAK was strictly dependent upon c-Crk II expression | Crk-inducible FAK tyrosine phosphorylation was completely abrogated by co-expression with R38K Crk (lane 2), and decreased by co-expression with W170K Crk (lane 3), indicating that the SH2 domain of c-Crk is absolutely essential for this effect. In contrast, mutants in the C-terminus of Crk that include Y222F c-Crk, which abrogates the c-Abl phosphorylation site, and W276K Crk, which mutates the C-terminal SH3 domain, modestly increased FAK activation compared to wild-type c-Crk II.

SIGNOR-250777

Q00987

O15151

2

ubiquitination

down-regulates

0.733

The mdm2 homolog mdmx is an important regulator of p53 during mouse embryonic development. Dna damage promotes mdmx phosphorylation, nuclear translocation, and degradation by mdm2.

SIGNOR-144970

Q8IUC6

Q13546

1

binding

up-regulates activity

0.733

TRIF also recruits the adaptor RIP1 through the distinct RIP homotypic interaction motif. RIP1 undergoes K63-linked polyubiquitination after stimulation by TLR3 agonists, and this modification is required for NF-_B activation.

SIGNOR-216313

P28482

P15336

1

phosphorylation

up-regulates

0.733

Here, we show that in fibroblasts, insulin, epidermal growth factor (egf) and serum activate atf2 via a so far unknown two-step mechanism involving two distinct ras effector pathways: the raf-mek-erk pathway induces phosphorylation of atf2 thr71, whereas subsequent atf2 thr69 phosphorylation requires the ral-ralgds-src-p38 pathway.

SIGNOR-90517

P17706

P51692

1

dephosphorylation

down-regulates activity

0.733

In the previous study, we demonstrated that the nuclear isoform of T-cell protein-tyrosine phosphatase (TC-PTP) dephosphorylated and deactivated signal transducer and activator of transcription 5a (STAT5a) and STAT5b, thereby negatively regulating prolactin (PRL)-mediated signaling pathway.

SIGNOR-277126

P04049

P36507

1

phosphorylation

up-regulates

0.733

To understand the mechanism of activation of MAPKK, we have identified Ser217 and Ser221 of MAPKK1 as the sites phosphorylated by p74raf-1.

SIGNOR-36553

Q9Y4P8

Q676U5

1

binding

up-regulates quantity

0.733

WIPI1 assists WIPI2 in recruiting ATG16L for LC3 lipidation. WIPI1-WIPI2 heterodimer may function more efficiently in ATG16L complex recruitment.

SIGNOR-268478

O15151

Q00987

2

binding

up-regulates quantity by stabilization

0.733

MDM2 has been shown to be degraded by the ubiquitin-proteasome pathway, while MDMX was a stable protein. Interaction of MDMX with MDM2 through the C-terminal RING finger domains resulted in inhibiting degradation of MDM2. These data indicate that MDMX functions as a regulator of MDM2.

SIGNOR-272932

O00206

Q86XR7

1

binding

up-regulates

0.733

Mappit analysis of early toll-like receptor signalling events.

SIGNOR-160424

P17706

P42229

1

dephosphorylation

down-regulates activity

0.733

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-133547

P22681

P08581

1

ubiquitination

down-regulates quantity by destabilization

0.732

Tyrosine y1001, which when phosphorylated upon met activation, is involved in cbl recruitment, allowing receptor ubiquitination and down regulation

SIGNOR-185680

Q9P0J1

P08559

1

dephosphorylation

up-regulates activity

0.732

Sites 1, 2, and 3 were dephosphorylated either individually or in the presence of the other sites by the phospho-E1-phosphatase resulting in complete reactivation of the E1. The rates of dephosphorylation and reactivation were similar for sites 1, 2, and 3, indicating a random dephosphorylation mechanism

SIGNOR-252055

P31749

O14746

1

phosphorylation

up-regulates

0.732

Akt kinase enhances human telomerase activity through phosphorylation of htert subunit as one of its substrate proteins.

SIGNOR-67313

P36894

Q15797

1

phosphorylation

up-regulates activity

0.732

Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.

SIGNOR-255263

O15530

P31751

1

phosphorylation

up-regulates activity

0.732

Akt1 and akt2 are phosphorylated and activated by the protein kinase pdk1 at thr-308 or thr-309, respectively, in the activation t-loop, and further activation occurs through phosphorylation at ser-473 or ser-474, respectively. Pdk1 phosphorylates akt-2 at thr 309 in the catalytic domain, leading to enzymatic activation.

SIGNOR-134485

P06241

P29353

1

phosphorylation

up-regulates

0.732

Syk and zap-70 were able to phosphorylate the y239 and y240 sites, and less efficiently the y317 site. Of the two potential grb2 binding sites (y239 and y317), y239 appears to play a greater role in recruiting sos through grb2.

SIGNOR-59623

P05067

Q13564

1

binding

up-regulates activity

0.732

Alzheimer's disease (AD) is the gradual loss of the cognitive function due to neuronal death. Currently no therapy is available to slow down, reverse or prevent the disease. Here we analyze the existing data in literature and hypothesize that the physiological function of the Amyloid Precursor Protein (APP) is activating the AppBp1 pathway and this function is gradually lost during the progression of AD pathogenesis.

SIGNOR-251577

O14713

P05556

1

binding

down-regulates activity

0.732

Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation

SIGNOR-257638

Q9Y4K3

Q92985

1

ubiquitination

up-regulates activity

0.732

We have shown that TRAF6 E3 ligase promotes IRF7 K63-linked ubiquitination that is required for EBV LMP1 activation of IRF7 [ xref ]; however, A20, a member with both E3 ligase and deubiquitinase activities in the OTU family, inhibits LMP1-stimulated IRF7 activity by acting as a deubiquitinase [ xref ].

SIGNOR-278788

Q16288

P29353

1

binding

up-regulates

0.732

We demonstrate that the phosphotyrosine binding domain of frs-2 directly binds the trk receptors at the same phosphotyrosine residue that binds the signaling adapter shc, suggesting a model in which competitive binding between frs-2 and shc regulates differentiation versus proliferation.

SIGNOR-65958

Q76I76

P23528

1

dephosphorylation

up-regulates activity

0.732

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

SIGNOR-248733

O14543

P23458

1

binding

down-regulates activity

0.732

SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition

SIGNOR-253051

Q00535

P04637

1

phosphorylation

up-regulates

0.732

We show that cdk5 phosphorylates p53 on ser15, ser33 and ser46 cdk5-stabilized p53 protein is transcriptionally active

SIGNOR-156422

O15524

P23458

1

binding

down-regulates

0.732

Socs1 and socs3 target jak1 and gp130, respectively, near the plasma membrane to prevent cytoplasmic stats from being activated, whereas pias1 principally targets activated stat1 in the cell nucleus and prevents it from binding to dna.

SIGNOR-202042

P10767

P22455

1

binding

up-regulates

0.732

Our results establish an fgf binding profile for fgfr-4 with afgf having the highest affinity, followed by k-fgf/hst-1 and bfgf. In addition, fgf-6 was found to bind to fgfr-4 in ligand competition experiments. Ligands binding to fgfr-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides.

SIGNOR-18570

P17252

P31431

1

phosphorylation

up-regulates activity

0.732

The phosphorylation state of Ser(183) in the cytoplasmic tail of syndecan-4 determines the binding affinity of the cytoplasmic tail to phosphatidylinositol 4,5-bisphosphate (PIP(2)), the capacity of the tail to multimerize, and its ability to activate protein kinase C (PKC) alpha. We sought to identify the kinase responsible for this phosphorylation and to determine its downstream effects on PKCalpha activity and on endothelial cell function. Among several PKC isoenzymes tested, only PKCalpha and -delta were able to specifically phosphorylate Ser(183) in vitro. However, studies in cultured endothelial cells showed that the phosphorylation level of syndecan-4 was significantly reduced in endothelial cells expressing a dominant negative (DN) PKCdelta but not a DN PKCalpha mutant.

SIGNOR-249149

Q13464

P15311

1

phosphorylation

up-regulates

0.732

Activation of ezrin is mediated by initial pip2 binding and subsequent phosphorylation of threonine 567. We performed an in vitro kinase assay with 80 selected kinases on an ezrin peptide containing the t567 phosphorylation site (figure 3a). In this screen, we identified the mst and rock kinases as the most potent kinases for the ezrin peptide

SIGNOR-185567

Q96GX5

O43768

1

phosphorylation

up-regulates activity

0.732

We identified cyclic adenosine monophosphateregulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry.

SIGNOR-243690

Q9H0M0

O15105

1

relocalization

up-regulates activity

0.731

We found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor.

SIGNOR-126578

P27361

O43521

1

phosphorylation

down-regulates quantity by destabilization

0.731

In vitro, bimel was phosphorylated by extracellular signal-regulated kinase on ser(69), which resides in the bimel-specific insert region. Using phosphospecific antibody against this site, we show that this residue is actually phosphorylated in cells. We also show that phosphorylation of ser(69) promotes ubiquitination of bimel. We conclude that mek inhibitors sensitize mda-mb231 and hbc4 cells to anoikis by blocking phosphorylation and hence degradation of bimel

SIGNOR-129878

Q9Y6X2

P40763

1

sumoylation

down-regulates

0.731

Stat3 mediated signaling pathways can be inhibited by pias3 (protein inhibitor of activated stat3), which was recently found to regulate protein stability and function by its sumo (small-ubiquitin like modifiers) ligase activity in promoting sumoylation of important nuclear proteins.

SIGNOR-124723

Q9H4B4

P30307

1

phosphorylation

up-regulates

0.731

Cdc25c phosphorylation on serine 191 by plk3 promotes its nuclear translocation

SIGNOR-122090

P28289

P06753

1

binding

down-regulates activity

0.731

Tropomodulin is a 40.6-kDa protein that binds to one end of the rod-like tropomyosin and inhibits its cooperativity and binding to actin. [.] we demonstrate that it is the N-terminus of tropomyosin that interacts with tropomodulin. Among several tropomyosin isoforms tested, hTM5 encoded by the human gamma-tropomyosin gene has the highest affinity toward human erythrocyte tropomodulin.

SIGNOR-259111

Q06124

Q05397

1

dephosphorylation

down-regulates

0.731

Dca concomitantly and significantly increased association of tyrosine phosphatase shp2 with fak. Incubation of immunoprecipitated fak, in vitro, with glutathione-s-transferase-shp2 fusion protein resulted in tyrosine dephosphorylation of fak in a concentration-dependent manner.

SIGNOR-148926

Q96GD4

Q99661

1

phosphorylation

up-regulates

0.731

Here, we show that the binding of mcak to chromosome arms is also regulated by aurora b and that aurora b-dependent chromosome arm and centromere localization is regulated by distinct two-site phosphoregulatory mechanisms. Mcak association with chromosome arms is promoted by phosphorylation of t95 on mcak, whereas phosphorylation of s196 on mcak promotes dissociation from the arms. Although targeting of mcak to centromeres requires phosphorylation of s110 on mcak, dephosphorylation of t95 on mcak increases the binding of mcak to centromeres.

SIGNOR-155890

P84022

P15172

1

binding

down-regulates activity

0.731

We show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors.

SIGNOR-252071

P49841

P49815

1

phosphorylation

up-regulates activity

0.731

Gsk3 inhibits the mtor pathway by phosphorylating tsc2 in a manner dependent on ampk-priming phosphorylation.

SIGNOR-149380

Q16619

P42702

1

binding

up-regulates

0.731

We conclude that gp130/lif receptor and et(a) receptor activation are essential for cardiac fibroblast growth by ct-1

SIGNOR-114758

O75582

P16220

1

phosphorylation

up-regulates

0.731

Msk1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates creb at ser133_ .MSK1 Is activated in vitro by mapk2/erk2 or sapk2/p38. Endogenous msk1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to uv radiation, and oxidative and chemical stres msk was the kinase responsible for phosphorylation of the transcription factor creb in response to tcr stimulation. Pka, ca2+-calmodulin-dependent kinase iv (camkiv), msk, p70s6k and rsk phosphorylate creb.

SIGNOR-59458

P53350

Q9Y266

1

phosphorylation

up-regulates activity

0.73

Here, we characterize the interaction between plk1 and nudc, show that plk1 phosphorylates nudc at conserved s274 and s326 residues in vitro, and present evidence that nudc is also a substrate for plk1 in vivo. Downregulation of nudc by rna interference results in multiple mitotic defects, including multinucleation and cells arrested at the midbody stage, which are rescued by ectopic expression of wild-type nudc, but not by nudc with mutations in the plk1 phosphorylation sites.

SIGNOR-103403

P17252

P29966

1

phosphorylation

down-regulates activity

0.73

Here we report that MARCKS is a filamentous (F) actin crosslinking protein, with activity that is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin

SIGNOR-249650

Q96CW9

Q9HBW1

1

binding

up-regulates activity

0.73

The NGL (netrin-G ligand; LRRC4) family of synaptic cell adhesion molecules belongs to the superfamily of leucine-rich repeat (LRR) proteins. The three known members of the NGL family, NGL-1, NGL-2, and NGL-3, are mainly localized to the postsynaptic side of excitatory synapses, and interact with the presynaptic ligands, netrin-G1, netrin-G2, and LAR, respectively.

SIGNOR-264048

Q96GX5

P56211

1

phosphorylation

up-regulates activity

0.73

We identified cyclic adenosine monophosphateregulated phosphoprotein 19 (Arpp19) and -Endosulfine as two substrates of Gwl that, when phosphorylated by this kinase, associate with and inhibit PP2A, thus promoting mitotic entry.

SIGNOR-243611

P08575

P06241

1

dephosphorylation

up-regulates activity

0.73

On the membrane SKAP55, via its phosphorylated Tyr-271, further binds the SH2 domain of Fyn to replace the low-affinity bound inhibitory site of the kinase. Consequently, CD45 may have transiently disassociated with the Tyr-232 residue of SKAP55 through dephosphorylation and simultaneously interacted with the released the phosphorylated inhibitory tyrosine residue of Fyn for dephosphorylation, resulting in activation of the Src family kinase Fyn and initiation of TCR-engaged signal transduction.

SIGNOR-248352

P14778

Q9NPH3

2

binding

up-regulates activity

0.73

Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)

SIGNOR-251981

O60664

P20645

1

relocalization

up-regulates activity

0.73

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

SIGNOR-253093

O76093

P21802

1

binding

up-regulates

0.73

Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes

SIGNOR-42368

Q9NPH3

P14778

2

binding

up-regulates

0.73

Here we report that the soluble form of the il-1 receptor accessory protein (acp) increases the affinity of binding of human il-1alpha and il-1beta to the soluble human type ii il-1 receptor by approximately 100-fold,

SIGNOR-97396

P27361

P51812

1

phosphorylation

up-regulates

0.73

We have generated two monoclonal antibodies that recognize two phosphorylated sites, p-ser227 and p-thr577, in the n- and c-terminal kinase domains of rsk2, respectively. phosphorylation and activation of rsk2 by uv light involves the erk pathway

SIGNOR-81460

O75096

O15146

1

binding

up-regulates activity

0.73

AGRN is released by the nerve and binds to LRP4, which then binds to MuSK. This interaction leads to MuSK autophosphorylation and activation of its kinase function, leading to anterograde signalling by subsequent phosphorylation of DOK7 (not shown), which binds MuSK as a dimer.

SIGNOR-273850

P51617

Q8N2H9

2

phosphorylation

up-regulates

0.729

Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity.

SIGNOR-103983

P45985

P45984

1

phosphorylation

up-regulates

0.729

Mkk4, which activates p38gamma, p38delta, and jnk2 to phosphorylate p53 on ser-33 and cause a transient g(1) arrest. 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) here we report that mkk4 shows a striking preference for the tyrosine residue (tyr-185), and mkk7 a striking preference for the threonine residue (thr-183) in three sapk1/jnk1 isoforms tested (jnk1 alpha 1, jnk2 alpha 2 and jnk3 alpha 1)

SIGNOR-197998

Q9Y4K3

Q9Y6Q6

1

binding

up-regulates activity

0.729

TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation.

SIGNOR-253045

P31751

P49815

1

phosphorylation

down-regulates

0.729

We demonstrate here that tuberin is phosphorylated on s939 and t1462 in response to pi3k activation. Our results are consistent with akt being the pi3k-depen-dent tuberin kinase. The pi3k-akt-mediated phosphorylation of tuberin would inhibit the function of the tuberin-hamartin complex.

SIGNOR-91041

P17676

P37231

1

transcriptional regulation

up-regulates quantity

0.729

Induction of C/EBP beta DNA-binding activity in NIH-3T3 beta 2 cells exposed to dexamethasone in the presence of insulin and fetal bovine serum activates the expression of an adipocyte-specific nuclear hormone receptor, PPAR gamma, that stimulates the conversion of these fibroblasts into committed preadipocytes

SIGNOR-255730

P31749

Q99683

1

phosphorylation

down-regulates activity

0.729

Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1.

SIGNOR-252465

P29350

O60674

1

dephosphorylation

down-regulates activity

0.729

Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1

SIGNOR-248466

Q8N2H9

P51617

2

ubiquitination

up-regulates

0.729

These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4.

SIGNOR-159061

Q6PGQ7

O14965

1

binding

up-regulates

0.729

Both drosophila and human bora can bind to aurora-a and activate the kinase in vitro.

SIGNOR-148661

Q13233

P45985

1

phosphorylation

up-regulates activity

0.729

The gck-ctd-mekk1 interaction is sufficiently stable to support mekk1 s phosphorylation of its substrate, sek1

SIGNOR-236380

P31749

P22736

1

phosphorylation

down-regulates activity

0.729

We show that akt interacts with nur77 and inactivates nur77 by phosphorylation at ser-350

SIGNOR-252466

Q5H8A3

Q9HB89

1

binding

up-regulates

0.729

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-133074

Q13492

P53675

1

binding

up-regulates

0.729

Calm interacts with the clathrin heavy chain through its c-terminal third and with phophoinositides through its ap180 n-terminal homology (anth) domain, promoting assembly of clathrin triskelia into clathrin cagesin vitro

SIGNOR-144733

P53350

Q9BQQ3

1

phosphorylation

down-regulates quantity

0.729

As GRASP65 is a substrate of cdc2 and polo-like kinase, manipulation of GRASP65 level may affect the localization and activity of these kinases in cell cycle progression, as suggested by a previous study ( ).|During mitosis, GRASP65 is phosphorylated by two mitotic kinases, cdc2 and polo-like kinase (plk), which leads to GRASP65 deoligomerization and thus Golgi unstacking ( xref , xref ).

SIGNOR-279554

Q96F81

Q15465

1

binding

up-regulates activity

0.729

We show that the vertebrate homologue, dispatched-a (dispa) interacts with human sonic hedgehog (hshh) via its cholesterol anchor, and that this interaction is necessary for hshh secretion. binding to dispa is necessary but not sufficient for hshh secretion

SIGNOR-191888

P42681

Q13094

1

phosphorylation

up-regulates

0.728

Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function

SIGNOR-44669

P28482

P51812

1

phosphorylation

up-regulates

0.728

Erk-activates the rsk family of serine/threonine kinases,rsk1, rsk2, and rsk3.

SIGNOR-161518

Q9NRM7

Q9Y2J4

2

phosphorylation

down-regulates activity

0.728

The N-terminal regions of Amot proteins contain a conserved HXRXXS consensus site for LATS1/2-mediated phosphorylation.|Amot family members. Knockdown of LATS1 and LATS2 endogenously reduced the phosphorylation of Amots detected by the phospho-specific antibodies. Mutation of the serine to alanine within this HXRXXS site in Amot and AmotL2 established that this site was essential for Hippo core kinase-mediated phosphorylation. Wild-type and non-phosphorylated Amot (Amot-S175A) were targeted to actin filaments, whereas phospho-mimic Amot (Amot-S175D) failed to be localized with actin.

SIGNOR-272084

P46734

Q16539

1

phosphorylation

up-regulates activity

0.728

Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase.

SIGNOR-232156

Q9UNE7

P11142

1

polyubiquitination

down-regulates quantity by destabilization

0.728

BAG-1 stimulates CHIP-induced degradation of the glucocorticoid hormone receptor (GR). A model for the cooperation of CHIP and BAG-1 in coupling Hsc/Hsp70 to the ubiquitin/proteasome system. CHIP associates with Hsc/Hsp70 via its TPR chaperone adaptor (TPR) and, at the same time, recruits E2 ubiquitin-conjugating enzymes of the Ubc4/5 family to the chaperone complex. BAG-1 binds to Hsp70 via its BAG domain (BAG) and utilizes its ubiquitin-like domain (ubl) for proteasomal association

SIGNOR-272588

P19525

P05198

1

phosphorylation

down-regulates activity

0.728

Besides PERK, eIF2Î± can also be phosphorylated by three other kinases: heme-regulated inhibitor kinase (HRI), general control nonderepressible 2 (GCN2), and PKR. PKR is an interferon-stimulated gene (ISG) activated by binding of double-stranded RNA (dsRNA), a common intermediate during the replication of DNA and RNA viruses. Together, these four eIF2Î± kinases and their convergent downstream signaling pathways are known as the integrated stress response (ISR)

SIGNOR-260168

Q9H461

O75197

1

binding

up-regulates activity

0.728

Ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) to activate WntBeta-catenin signaling.

SIGNOR-169635

P61962

Q9Y463

1

binding

up-regulates activity

0.728

Two isoforms of DYRK, DYRK1A and DYRK1B, co-immunoprecipitate with HAN11 when coexpressed in COS cells indicating that the proteins interact in mammalian cells. HAN11 might target DYRKs to cytosolic locations for regulation of specific cellular functions.

SIGNOR-260631

Q9Y2J4

Q9NRM7

2

relocalization

up-regulates activity

0.728

Ubiquitinated AMOTL2 then serves as a physical docking site for LATS2, which phosphorylates YAP to promote its cytoplasmic retention and degradation.

SIGNOR-271875

P12755

P84022

1

binding

down-regulates activity

0.728

Smad2/3 interacts with c-ski through its c-terminal mh2 domain in a tgf-beta-dependent mannerc-ski is incorporated in the smad dna binding complex, interferes with the interaction of smad3 with a transcriptional co-activator, p300, and in turn recruits hdac. c-ski is thus a transcriptional co-repressor that links smads to hdac in tgf-beta signaling.

SIGNOR-232123

P05000

P17181

1

binding

up-regulates

0.728

Ifn-alpha, ifn-beta, and ifn-omega, induce somewhat different cellular effects but act through a common receptor complex, ifnar, composed of subunits ifnar-1 and ifnar-2.

SIGNOR-105979

Q9UBN6

P50591

1

binding

down-regulates

0.728

One function of trail-r4 may be inhibition of trail cytotoxicy. Dcr2 functions as an inhibitory apo2l receptor.

SIGNOR-53447

P49841

P04637

1

phosphorylation

up-regulates activity

0.728

Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity.

SIGNOR-251258