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
O43865	Q9Y6R1	1	binding	up-regulates activity	0.671	IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities.	SIGNOR-263135
Q92630	P04637	1	phosphorylation	up-regulates	0.67	Here, we demonstrate that the dual-specificity tyrosine-phosphorylation-regulated kinase 2 (dyrk2) directly phosphorylates p53 at ser46. these findings indicate that dyrk2 regulates p53 to induce apoptosis in response to dna damage.	SIGNOR-153544
O60674	P42226	1	phosphorylation	up-regulates activity	0.67	Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6.	SIGNOR-249532
O15111	O14920	1	phosphorylation	up-regulates activity	0.67	Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays.	SIGNOR-250772
Q9UL54	P46734	1	binding	up-regulates activity	0.67	Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7.	SIGNOR-70947
P27361	Q15256	1	phosphorylation	up-regulates activity	0.67	Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.	SIGNOR-249477
P08254	P10451	1	cleavage	up-regulates activity	0.67	In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA.	SIGNOR-253320
P06213	P27986	1	phosphorylation	up-regulates activity	0.67	The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor.	SIGNOR-251321
Q92794	P04637	1	acetylation	up-regulates	0.67	We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression	SIGNOR-201486
Q13608	O43933	1	binding	up-regulates activity	0.67	Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions.	SIGNOR-253615
P00533	P21860	1	phosphorylation	up-regulates	0.67	The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism.	SIGNOR-34748
P56706	Q9UP38	1	binding	up-regulates	0.67	Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling.	SIGNOR-137931
Q13467	O75197	1	binding	up-regulates activity	0.67	Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain.	SIGNOR-258969
P38435	P00734	1	carboxylation	up-regulates activity	0.669	We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)\|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood.	SIGNOR-263676
P10082	P50391	1	binding	up-regulates	0.669	Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid.	SIGNOR-29767
O14641	O15169	1	binding	up-regulates activity	0.669	Dishevelled (dvl) transduces the wnt signal by interacting with the cytoplasmic axin complex.	SIGNOR-155221
Q9HCE7	O15198	1	ubiquitination	down-regulates	0.669	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-195669
Q16629	Q9UBU9	1	binding	up-regulates	0.669	9g8 and srp20 also enhance the tap rna-binding activity	SIGNOR-161338
P28482	P19634	1	phosphorylation	up-regulates	0.669	We have demonstrated that the map kinases extracellular signal-regulated kinases 1 and 2 (erk1/2) are implicated in growth factor activation of nhe1. / our results suggest that amino acids ser770 and ser771 mediate erk-dependent activation of the na+/h+ exchanger in vivo.	SIGNOR-151925
P28482	P22736	1	phosphorylation	up-regulates activity	0.669	NGFI-B is an inducible orphan nuclear receptor that initiates apoptosis. Growth factors such as EGF activate the MAP kinase ERK, whose activity may determine if a cell survives or undergoes apoptosis. EGF stimulation of cells leads to phosphorylation of threonine in NGFI-B. Thr-142 of NGFI-B is comprised in a consensus MAP kinase site and was identified as a preferred substrate for ERK2 (but not ERK1) in vitro.	SIGNOR-249430
P49674	Q92997	2	phosphorylation	down-regulates activity	0.669	Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3.	SIGNOR-276645
Q92997	P49674	2	binding	up-regulates	0.669	Ckiepsilon was in a complex with axin and other downstream components of the wnt pathway, including dishevelled.	SIGNOR-71759
P42229	Q9NSE2	1	transcriptional regulation	up-regulates quantity by expression	0.669	The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD	SIGNOR-261544
Q06330	Q86X95	1	binding	up-regulates	0.669	In the mechanism of cbf1-mediated repression, cbf1 binds to a unique corepressor cir. Targeting of cir to cbf1 is an important component of repression. Cir binds to histone deacetylase and to sap30 and serves as a linker between cbf1 and the histone deacetylase complex.	SIGNOR-62932
O14757	Q99638	1	phosphorylation	up-regulates activity	0.669	Chk1 inhibition with small interfering RNA (siRNA) reduces Rad9A stabilization and accumulation.\|In the case of DNA damage, an activated Chk1 phosphorylates Rad9A or other proteins (TLK1) as a feedback mechanism to prevent Rad9A (poly) ubiquitination and degradation.	SIGNOR-279503
Q86VW2	P60953	1	guanine nucleotide exchange factor	up-regulates	0.669	Exogenous expression of geft promotes myogenesis of c2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process.	SIGNOR-235391
P10276	P48443	1	binding	up-regulates	0.669	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16466
O95185	P43146	1	binding	down-regulates activity	0.669	In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.	SIGNOR-268165
P35813	Q15796	1	dephosphorylation	down-regulates	0.668	Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.	SIGNOR-146919
P01111	P42338	1	binding	up-regulates	0.668	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-175225
Q86UE8	Q9Y294	1	phosphorylation	up-regulates quantity by stabilization	0.668	We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 \| Consistent	SIGNOR-260787
P29350	P35968	1	dephosphorylation	down-regulates activity	0.668	Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration\|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175	SIGNOR-248474
O43150	P62330	1	gtpase-activating protein	up-regulates activity	0.668	Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6. Pap protein exhibits Arf GAP activity in vitro.	SIGNOR-269706
P31749	O15111	1	phosphorylation	up-regulates	0.668	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-187006
P12931	P61586	1	phosphorylation	down-regulates activity	0.668	When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.\|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity	SIGNOR-271701
P68400	P04637	1	phosphorylation	up-regulates activity	0.668	Furthermore, we demonstrate that anisomycin- and tumor necrosis factor-alpha-induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase and CK2 activities.	SIGNOR-250967
P62136	P46937	1	dephosphorylation	up-regulates activity	0.668	In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2.\|PP1A dephosphorylates endogenous YAP2 at serine 127.	SIGNOR-276999
P01213	P41145	1	binding	up-regulates activity	0.668	We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.	SIGNOR-258411
P53778	Q13424	1	phosphorylation	up-regulates	0.668	Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates.	SIGNOR-67061
A1A4S6	P61586	1	gtpase-activating protein	down-regulates activity	0.668	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-260465
Q16539	P47712	1	phosphorylation	up-regulates activity	0.668	These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets	SIGNOR-44673
Q13114	Q99558	1	ubiquitination	down-regulates quantity by destabilization	0.668	TRAF2 and TRAF3 mediate NIK ubiquitination by forming a complex with the E3 ligase cIAP (cIAP1 or cIAP2).\|We demonstrated further that TRAF3 mediates the degradation of NIK and thereby serves as a pivotal negative regulator of noncanonical NF-kappaB signaling.	SIGNOR-278673
P28702	P37231	1	binding	up-regulates	0.668	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105454
P12931	P14923	1	phosphorylation	up-regulates activity	0.668	Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcriptionFor instance, Src, which mainly phosphorylates Tyr86 in beta-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and alpha-catenin and increasing the interaction with the alpha-catenin-equivalent protein in desmosomes, desmoplakin.	SIGNOR-247310
P42229	O14508	1	transcriptional regulation	up-regulates quantity by expression	0.668	We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling	SIGNOR-261547
P27361	P17676	1	phosphorylation	up-regulates	0.668	Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes.	SIGNOR-184917
P35638	P17676	1	transcriptional regulation	down-regulates quantity	0.668	We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process.	SIGNOR-255914
Q9H1J7	O60353	1	binding	up-regulates	0.668	Human wnt5a, wnt5b and wnt11 are non-canonical wnt ligands transducing pcp signals through fzd3 or fzd6 receptors.	SIGNOR-141443
Q9NR80	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.667	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-260531
P09958	P46531	1	binding	up-regulates	0.667	The proteolytic activity of furin responsible for processing full length notch-1 (p300) plays a critical role in notch signaling.	SIGNOR-196914
Q02410	Q9ULB1	1	binding	up-regulates activity	0.667	Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa.	SIGNOR-264038
Q14332	O14640	1	binding	up-regulates activity	0.667	Upon ligand binding, DVL proteins are recruited to Frizzled receptors at the plasma membrane and co-recruit cytoplasmic transducers, such as Axin, CK1 and GSK3 binding protein (GBP), presumably along with their partners, to promote ?-catenin-dependent signalling.	SIGNOR-258956
P01213	P41143	1	chemical activation	up-regulates activity	0.667	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258415
Q6JBY9	P52907	1	binding	up-regulates	0.667	An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B). Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263088
P62258	Q9GZM8	1	binding	up-regulates activity	0.667	14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. 14-3-3ε binds to NUDEL phosphorylated by cyclin-dependent kinase (cdk5) and maintains NUDEL phosphorylation. Deficiency of 14-3-3ε causes mislocalization of the NUDEL/LIS1 complex from axons, suggesting that 14-3-3ε regulates the axonal targeting of the NUDEL/LIS1 complex by sustaining NUDEL phosphorylation	SIGNOR-252160
Q00987	P06400	1	ubiquitination	down-regulates quantity by destabilization	0.667	In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB	SIGNOR-278530
Q14332	O75581	1	binding	up-regulates activity	0.667	Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction.	SIGNOR-258965
P43405	P14317	1	phosphorylation	up-regulates	0.667	Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis.	SIGNOR-47342
P12931	P29353	1	phosphorylation	up-regulates activity	0.666	Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway.	SIGNOR-44870
P28482	Q07666	1	phosphorylation	up-regulates	0.666	In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites	SIGNOR-96414
Q9P2B4	Q9NRL3	1	binding	up-regulates activity	0.666	Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A.	SIGNOR-261701
Q6P0Q8	P60484	1	phosphorylation	up-regulates	0.666	We further demonstrate that binding of pten to specific pdz domains diminishes its degradation rate and facilitates its phosphorylation by mast kinases. Our results suggest a regulatory role of pdz domain binding on pten function by controlling its stability and phosphorylation status.	SIGNOR-138051
O00585	Q9NPB9	1	binding	up-regulates activity	0.666	In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.	SIGNOR-268417
O94782	Q9NVI1	1	deubiquitination	down-regulates activity	0.666	Phosphorylation of FANCI may also turn the ubiquitinated ID complex into a poor substrate for deubiquitination by the USP1–UAF1 complex, resulting in increased levels of monoubiquitinated FANCD2.	SIGNOR-263272
P08575	P07948	1	dephosphorylation	down-regulates activity	0.666	CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.\| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)	SIGNOR-248354
Q96CA5	Q9NR28	1	binding	down-regulates	0.666	These results suggest that ml-iap might regulate apoptosis by sequestering smac and preventing it from antagonizing xiap-mediated caspases, rather than by direct caspases.	SIGNOR-129869
P24941	P30291	2	null	down-regulates quantity by destabilization	0.666	PS123 primes CK2 to phosphorylate S121, resulting in creation of a β-TrCP phosphodegron (EEGFGpS121) that is responsible for the instability of Wee1A during interphase.	SIGNOR-276039
P15882	P63000	1	gtpase-activating protein	down-regulates activity	0.666	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-260499
P30291	P24941	2	phosphorylation	down-regulates	0.666	Identification and characterization of human wee1b, a new member of the wee1 family of cdk-inhibitory kinases.	SIGNOR-83139
P10826	P28702	2	binding	up-regulates	0.666	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16581
Q9NQC3	Q96FE5	1	binding	up-regulates	0.666	Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1,	SIGNOR-133752
P28702	P10826	2	binding	up-regulates	0.666	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16677
P51452	P27361	1	dephosphorylation	down-regulates activity	0.665	The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase (14), protein-tyrosine phosphatase (ptp) (14, 15), or dual specificity phosphatases	SIGNOR-103035
Q14653	P01574	1	transcriptional regulation	up-regulates quantity by expression	0.665	Similarly, exogenous expression of wild-type Pin1 suppressed TLR3-mediated, IRF3-dependent activation of the IFN-beta promoter and reduced IFN-beta secretion in culture supernatants	SIGNOR-252257
O14965	P53350	1	phosphorylation	up-regulates	0.665	We find that aurora a (aurka) can directly phosphorylate plk1 on thr 210;activation of plk1 requires phosphorylation of a conserved threonine residue (thr 210).	SIGNOR-179422
Q13115	Q16539	1	dephosphorylation	down-regulates	0.665	This result suggests that dusp4 represses gluconeogenesis through dephosphorylation of p38	SIGNOR-147958
P11802	P38398	1	phosphorylation	down-regulates	0.665	In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo.	SIGNOR-153450
Q99942	P13569	1	ubiquitination	down-regulates quantity by destabilization	0.665	JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation.	SIGNOR-271494
Q9HC23	Q8NFJ6	1	binding	up-regulates	0.665	We have cloned two closely related receptors for pk1 and pk2. These receptors, named prokineticin receptor 1 and 2 (pkr1 and pkr2)	SIGNOR-87919
P10911	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.665	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-260557
Q8NEB9	P60484	1	binding	up-regulates	0.665	Direct positive regulation of pten by the p85 subunit of phosphatidylinositol 3-kinase.Thus p85 regulates both p110-pi3k and pten-phosphatase enzymes through direct interaction	SIGNOR-164075
P35398	Q99743	1	transcriptional regulation	up-regulates quantity by expression	0.665	Direct Regulation of the NPAS2 Promoter by 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-267980
Q5TD97	Q03060	1	binding	up-regulates activity	0.665	ACT (for activator of CREM in testis), a LIM-only protein which specifically associates with CREM. ACT is expressed coordinately with CREM in a tissue- and developmentally regulated manner. It strongly stimulates CREM transcriptional activity in yeast and mammalian cells and contains an intrinsic activation function.	SIGNOR-222111
P27037	Q04771	1	binding	up-regulates	0.664	The major bmp7 type i receptor observed was alk2,	SIGNOR-60234
Q9Y297	P08151	1	ubiquitination	down-regulates quantity by destabilization	0.664	Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation. We identify two independent destruction signals in Gli1, D(N) and D(C), and show that removal of these signals stabilizes Gli1 protein and rapidly accelerates tumor formation in transgenic animals.Levels of _TrCP appeared to be limiting for Gli1 degradation, as increasing the levels of _TrCP protein significantly decreased steady-state levels of Gli1 protein	SIGNOR-235631
O00744	Q9UP38	1	binding	up-regulates	0.664	Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6	SIGNOR-89134
P38936	Q00526	1	binding	down-regulates	0.664	P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. We have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases.	SIGNOR-29954
Q8IXL6	Q9NP70	1	phosphorylation	up-regulates activity	0.664	Disruption of Fam20C completely eliminated AMBN phosphorylation, suggesting that Fam20C is the kinase that phosphorylates enamel matrix proteins in vivo (XREF_FIG).	SIGNOR-280010
Q99731	Q9NPB9	1	binding	up-regulates activity	0.664	In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.	SIGNOR-268416
P19883	O95390	1	binding	down-regulates activity	0.664	Follistatin (FST) is a member of the tissue growth factor β family and is a secreted glycoprotein that antagonizes many members of the family, including activin A, growth differentiation factor 11, and myostatin. \|FST315-ΔHBS-Fc induced improvements in muscle repair after injury/atrophy by modulating the early inflammatory phase allowing for increased macrophage density, and Pax7-positive cells leading to an accelerated restoration of myofibers and muscle function.	SIGNOR-251716
O15444	Q9NPB9	1	binding	up-regulates activity	0.664	In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.	SIGNOR-268418
Q9UPT6	P45984	2	binding	up-regulates	0.663	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-134561
P45984	Q9UPT6	2	phosphorylation	up-regulates	0.663	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134576
P19793	P10827	1	binding	up-regulates	0.663	Like many receptors belonging to the superfamily of steroid/thyroid nuclear receptors, thyroid hormone receptors (trs) bind to specific th-dna responsive elements (tre) upstream of target gene in heterodimeric complex with the 9-cis retinoid acid receptor (rxr).	SIGNOR-81446
Q9P209	Q96SN8	1	relocalization	up-regulates activity	0.663	By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically.	SIGNOR-271720
Q9BXH1	P10415	1	binding	down-regulates activity	0.663	Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.	SIGNOR-133808
Q13490	O15519	1	ubiquitination	down-regulates quantity	0.663	Moreover, API-1 increased c-FLIP ubiquitination and decreased c-FLIP stability.\|Thus, we conclude that API-1 reduces c-FLIP levels by facilitating its degradation through the ubiquitin and proteasome dependent pathway.	SIGNOR-278687
P16473	P63092	1	binding	up-regulates activity	0.663	The primary signal transduction pathway for TSH receptor is activation of adenylate cyclase via a Gαs G protein-coupled receptor.	SIGNOR-267136
P53350	P30305	1	phosphorylation	up-regulates activity	0.663	These data indicated that PLK1 phosphorylates CDC25B and that pre-phosphorylation of CDC25B by CDK1/CyclinB enhances its substrate properties for PLK1 in vitro	SIGNOR-267560
Q14694	P04637	1	deubiquitination	up-regulates quantity by stabilization	0.662	Since USP10 is known as a deubiquitinating protease of p53 (Yuan et al., 2010), inhibition of USP10 by spautin-1 may promote the degradation of p53.	SIGNOR-260297

O43865

Q9Y6R1

1

binding

up-regulates activity

0.671

IRBIT opposed the effects of WNKs and SPAK by recruiting PP1 to the complex to dephosphorylate CFTR and NBCe1-B, restoring their cell surface expression, in addition to stimulating their activities.

SIGNOR-263135

Q92630

P04637

1

phosphorylation

up-regulates

0.67

Here, we demonstrate that the dual-specificity tyrosine-phosphorylation-regulated kinase 2 (dyrk2) directly phosphorylates p53 at ser46. these findings indicate that dyrk2 regulates p53 to induce apoptosis in response to dna damage.

SIGNOR-153544

O60674

P42226

1

phosphorylation

up-regulates activity

0.67

Downstream intracellular signaling from the IL-4IL-4Rc complex involves activation of the Jak1 and Jak3 kinases, phosphorylation of the Stat6 transcription factor, and activation of the insulin receptor substrate (IRS)-2 and Dok2-signaling intermediates. IL-13 initially binds to IL-13R1 with intermediate affinity, and then heterodimerizes with IL-4R. The IL-13IL-13R1IL-4R complex activates the Tyk2, Jak2, and Jak1 kinases and Stat6.

SIGNOR-249532

O15111

O14920

1

phosphorylation

up-regulates activity

0.67

Our data indicate that IKKα stimulates IKKβ kinase activity for the IκBα substrate. Finally, we demonstrate that IKKα can phosphorylate IKKβ in in vitro kinase assays.

SIGNOR-250772

Q9UL54

P46734

1

binding

up-regulates activity

0.67

Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7.

SIGNOR-70947

P27361

Q15256

1

phosphorylation

up-regulates activity

0.67

Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL.

SIGNOR-249477

P08254

P10451

1

cleavage

up-regulates activity

0.67

In this study, we found a novel motif, LRSKSRSFQVSDEQY, in the C-terminal fragment of MMP-3/7-cleaved mouse OPN binds to α9β1 integrin. Importantly, this novel motif is involved in the development of anti-type II collagen antibody-induced arthritis (CAIA). This study provides the first in vitro and in vivo evidence that OPN cleavage by MMP-3/7 is an important regulatory mechanism for CAIA.

SIGNOR-253320

P06213

P27986

1

phosphorylation

up-regulates activity

0.67

The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor.

SIGNOR-251321

Q92794

P04637

1

acetylation

up-regulates

0.67

We show here that moz is an acetyltransferase of p53 at k120 and k382 and colocalizes with p53 in promyelocytic leukemia (pml) nuclear bodies following cellular stress. The moz-pml-p53 interaction enhances moz-mediated acetylation of p53, and this ternary complex enhances p53-dependent p21 expression

SIGNOR-201486

Q13608

O43933

1

binding

up-regulates activity

0.67

Pex26 recruits Pex6–Pex1 complexes to peroxisomes. Pex26 anchors Pex6 and Pex1 through Pex26–Pex6 and Pex6–Pex1 interactions.

SIGNOR-253615

P00533

P21860

1

phosphorylation

up-regulates

0.67

The erbb3 protein which possesses little or no intrinsic protein tyrosine kinase activiity is phosphorylated by the activated egf receptor protein tyrosine kinase on tyrosine residues within the yxxm sequence motif. These phosphorylated tyrosine residues interact with the p85 regulatory subunit of pi 3-kinase, which could result in the activation of the p110 catalytic subunit via a conformational mechanism.

SIGNOR-34748

P56706

Q9UP38

1

binding

up-regulates

0.67

Wnt7b can bind to fzd1 and -10 on the cell surface and cooperatively activate canonical wnt signaling.

SIGNOR-137931

Q13467

O75197

1

binding

up-regulates activity

0.67

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

SIGNOR-258969

P38435

P00734

1

carboxylation

up-regulates activity

0.669

We analyzed the number of glutamic acid (Glu) residues and their positions in the Gla domain (GD) of DCP to investigate the gamma-carboxylation mechanism of VK-dependent carboxylase. Several DCPs were found in each subject studied. The 10 Gla residues of human prothrombin were carboxylated in order from the N-terminal (residues 26, 25, 16, 29, 20, 19, 14, 32, 7 and 6)|In the absence of VK or in the presence of VK antagonists, hepatic VKdependent carboxylase activity is inhibited and des-g-carboxyprothrombin (abnormal prothrombin or PIVKA; protein induced by vitamin K antagonist, prothrombin) is released into the blood.

SIGNOR-263676

P10082

P50391

1

binding

up-regulates

0.669

Human y4 bound human pp family members in i-pyy membrane binding assays with a distinctive rank order (table 1): pp > pyy > npy > npy free acid.

SIGNOR-29767

O14641

O15169

1

binding

up-regulates activity

0.669

Dishevelled (dvl) transduces the wnt signal by interacting with the cytoplasmic axin complex.

SIGNOR-155221

Q9HCE7

O15198

1

ubiquitination

down-regulates

0.669

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps

SIGNOR-195669

Q16629

Q9UBU9

1

binding

up-regulates

0.669

9g8 and srp20 also enhance the tap rna-binding activity

SIGNOR-161338

P28482

P19634

1

phosphorylation

up-regulates

0.669

We have demonstrated that the map kinases extracellular signal-regulated kinases 1 and 2 (erk1/2) are implicated in growth factor activation of nhe1. / our results suggest that amino acids ser770 and ser771 mediate erk-dependent activation of the na+/h+ exchanger in vivo.

SIGNOR-151925

P28482

P22736

1

phosphorylation

up-regulates activity

0.669

NGFI-B is an inducible orphan nuclear receptor that initiates apoptosis. Growth factors such as EGF activate the MAP kinase ERK, whose activity may determine if a cell survives or undergoes apoptosis. EGF stimulation of cells leads to phosphorylation of threonine in NGFI-B. Thr-142 of NGFI-B is comprised in a consensus MAP kinase site and was identified as a preferred substrate for ERK2 (but not ERK1) in vitro.

SIGNOR-249430

P49674

Q92997

2

phosphorylation

down-regulates activity

0.669

Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3.

SIGNOR-276645

Q92997

P49674

2

binding

up-regulates

0.669

Ckiepsilon was in a complex with axin and other downstream components of the wnt pathway, including dishevelled.

SIGNOR-71759

P42229

Q9NSE2

1

transcriptional regulation

up-regulates quantity by expression

0.669

The STAT5 target gene CIS, a member of the suppressor of cytokine signaling (SOCS) protein family, was highly induced by Flt3-ITD

SIGNOR-261544

Q06330

Q86X95

1

binding

up-regulates

0.669

In the mechanism of cbf1-mediated repression, cbf1 binds to a unique corepressor cir. Targeting of cir to cbf1 is an important component of repression. Cir binds to histone deacetylase and to sap30 and serves as a linker between cbf1 and the histone deacetylase complex.

SIGNOR-62932

O14757

Q99638

1

phosphorylation

up-regulates activity

0.669

Chk1 inhibition with small interfering RNA (siRNA) reduces Rad9A stabilization and accumulation.|In the case of DNA damage, an activated Chk1 phosphorylates Rad9A or other proteins (TLK1) as a feedback mechanism to prevent Rad9A (poly) ubiquitination and degradation.

SIGNOR-279503

Q86VW2

P60953

1

guanine nucleotide exchange factor

up-regulates

0.669

Exogenous expression of geft promotes myogenesis of c2c12 cells via activation of rhoa, rac1, and cdc42 and their downstream effector proteins, while a dominant negative mutant of geft inhibits this process.

SIGNOR-235391

P10276

P48443

1

binding

up-regulates

0.669

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

SIGNOR-16466

O95185

P43146

1

binding

down-regulates activity

0.669

In the presence of netrin-1, UNC5 co-immuno-precipitates with DCC, suggesting the formation of a ternary complex of netrin-1 with ecto-domains of DCC and UNC5. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists. DCC binding to netrin-1 alone leads to axon attraction. Importantly, DCC has the ability to switch the netrin-1-mediated responses from attraction to repulsion when another receptor UNC5 co-exists.

SIGNOR-268165

P35813

Q15796

1

dephosphorylation

down-regulates

0.668

Ppm1a dephosphorylates and promotes nuclear export of tgfbeta-activated smad2/3; these results suggest that phospho-smad2 is a direct substrate of mg2+-dependent ppm1a. in conclusion, ppm1a is a bona fide phosphatase that directly dephosphorylates the critical sxs motif of r-smads.

SIGNOR-146919

P01111

P42338

1

binding

up-regulates

0.668

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-175225

Q86UE8

Q9Y294

1

phosphorylation

up-regulates quantity by stabilization

0.668

We found that only S192A in hASF1a and S198A in hASF1b significantly affected phosphorylation by hTLK2 | Consistent

SIGNOR-260787

P29350

P35968

1

dephosphorylation

down-regulates activity

0.668

Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration|Knockdown of SHP-1 by siRNA or inhibition of c-Src by an inhibitor, results in augmented DNA synthesis perhaps due to increased phosphorylation of at least three tyrosine residues of KDR 996, 1059 and 1175

SIGNOR-248474

O43150

P62330

1

gtpase-activating protein

up-regulates activity

0.668

Pap is a multidomain protein composed of an N-terminal alpha-helical region with a coiled-coil motif, followed by a pleckstrin homology domain, an Arf-GAP domain, an ankyrin homology region, a proline-rich region, and a C-terminal SH3 domain. In addition, in vitro recombinant Pap exhibits strong GTPase-activating protein (GAP) activity towards the small GTPases Arf1 and Arf5 and weak activity towards Arf6. Pap protein exhibits Arf GAP activity in vitro.

SIGNOR-269706

P31749

O15111

1

phosphorylation

up-regulates

0.668

Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta

SIGNOR-187006

P12931

P61586

1

phosphorylation

down-regulates activity

0.668

When these RhoA mutants were coexpressed with Bcr-Abl, phosphorylation levels of Y34F and Y66F RhoA mutants dramatically decreased to 32% and 17%, respectively. As expected, when Y34 and Y66 were both mutated to phenylalanine, phosphorylation was completely abolished. Together, these observations indicate that Y34 and Y66 are the two predominant phosphorylation sites, and that the Src kinase and Bcr-Abl are the two candidate kinases that may phosphorylate these sites.|In contrast to active RhoA, RhoAQ63L(Y34,66E) had a dramatic decrease in RBD binding. This binding fraction was even lower than that of WT RhoA, suggesting phosphorylation at these sites could have a negative effect on RhoA activity

SIGNOR-271701

P68400

P04637

1

phosphorylation

up-regulates activity

0.668

Furthermore, we demonstrate that anisomycin- and tumor necrosis factor-alpha-induced phosphorylation of p53 at Ser-392, which is important for the transcriptional activity of this growth suppressor protein, requires p38 MAP kinase and CK2 activities.

SIGNOR-250967

P62136

P46937

1

dephosphorylation

up-regulates activity

0.668

In the present study, we demonstrate that PP1A (catalytic subunit of protein phosphatase-1) interacts with and dephosphorylates YAP2 in vitro and in vivo, and PP1A-mediated dephosphorylation induces the nuclear accumulation and transcriptional activation of YAP2.|PP1A dephosphorylates endogenous YAP2 at serine 127.

SIGNOR-276999

P01213

P41145

1

binding

up-regulates activity

0.668

We recently cloned a human kappa opioid receptor and stably expressed it in Chinese hamster ovary (CHO) cells. In this study, the effects of activation of the human kappa receptor by agonists on [35S]GTPgammaS binding to CHO cell membranes were examined.. The rank order of potencies of opioid ligands tested in stimulating [35S]GTPgammaS binding was dynorphin A 1-17 > (+/-)-ethylketocyclazocine > beta-funaltrexamine, (-)-U50,488H, tifluadom > nalorphine > pentazocine, nalbuphine > buprenorphine.

SIGNOR-258411

P53778

Q13424

1

phosphorylation

up-regulates

0.668

Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates.

SIGNOR-67061

A1A4S6

P61586

1

gtpase-activating protein

down-regulates activity

0.668

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-260465

Q16539

P47712

1

phosphorylation

up-regulates activity

0.668

These results provide the first direct evidence that p38 kinase is responsible for cpla2 phosphorylation in sfllrn-stimulated platelets and is involved in the early phosphorylation of cpla2 in thrombin-stimulated platelets

SIGNOR-44673

Q13114

Q99558

1

ubiquitination

down-regulates quantity by destabilization

0.668

TRAF2 and TRAF3 mediate NIK ubiquitination by forming a complex with the E3 ligase cIAP (cIAP1 or cIAP2).|We demonstrated further that TRAF3 mediates the degradation of NIK and thereby serves as a pivotal negative regulator of noncanonical NF-kappaB signaling.

SIGNOR-278673

P28702

P37231

1

binding

up-regulates

0.668

Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology

SIGNOR-105454

P12931

P14923

1

phosphorylation

up-regulates activity

0.668

Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates beta-catenin-mediated transcriptionFor instance, Src, which mainly phosphorylates Tyr86 in beta-catenin, modifies Tyr643 in plakoglobin, decreasing the interaction with E-cadherin and alpha-catenin and increasing the interaction with the alpha-catenin-equivalent protein in desmosomes, desmoplakin.

SIGNOR-247310

P42229

O14508

1

transcriptional regulation

up-regulates quantity by expression

0.668

We have also found SOCS2 and SOCS3 specifically induced in 32D/Flt3-ITD, both of which are STAT3/5 target genes and known negative regulators of receptor signaling

SIGNOR-261547

P27361

P17676

1

phosphorylation

up-regulates

0.668

Thr235 phosphorylation occurs in nuclei of differentiated macrophages, but not in monocytes.

SIGNOR-184917

P35638

P17676

1

transcriptional regulation

down-regulates quantity

0.668

We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process.

SIGNOR-255914

Q9H1J7

O60353

1

binding

up-regulates

0.668

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

SIGNOR-141443

Q9NR80

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.667

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-260531

P09958

P46531

1

binding

up-regulates

0.667

The proteolytic activity of furin responsible for processing full length notch-1 (p300) plays a critical role in notch signaling.

SIGNOR-196914

Q02410

Q9ULB1

1

binding

up-regulates activity

0.667

Mint1 and Mint2 Interact with the Cytoplasmic Domain of Neurexin I. The interaction of Mint1 with neurexins is mediated by its PDZ domains and allows the formation of mixed CASK-Mint complexes. Both CASK and Mint1 can bind directly to neurexins and to each other. Therefore, the assembly of various multimeric complexes could proceed as CASK could be indirectly recruited to neurexin-bound Mint1 and vice versa.

SIGNOR-264038

Q14332

O14640

1

binding

up-regulates activity

0.667

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

SIGNOR-258956

P01213

P41143

1

chemical activation

up-regulates activity

0.667

Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.

SIGNOR-258415

Q6JBY9

P52907

1

binding

up-regulates

0.667

An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B). Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.

SIGNOR-263088

P62258

Q9GZM8

1

binding

up-regulates activity

0.667

14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. 14-3-3ε binds to NUDEL phosphorylated by cyclin-dependent kinase (cdk5) and maintains NUDEL phosphorylation. Deficiency of 14-3-3ε causes mislocalization of the NUDEL/LIS1 complex from axons, suggesting that 14-3-3ε regulates the axonal targeting of the NUDEL/LIS1 complex by sustaining NUDEL phosphorylation

SIGNOR-252160

Q00987

P06400

1

ubiquitination

down-regulates quantity by destabilization

0.667

In this study, we found that Mdm2, a ubiquitin ligase for p53, promoted ubiquitin-dependent degradation of pRB

SIGNOR-278530

Q14332

O75581

1

binding

up-regulates activity

0.667

Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction.

SIGNOR-258965

P43405

P14317

1

phosphorylation

up-regulates

0.667

Here, we show that bcr-associated tyrosine kinases lyn and syk synergistically phosphorylate hs1, and that tyr-378 and tyr-397 of hs1 are the critical residues for its bcr-induced phosphorylation. once the two tyrosine residues are both phosphorylated, processive phosphorylation of hs1 by lyn and the other src family kinases would take place, producing hyperphosphorylated form of hs1. Finally, it is this hyperphosphorylated form of hs1 that translocates to the nucleus and activates b cell apoptosis.

SIGNOR-47342

P12931

P29353

1

phosphorylation

up-regulates activity

0.666

Here, we report the identification of two major and novel Shc tyrosine phosphorylation sites, Y239 and Y240. Y239/240 are co-ordinately phosphorylated by the src protein-tyrosine kinase in vitro, and in response to epidermal growth factor stimulation or in v-src-transformed cells in vivo. phosphorylation of y317 has been implicated in grb2 binding and activation of the ras pathway.

SIGNOR-44870

P28482

Q07666

1

phosphorylation

up-regulates

0.666

In support of this assumption, purified gst_sam68 protein was phosphorylated by recombinant erk2we found that sam68 mutated in ser 58, thr 71 and thr 84 showed the same extent of impairment in induced exon inclusion as did sam68 mutated in all s/tp sites

SIGNOR-96414

Q9P2B4

Q9NRL3

1

binding

up-regulates activity

0.666

Although CTTNBP2 and CTTNBP2NL are different in terms of tissue and subcellular distribution, our data indicate that, similar to CTTNBP2NL, CTTNBP2 associates with members of the striatin family, namely striatin and zinedin. Moreover, CTTNBP2 is critical for the distribution of striatin and zinedin in dendritic spines. The role of CTTNBP2 in the regulation of the synaptic distribution of striatin and zinedin suggests that CTTNBP2 regulates synaptic signaling through PP2A.

SIGNOR-261701

Q6P0Q8

P60484

1

phosphorylation

up-regulates

0.666

We further demonstrate that binding of pten to specific pdz domains diminishes its degradation rate and facilitates its phosphorylation by mast kinases. Our results suggest a regulatory role of pdz domain binding on pten function by controlling its stability and phosphorylation status.

SIGNOR-138051

O00585

Q9NPB9

1

binding

up-regulates activity

0.666

In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.

SIGNOR-268417

O94782

Q9NVI1

1

deubiquitination

down-regulates activity

0.666

Phosphorylation of FANCI may also turn the ubiquitinated ID complex into a poor substrate for deubiquitination by the USP1–UAF1 complex, resulting in increased levels of monoubiquitinated FANCD2.

SIGNOR-263272

P08575

P07948

1

dephosphorylation

down-regulates activity

0.666

CD45 negatively regulates lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells.| Phosphoamino acid analysis confirmed that Lyn is tyrosine phosphorylated with little serine or threonine phosphorylation. In CD45-negative cells, two bands at 8.2 and 4.1 kDa were phosphorylated in the absence of B cell Ag receptor (BCR) ligation. The 8.2-kDa band corresponded to a fragment containing the positive regulatory site (Tyr397), as assessed by its size and its phosphorylation in an in vitro kinase assay. The 4.1-kDa band was phosphorylated by COOH-terminal Src kinase, suggesting that it contains the COOH-terminal negative regulatory site (Tyr508)

SIGNOR-248354

Q96CA5

Q9NR28

1

binding

down-regulates

0.666

These results suggest that ml-iap might regulate apoptosis by sequestering smac and preventing it from antagonizing xiap-mediated caspases, rather than by direct caspases.

SIGNOR-129869

P24941

P30291

2

null

down-regulates quantity by destabilization

0.666

PS123 primes CK2 to phosphorylate S121, resulting in creation of a β-TrCP phosphodegron (EEGFGpS121) that is responsible for the instability of Wee1A during interphase.

SIGNOR-276039

P15882

P63000

1

gtpase-activating protein

down-regulates activity

0.666

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-260499

P30291

P24941

2

phosphorylation

down-regulates

0.666

Identification and characterization of human wee1b, a new member of the wee1 family of cdk-inhibitory kinases.

SIGNOR-83139

P10826

P28702

2

binding

up-regulates

0.666

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

SIGNOR-16581

Q9NQC3

Q96FE5

1

binding

up-regulates

0.666

Nogo-a, myelin-associated glycoprotein (mag), and oligodendrocyte myelin glycoprotein (omgp)...signal through a common receptor complex in neurons, which includes the ligand binding nogo-66 receptor (ngr), and two signal-transducing binding partners, p75 and lingo-1,

SIGNOR-133752

P28702

P10826

2

binding

up-regulates

0.666

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

SIGNOR-16677

P51452

P27361

1

dephosphorylation

down-regulates activity

0.665

The activation of the mapk activity requires the dual phosphorylation of the ser/thr and tyr residues in the txy kinase activation motif (1113), and deactivation occurs through the action of either ser/thr protein phosphatase (14), protein-tyrosine phosphatase (ptp) (14, 15), or dual specificity phosphatases

SIGNOR-103035

Q14653

P01574

1

transcriptional regulation

up-regulates quantity by expression

0.665

Similarly, exogenous expression of wild-type Pin1 suppressed TLR3-mediated, IRF3-dependent activation of the IFN-beta promoter and reduced IFN-beta secretion in culture supernatants

SIGNOR-252257

O14965

P53350

1

phosphorylation

up-regulates

0.665

We find that aurora a (aurka) can directly phosphorylate plk1 on thr 210;activation of plk1 requires phosphorylation of a conserved threonine residue (thr 210).

SIGNOR-179422

Q13115

Q16539

1

dephosphorylation

down-regulates

0.665

This result suggests that dusp4 represses gluconeogenesis through dephosphorylation of p38

SIGNOR-147958

P11802

P38398

1

phosphorylation

down-regulates

0.665

In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo.

SIGNOR-153450

Q99942

P13569

1

ubiquitination

down-regulates quantity by destabilization

0.665

JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation.

SIGNOR-271494

Q9HC23

Q8NFJ6

1

binding

up-regulates

0.665

We have cloned two closely related receptors for pk1 and pk2. These receptors, named prokineticin receptor 1 and 2 (pkr1 and pkr2)

SIGNOR-87919

P10911

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.665

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-260557

Q8NEB9

P60484

1

binding

up-regulates

0.665

Direct positive regulation of pten by the p85 subunit of phosphatidylinositol 3-kinase.Thus p85 regulates both p110-pi3k and pten-phosphatase enzymes through direct interaction

SIGNOR-164075

P35398

Q99743

1

transcriptional regulation

up-regulates quantity by expression

0.665

Direct Regulation of the NPAS2 Promoter by 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-267980

Q5TD97

Q03060

1

binding

up-regulates activity

0.665

ACT (for activator of CREM in testis), a LIM-only protein which specifically associates with CREM. ACT is expressed coordinately with CREM in a tissue- and developmentally regulated manner. It strongly stimulates CREM transcriptional activity in yeast and mammalian cells and contains an intrinsic activation function.

SIGNOR-222111

P27037

Q04771

1

binding

up-regulates

0.664

The major bmp7 type i receptor observed was alk2,

SIGNOR-60234

Q9Y297

P08151

1

ubiquitination

down-regulates quantity by destabilization

0.664

Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation. We identify two independent destruction signals in Gli1, D(N) and D(C), and show that removal of these signals stabilizes Gli1 protein and rapidly accelerates tumor formation in transgenic animals.Levels of _TrCP appeared to be limiting for Gli1 degradation, as increasing the levels of _TrCP protein significantly decreased steady-state levels of Gli1 protein

SIGNOR-235631

O00744

Q9UP38

1

binding

up-regulates

0.664

Inhibition of adipogenesis by wnt10b is likely mediated by wnt receptors, frizzled 1, 2, and/or 5, and co-receptors low density lipoprotein receptor-related proteins 5 and 6

SIGNOR-89134

P38936

Q00526

1

binding

down-regulates

0.664

P21cip1 is a cyclin-dependent kinase (cdk) inhibitor that is transcriptionally activated by p53 in response to dna damage. We have explored the interaction of p21 with the currently known cdks. p21 effectively inhibits cdk2, cdk3, cdk4, and cdk6 kinases.

SIGNOR-29954

Q8IXL6

Q9NP70

1

phosphorylation

up-regulates activity

0.664

Disruption of Fam20C completely eliminated AMBN phosphorylation, suggesting that Fam20C is the kinase that phosphorylates enamel matrix proteins in vivo (XREF_FIG).

SIGNOR-280010

Q99731

Q9NPB9

1

binding

up-regulates activity

0.664

In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.

SIGNOR-268416

P19883

O95390

1

binding

down-regulates activity

0.664

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

SIGNOR-251716

O15444

Q9NPB9

1

binding

up-regulates activity

0.664

In the present study, however, we demonstrate for the first time the concentration-dependent recruitment of β-arrestins to the atypical chemokine receptor CCX-CKR upon stimulation with CCL19, CCL21, or CCL25 using three different methodologies in various transfected cell lines.

SIGNOR-268418

Q9UPT6

P45984

2

binding

up-regulates

0.663

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

SIGNOR-134561

P45984

Q9UPT6

2

phosphorylation

up-regulates

0.663

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

SIGNOR-134576

P19793

P10827

1

binding

up-regulates

0.663

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

SIGNOR-81446

Q9P209

Q96SN8

1

relocalization

up-regulates activity

0.663

By bringing CDK5RAP2 to the centrosome, the centriolar satellite proteins CEP72 and SPAG5 are required for the centrosomal localization of the other three MCPH proteins despite not interacting with them biochemically.

SIGNOR-271720

Q9BXH1

P10415

1

binding

down-regulates activity

0.663

Only bimbh3 and bbc3 had comparable strong affinitiesfor all the prosurvival proteins. The members that promote cell survival, including mammalian bcl-2, bcl-xl,bcl-w, mcl-1, and a1.

SIGNOR-133808

Q13490

O15519

1

ubiquitination

down-regulates quantity

0.663

Moreover, API-1 increased c-FLIP ubiquitination and decreased c-FLIP stability.|Thus, we conclude that API-1 reduces c-FLIP levels by facilitating its degradation through the ubiquitin and proteasome dependent pathway.

SIGNOR-278687

P16473

P63092

1

binding

up-regulates activity

0.663

The primary signal transduction pathway for TSH receptor is activation of adenylate cyclase via a Gαs G protein-coupled receptor.

SIGNOR-267136

P53350

P30305

1

phosphorylation

up-regulates activity

0.663

These data indicated that PLK1 phosphorylates CDC25B and that pre-phosphorylation of CDC25B by CDK1/CyclinB enhances its substrate properties for PLK1 in vitro

SIGNOR-267560

Q14694

P04637

1

deubiquitination

up-regulates quantity by stabilization

0.662

Since USP10 is known as a deubiquitinating protease of p53 (Yuan et al., 2010), inhibition of USP10 by spautin-1 may promote the degradation of p53.

SIGNOR-260297