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
Q9NWZ3	P51617	1	phosphorylation	up-regulates activity	0.687	In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1.	SIGNOR-117315
P27694	P09884	1	binding	up-regulates activity	0.687	In our studies, we have shown that T antigen, DNA polymerase R, and the activation domain of VP16 all interact with overlapping regions of the 70-kDa subunit of RPA.\| In the latter, both the direct protein-protein interaction and ssDNA-binding activities of RPA were needed for RPA to modulate polymerase processivity. We also found that SV40 T antigen inhibited the ability of RPA to increase processivity of DNA polymerase alpha, suggesting that this activity of RPA may be important for elongation but not during the initiation of DNA replication.	SIGNOR-261272
Q13131	Q8N122	1	phosphorylation	down-regulates activity	0.687	Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2.	SIGNOR-173035
P31749	Q13370	1	phosphorylation	up-regulates	0.687	Pde3b is a physiological substrate of akt and that akt-mediated phosphorylation of pde3b on serine-273 is important for insulin-induced activation of pde3b.	SIGNOR-252583
P29597	P40763	1	phosphorylation	up-regulates	0.687	Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated	SIGNOR-256255
O00587	Q04721	1	binding	up-regulates	0.687	These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch (30, 31). It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2.	SIGNOR-107708
P38435	P02818	1	carboxylation	up-regulates activity	0.687	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265922
O60258	P21802	1	binding	up-regulates	0.687	Fgfs bind and activate high-affinity receptor tyrosine kinases. The cloning of fgf receptors (fgfrs) has identified four distinct genes	SIGNOR-42365
P27037	P36896	1	phosphorylation	up-regulates	0.687	In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase	SIGNOR-99995
P41743	Q6P1M3	1	phosphorylation	up-regulates activity	0.687	This finding indicates that both mLgl-2 and mLgl-1 are phosphorylated in vivo in an aPKC lambda activity-dependent manner.	SIGNOR-263180
P49841	P13807	1	phosphorylation	down-regulates activity	0.686	Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-.	SIGNOR-253007
Q4G0J3	O94992	1	binding	down-regulates activity	0.686	To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system.	SIGNOR-261183
P45983	Q92934	1	phosphorylation	down-regulates	0.686	Jnk phosphorylates bad at threonine 201, thereby inhibiting bad association with the antiapoptotic molecule bcl-x(l)	SIGNOR-121940
Q9H6I2	P35222	1	binding	down-regulates	0.686	Two additional sox proteins, xsox17alfa and xsox3 , likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity	SIGNOR-72006
Q16654	P08559	1	phosphorylation	down-regulates	0.686	Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase.	SIGNOR-33201
P15927	Q8WXE1	1	binding	up-regulates	0.686	Ssdna lesions are then coated by replication protein a (rpa), recruiting atr/atrip (atr-interacting protein) complexes via recognition and association of rpa-ssdna by atrip.	SIGNOR-163176
P19793	P13631	2	binding	up-regulates	0.686	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16671
Q14164	Q12933	1	phosphorylation	up-regulates activity	0.686	IKKepsilon phosphorylates TRAF2 at Ser11 to activate NF-kappaB and promote malignant transformation.	SIGNOR-279195
Q12888	Q5UIP0	1	binding	up-regulates activity	0.686	RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination.	SIGNOR-259058
P06493	Q99661	1	phosphorylation	down-regulates	0.686	We show here that cyclin-dependent kinase 1 (cdk1) phosphorylates t537 in the core domain of mcak and attenuates its microtubule-destabilizing activity in vitro and in vivo. Phosphorylation of mcak by cdk1 promotes the release of mcak from centrosomes and is required for proper spindle formation.	SIGNOR-164761
P35968	P62993	1	relocalization	up-regulates activity	0.686	In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.	SIGNOR-261948
P35222	O43474	1	binding	up-regulates activity	0.686	The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes.	SIGNOR-242100
Q9HD67	P43146	2	relocalization	up-regulates quantity	0.686	Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin.	SIGNOR-268282
P46108	Q92918	1	binding	up-regulates	0.686	We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk.	SIGNOR-63988
P12830	P35221	1	binding	up-regulates	0.686	Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm.	SIGNOR-203468
Q7Z5G4	Q9Y397	1	binding	up-regulates activity	0.686	DHHC9 and GCP16 form a protein complex, and DHHC9 requires GCP16 for protein fatty acyltransferase activity and protein stability.	SIGNOR-261353
P43146	Q9HD67	2	binding	up-regulates activity	0.686	Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin.	SIGNOR-268281
O75888	Q02223	1	binding	up-regulates	0.686	April is involved in stimulation of b and t cell function. April functions via binding to bcma and taci and competes with tall-i for receptor binding.	SIGNOR-81386
P13631	P19793	2	binding	up-regulates	0.686	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16659
P06493	O15392	1	phosphorylation	up-regulates	0.686	Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosisin synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on thr(34), in vivo	SIGNOR-115129
P15498	P62993	1	binding	up-regulates	0.686	Recently, we have shown that the proto-oncogene vav product (vav) is also tyrosine-phosphorylated by treatment with gm-csf and epo and is constitutively associated with the sh3 domain of grb2/ash in ut-7.	SIGNOR-49362
P00519	P43351	1	phosphorylation	up-regulates activity	0.685	C-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. he functional significance of c-Abl-dependent phosphorylation of Rad52 is underscored by our findings that cells that express the phosphorylation-resistant Rad52 mutant, in which tyrosine 104 is replaced by phenylalanine, exhibit compromised nuclear foci formation in response to IR.	SIGNOR-251435
Q6ZNA4	Q15796	1	ubiquitination	down-regulates quantity by destabilization	0.685	Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.	SIGNOR-236873
Q15554	Q13315	1	binding	down-regulates activity	0.685	It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex	SIGNOR-263323
P84022	P01106	2	transcriptional regulation	down-regulates quantity by repression	0.685	Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter.	SIGNOR-251494
Q9Y4H2	P42336	1	binding	up-regulates activity	0.685	These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients.	SIGNOR-251492
P78543	P17482	1	binding	up-regulates activity	0.685	The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation.	SIGNOR-220987
Q13464	P19634	1	phosphorylation	up-regulates activity	0.685	We then engineered the T653A NHE1 mutant (ROCKA mutant), which can not be phosphorylated by p160ROCK.\|p160ROCK has also been shown to activate NHE1 at threonine 653 , in close vicinity to the Akt phosphorylation site at serine 648.	SIGNOR-279566
P22455	Q8WU20	1	phosphorylation	up-regulates activity	0.685	In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.	SIGNOR-242661
O94856	P16157	1	relocalization	up-regulates quantity	0.685	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266718
O43264	Q13561	1	relocalization	up-regulates activity	0.685	ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores	SIGNOR-265016
O43353	Q9Y4K3	1	binding	up-regulates activity	0.685	Binding of bacterial MDP or viral RNA to NOD2 results in the association of RIPK2 with TRAF6 and subsequent activation of TRAF6.	SIGNOR-280456
O15198	Q13485	1	phosphorylation	up-regulates	0.685	Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.	SIGNOR-168740
P01106	P84022	2	binding	down-regulates activity	0.685	Through its direct interaction with smads, c-myc binds to the sp1-smad complex on the promoter of the p15(ink4b) gene, thereby inhibiting the tgf-beta-induced transcriptional activity of sp1 and smad/sp1-dependent transcription of the p15(ink4b) gene. These results suggest that oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads.	SIGNOR-114284
P01229	P22888	1	binding	up-regulates	0.684	Hcg is a heterodimeric glycoprotein hormone, consisting of a common? -subunit and a hormone-specific ?-Subunit (2). It binds to the lh receptor (lhr).	SIGNOR-70028
P35869	P04798	1	transcriptional regulation	up-regulates quantity by expression	0.684	Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1.	SIGNOR-259909
P10721	Q06124	1	phosphorylation	up-regulates activity	0.684	SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation.	SIGNOR-256140
P53350	O00139	1	phosphorylation	up-regulates activity	0.684	Taken together, KIF2A is phosphorylated at T554 by PLK1 in the subdistal appendages of the mother centriole, which enhances MT depolymerization to disassemble primary cilia in a growth-signal-dependent manner.\|Thus, PLK1 and APC/C mediated dual regulation connect the MT depolymerizing activity of KIF2A to a physiological primary cilia disassembly during the proliferative phase.	SIGNOR-278380
P24941	Q12834	1	phosphorylation	down-regulates activity	0.684	Here we show that cyclin A2-Cdk2 binds and phosphorylates Cdc20 in interphase and this inhibits APC/C-Cdc20 activity.\|Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry.	SIGNOR-279322
Q16816	P11217	1	phosphorylation	up-regulates activity	0.684	It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15	SIGNOR-267398
P12931	P49407	1	phosphorylation	down-regulates	0.684	Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors.	SIGNOR-154564
P42574	O76075	1	cleavage	up-regulates	0.684	Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation	SIGNOR-47419
Q13635	P14635	1	binding	up-regulates	0.684	In addition, we demonstrate that endogenous ptc1 and endogenous cyclin B1 interact in vivo. The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. Thus, we propose that ptc1 participates in a G2/M checkpoint by regulating the localization of MPF.	SIGNOR-199147
P38435	P00740	1	carboxylation	up-regulates activity	0.683	The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. \|In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes\|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.	SIGNOR-263687
Q6ZVD8	Q9Y243	1	dephosphorylation	down-regulates activity	0.683	The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.\|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.	SIGNOR-248731
Q5VTY9	Q15465	1	palmitoylation	up-regulates	0.683	Our molecular analysis of knockout mice deficient in skn, the murine homolog of the drosophila ski gene, which catalyzes hh palmitoylation, and gene-targeted mice producting a non palmitoylated form of shh indicates that hh palmitoylation is essential for its activity as well as the generation of a protein gradient in the developing embryos	SIGNOR-124118
Q96DX5	P12277	1	polyubiquitination	down-regulates quantity by destabilization	0.683	We demonstrate that creatine kinase B (CKB) interacts with Asb-9 in a specific, SOCS box-independent manner. This interaction increases the polyubiquitylation of CKB and decreases total CKB levels within the cell. The targeting of CKB for degradation by Asb-9 was primarily SOCS box-dependent and suggests that Asb-9 acts as a specific ubiquitin ligase regulating levels of this evolutionarily conserved enzyme.	SIGNOR-271623
Q8IXL6	P10451	1	phosphorylation	down-regulates quantity	0.683	OPN phosphorylation by Fam20C decreased OPN secretion, and OPN neutralization reduced Fam20C-deficiency-induced osteoclast differentiation and bone metastasis.	SIGNOR-278936
Q9UL15	P0DMV9	1	binding	down-regulates activity	0.683	Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction.	SIGNOR-261197
Q86VP1	P21580	1	binding	up-regulates activity	0.683	Tx1bp1 appears to be a novel a20-binding protein which mediate the anti-apoptotic activity of a20; tax1bp1 phosphorylation was pivotal for cytokine-dependent interactions among tax1bp1, a20, itch and rnf11 and downregulation of signaling by the transcription factor nf-Kb.	SIGNOR-69921
Q8NFG4	Q9NQL2	1	gtpase-activating protein	up-regulates activity	0.683	The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur	SIGNOR-256504
Q15418	P17676	1	phosphorylation	up-regulates activity	0.683	13 The data presented support previous findings that C/EBPbeta can be a molecular target of RSK1, 16 but provide the first indication that RSK1 can phosphorylate and activate C/EBPbeta to mediate the IL-6 signalling events in cholangiocarcinoma.\|As mentioned above, RSK1 has been shown to activate C/EBPbeta in hepatic stellate cells in an experimental model of liver fibrosis.	SIGNOR-280112
P19793	P10826	2	binding	up-regulates	0.682	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16668
P31751	P38936	1	binding	down-regulates activity	0.682	Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.	SIGNOR-149705
Q13131	P49815	1	phosphorylation	up-regulates activity	0.682	However, AMP-activated protein kinase (AMPK), an essential cellular energy sensor, phosphorylates and activates TSC2 [ xref ].	SIGNOR-278981
P26441	P40189	1	binding	up-regulates	0.682	Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2.	SIGNOR-47991
Q6PJG9	P78352	1	binding	up-regulates activity	0.682	SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. One possibility is that SALM3, which is capable of inducing presynaptic differentiation in contacting axons [19], recruits PSD-95 or SAP102 to the sites of early synaptic adhesion.	SIGNOR-264096
P10826	P19793	2	binding	up-regulates	0.682	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16519
Q9Y239	Q676U5	1	binding	up-regulates activity	0.681	By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.	SIGNOR-252406
O15297	Q00987	1	dephosphorylation	up-regulates	0.681	Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation.	SIGNOR-158328
Q07817	P55211	1	binding	down-regulates activity	0.681	Bcl2l1 associates with casp9 and apaf-1 in mammalian cells.Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation	SIGNOR-56402
P28562	P45984	1	dephosphorylation	down-regulates	0.681	We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. the dual specific phosphatases pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively.	SIGNOR-40879
P13497	P02452	1	cleavage	up-regulates activity	0.681	BMP-1myc Expressed in COS-7 Cells Exhibits Procollagen C-proteinase Activity. Bone morphogenetic protein (BMP)-1, which belongs to the tolloid subgroup of astacin-like zinc metalloproteinases, cleaves the C-propeptides of procollagen at the physiologic site and is, therefore, a procollagen C-proteinase (PCP). Cleavage occurs between a specific alanine or glycine residue (depending on the procollagen chain) and an invariant aspartic acid residue in each of the three chains of procollagen.	SIGNOR-256342
Q09472	P15172	1	acetylation	up-regulates	0.681	Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.	SIGNOR-81053
P28482	P49815	1	phosphorylation	down-regulates activity	0.681	Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. \|Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.	SIGNOR-249454
P21675	P04637	1	phosphorylation	down-regulates	0.681	Phosphorylation on thr-55 by taf1 mediates degradation of p53	SIGNOR-123651
Q05086	P04637	1	ubiquitination	down-regulates quantity	0.681	E6-AP also directly ubiquitylated p53 in an in vitro ubiquitylation assay.\|Our result suggests that E6-AP not only enhances the degradation of p53 but also regulates the neuronal cell growth.	SIGNOR-278681
Q13043	O43524	1	phosphorylation	up-regulates	0.681	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity.	SIGNOR-178190
Q13627	Q52LA3	1	phosphorylation	up-regulates activity	0.681	Here we report that DYRK1A can specifically phosphorylate LIN52 on serine residue 28, and that this phosphorylation is required for DREAM assembly.	SIGNOR-262846
Q06124	P01112	1	dephosphorylation	up-regulates activity	0.681	Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.	SIGNOR-252094
P08631	P19174	1	phosphorylation	up-regulates activity	0.681	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249361
O14965	Q9NWT8	1	phosphorylation	up-regulates quantity by stabilization	0.681	AIP is phosphorylated on Serine 70 by Aurora‐A but not Aurora‐B and expression of phosphorylation mimic mutant of AIP results in prolonged protein stability compared to unphosphorylatable mutant. Phosphorylation of AIP Prolongs its Protein Stability	SIGNOR-262648
P12931	P35228	1	phosphorylation	up-regulates	0.681	We identify human inos residue tyr(1055) as a target for src-mediated phosphorylation. src kinase-mediated phosphorylation stabilizes inducible nitric-oxide synthase in normal cells and cancer cells.	SIGNOR-188974
P20338	Q96T51	1	binding	up-regulates activity	0.68	Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.\|We also found that enlargement of early endosomes mediated by RUFY1 requires its interaction with Rab4	SIGNOR-261280
P68400	P60484	1	phosphorylation	down-regulates activity	0.68	The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity	SIGNOR-89830
P84103	Q9UBU9	1	binding	up-regulates	0.68	9g8 and srp20 also enhance the tap rna-binding activity	SIGNOR-178111
Q13976	P41220	1	phosphorylation	up-regulates activity	0.68	Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction.	SIGNOR-249241
P28482	Q9UQC2	1	phosphorylation	up-regulates	0.68	Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623.	SIGNOR-128727
P28482	P35568	1	phosphorylation	down-regulates activity	0.68	Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation.	SIGNOR-123173
O00238	Q99717	1	phosphorylation	up-regulates activity	0.68	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-255260
P09619	P62993	1	binding	up-regulates	0.68	A pathway leading to activation of the gtp-binding protein ras involves the adaptor molecule grb2. Here we show that tyr-716, a novel autophosphorylation site in the pdgf beta-receptor kinase insert, mediates direct binding of grb2 in vitro and in vivo.	SIGNOR-34765
P06493	P49450	1	phosphorylation	down-regulates quantity by destabilization	0.68	Here, we report that the phosphorylation of CENP-A Ser68 primes the ubiquitin-proteasome-mediated proteolysis of CENP-A during mitotic phase in human cultured cells.the mitotic CENP-A degradation specifically depends on Cdk1 activity.	SIGNOR-277576
P62166	P14416	1	binding	down-regulates activity	0.68	Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization.	SIGNOR-263964
Q13464	P35241	1	phosphorylation	up-regulates activity	0.68	A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kcphosphorylated C-rad as T564-phosphorylated C-rad. \| In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active.	SIGNOR-248994
P17948	P19174	1	binding	up-regulates	0.679	We conclude that both flt-1 and kdr have the potential to signal through plc gamma via phosphotyrosine residues located in juxta-membrane and carboxyl tail regions	SIGNOR-53743
Q16236	P09601	1	transcriptional regulation	up-regulates quantity by expression	0.679	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256276
Q15119	P08559	1	phosphorylation	down-regulates	0.679	Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase.	SIGNOR-33141
P05362	P20702	1	binding	up-regulates	0.679	Using assays to quantify cd11c-mediated cell adhesion, we demonstrate that cd11c recognizes icam-2 and vcam-1. The cd11c-binding site on vcam-1 appears to be different from that used by the integrin alpha4.	SIGNOR-31388
P17706	P42226	1	dephosphorylation	down-regulates activity	0.679	These results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors	SIGNOR-235192
O15105	O75807	1	binding	up-regulates	0.679	We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI.	SIGNOR-121280

Q9NWZ3

P51617

1

phosphorylation

up-regulates activity

0.687

In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant-negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL-1 receptors, upstream of IRAK-1.

SIGNOR-117315

P27694

P09884

1

binding

up-regulates activity

0.687

In our studies, we have shown that T antigen, DNA polymerase R, and the activation domain of VP16 all interact with overlapping regions of the 70-kDa subunit of RPA.| In the latter, both the direct protein-protein interaction and ssDNA-binding activities of RPA were needed for RPA to modulate polymerase processivity. We also found that SV40 T antigen inhibited the ability of RPA to increase processivity of DNA polymerase alpha, suggesting that this activity of RPA may be important for elongation but not during the initiation of DNA replication.

SIGNOR-261272

Q13131

Q8N122

1

phosphorylation

down-regulates activity

0.687

Ampk in turn inactivates mtorc1 directly by phosphorylating raptor and indirectly by phosphorylating tsc2.

SIGNOR-173035

P31749

Q13370

1

phosphorylation

up-regulates

0.687

Pde3b is a physiological substrate of akt and that akt-mediated phosphorylation of pde3b on serine-273 is important for insulin-induced activation of pde3b.

SIGNOR-252583

P29597

P40763

1

phosphorylation

up-regulates

0.687

Since Jak-STAT pathway primarily activated in IL-15-me- diated cell proliferation, we tested whether it is also participates in IL-15-mediated proliferation of FAPs. Interestingly, we found the expression of phospho-Jak3 and phospho-Tyk2, as well as their downstream, phospho- STAT3 and phospho-STAT5, was significantly upregulated

SIGNOR-256255

O00587

Q04721

1

binding

up-regulates

0.687

These observations indicate that the fringe proteins directly modify notch2, which is consistent with the recent finding that fringe is a glycosyltransferase that directly modifies notch (30, 31). It was further indicated that lfng does this at a site from the n terminus through the 15th egf repeat of notch2, and mfng does so at a site from the 23rd through the 29th egf repeat of notch2.

SIGNOR-107708

P38435

P02818

1

carboxylation

up-regulates activity

0.687

Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.

SIGNOR-265922

O60258

P21802

1

binding

up-regulates

0.687

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

SIGNOR-42365

P27037

P36896

1

phosphorylation

up-regulates

0.687

In this complex, the actrii??/Iib kinase phosphorylates alk4 within a glycine- and serine-rich region called the gs domain, and this phosphorylation event activates the alk4 kinase

SIGNOR-99995

P41743

Q6P1M3

1

phosphorylation

up-regulates activity

0.687

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

SIGNOR-263180

P49841

P13807

1

phosphorylation

down-regulates activity

0.686

Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-.

SIGNOR-253007

Q4G0J3

O94992

1

binding

down-regulates activity

0.686

To investigate whether LARP7 is part of the known 7SK RNP implicated in the regulation of transcription, co‐immunoprecipitation studies were performed using the nuclear extracts of HeLa cells (Fig 3A, lanes 1–4). Antibodies against LARP7, CDK9 and HEXIM1 efficiently precipitated 7SK RNA, whereas no RNA was found in the control (Fig 3A, lower panel, lanes 1–4). Interestingly, HEXIM1, CDK9, CYCT1 and LARP7 were present in all immunopurifications, as determined by mass spectrometry of silver‐stained gels (Fig 3A; data not shown) and western blotting. In conclusion, these experiments show that LARP7 negatively regulates not only viral but also cellular POLII class genes through the 7SK P‐TEFb system.

SIGNOR-261183

P45983

Q92934

1

phosphorylation

down-regulates

0.686

Jnk phosphorylates bad at threonine 201, thereby inhibiting bad association with the antiapoptotic molecule bcl-x(l)

SIGNOR-121940

Q9H6I2

P35222

1

binding

down-regulates

0.686

Two additional sox proteins, xsox17alfa and xsox3 , likewise bind to beta-catenin and inhibit its tcf-mediated signaling activity

SIGNOR-72006

Q16654

P08559

1

phosphorylation

down-regulates

0.686

Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase.

SIGNOR-33201

P15927

Q8WXE1

1

binding

up-regulates

0.686

Ssdna lesions are then coated by replication protein a (rpa), recruiting atr/atrip (atr-interacting protein) complexes via recognition and association of rpa-ssdna by atrip.

SIGNOR-163176

P19793

P13631

2

binding

up-regulates

0.686

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

SIGNOR-16671

Q14164

Q12933

1

phosphorylation

up-regulates activity

0.686

IKKepsilon phosphorylates TRAF2 at Ser11 to activate NF-kappaB and promote malignant transformation.

SIGNOR-279195

Q12888

Q5UIP0

1

binding

up-regulates activity

0.686

RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination.

SIGNOR-259058

P06493

Q99661

1

phosphorylation

down-regulates

0.686

We show here that cyclin-dependent kinase 1 (cdk1) phosphorylates t537 in the core domain of mcak and attenuates its microtubule-destabilizing activity in vitro and in vivo. Phosphorylation of mcak by cdk1 promotes the release of mcak from centrosomes and is required for proper spindle formation.

SIGNOR-164761

P35968

P62993

1

relocalization

up-regulates activity

0.686

In a similar fashion, KDR associates with Grb2 and Nck in a ligand-dependent fashion, suggesting Shc, Grb2, and Nck as potential candidates involved in the regulation of endothelial function.

SIGNOR-261948

P35222

O43474

1

binding

up-regulates activity

0.686

The interaction of Beta-catenin with Tcf is important for Beta-catenin s's function in iPSCs induction. In addition, Beta-catenin interacts with Oct4, Sox2, and Klf4, respectively. In the reprogramming process, Beta-catenin further enhances expression of pluripotency-related genes.

SIGNOR-242100

Q9HD67

P43146

2

relocalization

up-regulates quantity

0.686

Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin.

SIGNOR-268282

P46108

Q92918

1

binding

up-regulates

0.686

We found that hpk1 interacted with crk and crkl adaptor proteins in vitro and in vivo and that the proline-rich motifs within hpk1 were involved in the differential interaction of hpk1 with the crk proteins and grb2. Crk and crkl not only activated hpk1 but also synergized with hpk1 in the activation of jnk.

SIGNOR-63988

P12830

P35221

1

binding

up-regulates

0.686

Additionally, the E-cadherin associated protein _-catenin regulates YAP directly by sequestering YAP/14-3-3 complexes in the cytoplasm.

SIGNOR-203468

Q7Z5G4

Q9Y397

1

binding

up-regulates activity

0.686

DHHC9 and GCP16 form a protein complex, and DHHC9 requires GCP16 for protein fatty acyltransferase activity and protein stability.

SIGNOR-261353

P43146

Q9HD67

2

binding

up-regulates activity

0.686

Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin.

SIGNOR-268281

O75888

Q02223

1

binding

up-regulates

0.686

April is involved in stimulation of b and t cell function. April functions via binding to bcma and taci and competes with tall-i for receptor binding.

SIGNOR-81386

P13631

P19793

2

binding

up-regulates

0.686

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

SIGNOR-16659

P06493

O15392

1

phosphorylation

up-regulates

0.686

Survivin is a member of the inhibitor of apoptosis gene family that has been implicated in both apoptosis inhibition and regulation of mitosisin synchronized cultures, cytosolic survivin abruptly increased at mitosis, physically associated with p34(cdc2), and was phosphorylated by p34(cdc2) on thr(34), in vivo

SIGNOR-115129

P15498

P62993

1

binding

up-regulates

0.686

Recently, we have shown that the proto-oncogene vav product (vav) is also tyrosine-phosphorylated by treatment with gm-csf and epo and is constitutively associated with the sh3 domain of grb2/ash in ut-7.

SIGNOR-49362

P00519

P43351

1

phosphorylation

up-regulates activity

0.685

C-Abl tyrosine kinase associates with and phosphorylates Rad52 on tyrosine 104. he functional significance of c-Abl-dependent phosphorylation of Rad52 is underscored by our findings that cells that express the phosphorylation-resistant Rad52 mutant, in which tyrosine 104 is replaced by phenylalanine, exhibit compromised nuclear foci formation in response to IR.

SIGNOR-251435

Q6ZNA4

Q15796

1

ubiquitination

down-regulates quantity by destabilization

0.685

Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblastsarkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.

SIGNOR-236873

Q15554

Q13315

1

binding

down-regulates activity

0.685

It is not yet clear how the presence of TRF2 at telomeres averts the activation of the ATM kinase.> In this regard, overexpression of TRF2can dampen the activation of the ATM kinase, even at nontelomeric sites of DNA damage (95). Furthermore, TRF2 can interact with the ATM kinase as well as with the Mre11 complex

SIGNOR-263323

P84022

P01106

2

transcriptional regulation

down-regulates quantity by repression

0.685

Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter.

SIGNOR-251494

Q9Y4H2

P42336

1

binding

up-regulates activity

0.685

These results strongly suggest that the IGF2–IGF1R–IRS2 axis signals to PI3K in CRC and imply that therapeutic targeting of the pathway could act to block PI3K activity in this subset of patients.

SIGNOR-251492

P78543

P17482

1

binding

up-regulates activity

0.685

The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation.

SIGNOR-220987

Q13464

P19634

1

phosphorylation

up-regulates activity

0.685

We then engineered the T653A NHE1 mutant (ROCKA mutant), which can not be phosphorylated by p160ROCK.|p160ROCK has also been shown to activate NHE1 at threonine 653 , in close vicinity to the Akt phosphorylation site at serine 648.

SIGNOR-279566

P22455

Q8WU20

1

phosphorylation

up-regulates activity

0.685

In this report, we demonstrate that FGF stimulation induces tyrosine phosphorylation of a novel lipid anchored docking protein, termed FRS2, that forms a complex with Grb2/Sos, thus linking FGF-receptor activation to the Ras/MAPK signaling pathway.

SIGNOR-242661

O94856

P16157

1

relocalization

up-regulates quantity

0.685

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

SIGNOR-266718

O43264

Q13561

1

relocalization

up-regulates activity

0.685

ZW10 interacts with dynamitin, a subunit of the dynein-dynactin complex (Echeverri et al., 1996), thereby recruiting this motor to kinetochores

SIGNOR-265016

O43353

Q9Y4K3

1

binding

up-regulates activity

0.685

Binding of bacterial MDP or viral RNA to NOD2 results in the association of RIPK2 with TRAF6 and subsequent activation of TRAF6.

SIGNOR-280456

O15198

Q13485

1

phosphorylation

up-regulates

0.685

Whereas alk5 signalling is mediated by phosphorylation of smad2 and smad3 proteins, alk1 signalling is mediated by smad1, smad5, and smad8. Activated smads form a complex with the common smad (co-smad; smad4 in mammals) and shuttle into the nucleus.

SIGNOR-168740

P01106

P84022

2

binding

down-regulates activity

0.685

Through its direct interaction with smads, c-myc binds to the sp1-smad complex on the promoter of the p15(ink4b) gene, thereby inhibiting the tgf-beta-induced transcriptional activity of sp1 and smad/sp1-dependent transcription of the p15(ink4b) gene. These results suggest that oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads.

SIGNOR-114284

P01229

P22888

1

binding

up-regulates

0.684

Hcg is a heterodimeric glycoprotein hormone, consisting of a common? -subunit and a hormone-specific ?-Subunit (2). It binds to the lh receptor (lhr).

SIGNOR-70028

P35869

P04798

1

transcriptional regulation

up-regulates quantity by expression

0.684

Kaempferol proved to be capable of inhibiting binding of agonist and agonist-induced formation of the AHR/ARNT DNA-binding complex and upregulation of the AHR target gene, CYP1A1.

SIGNOR-259909

P10721

Q06124

1

phosphorylation

up-regulates activity

0.684

SHP2 can be phosphorylated at 2 C-terminal tyrosyl residues by receptor tyrosine kinases, including KIT as well as cytosolic tyrosine kinases, including Src and Abl. The level of tyrosyl phosphorylation of SHP2 has been associated with its recruitment to the receptor.Thus, pharmacologic inhibition of SHP2 phosphatase function might permit SHP2 to return to its inactive conformation resulting in reduced tyrosine phosphorylation.

SIGNOR-256140

P53350

O00139

1

phosphorylation

up-regulates activity

0.684

Taken together, KIF2A is phosphorylated at T554 by PLK1 in the subdistal appendages of the mother centriole, which enhances MT depolymerization to disassemble primary cilia in a growth-signal-dependent manner.|Thus, PLK1 and APC/C mediated dual regulation connect the MT depolymerizing activity of KIF2A to a physiological primary cilia disassembly during the proliferative phase.

SIGNOR-278380

P24941

Q12834

1

phosphorylation

down-regulates activity

0.684

Here we show that cyclin A2-Cdk2 binds and phosphorylates Cdc20 in interphase and this inhibits APC/C-Cdc20 activity.|Interphase APC/C-Cdc20 inhibition by cyclin A2-Cdk2 ensures efficient mitotic entry.

SIGNOR-279322

Q16816

P11217

1

phosphorylation

up-regulates activity

0.684

It is well-characterized that GP is activated by PhK-mediated serine phosphorylation at Ser-15

SIGNOR-267398

P12931

P49407

1

phosphorylation

down-regulates

0.684

Using fluorescently tagged proteins combined with resonance energy transfer and image cross-correlation spectroscopy approaches, we show in live cells that beta2-adaptin phosphorylation is an important regulatory process for the dissociation of beta-arrestin-AP-2 complexes in CCPs. Finally, we show that beta2-adaptin phosphorylation is involved in the early steps of receptor internalization. Our findings not only unveil beta2-adaptin as a new Src target during AT1R internalization, but also support the role of receptor-mediated signaling in the control of clathrin-dependent endocytosis of receptors.

SIGNOR-154564

P42574

O76075

1

cleavage

up-regulates

0.684

Casp3_ cleaves the 45 kda subunit at two sites to generate an active factor that produces_ dna_ fragmentation

SIGNOR-47419

Q13635

P14635

1

binding

up-regulates

0.684

In addition, we demonstrate that endogenous ptc1 and endogenous cyclin B1 interact in vivo. The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. Thus, we propose that ptc1 participates in a G2/M checkpoint by regulating the localization of MPF.

SIGNOR-199147

P38435

P00740

1

carboxylation

up-regulates activity

0.683

The direct gamma-carboxyglutamic acid analysis and the N-terminal sequence analysis of the myotube-synthesized F.IX demonstrate efficient carboxylation at 11 of 12 γ-carboxyglutamic acid residues. |In previous work54 we have demonstrated that the γ-glutamyl carboxylase is present in skeletal muscle, but at a level only 5% to 10% of that found in the liver. This level of enzyme appears to be sufficient to provide full carboxylation of F.IX synthesized in myotubes|Glu 7, 8, 15, 17, 20, 21, 26, 27, 30, 33, and 36 are each less than 10% of the yield at the previous and subsequent cycles. Only a single γ-carboxylated residue, Gla 40, was not assessed by N-terminal sequencing.

SIGNOR-263687

Q6ZVD8

Q9Y243

1

dephosphorylation

down-regulates activity

0.683

The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells.|Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.

SIGNOR-248731

Q5VTY9

Q15465

1

palmitoylation

up-regulates

0.683

Our molecular analysis of knockout mice deficient in skn, the murine homolog of the drosophila ski gene, which catalyzes hh palmitoylation, and gene-targeted mice producting a non palmitoylated form of shh indicates that hh palmitoylation is essential for its activity as well as the generation of a protein gradient in the developing embryos

SIGNOR-124118

Q96DX5

P12277

1

polyubiquitination

down-regulates quantity by destabilization

0.683

We demonstrate that creatine kinase B (CKB) interacts with Asb-9 in a specific, SOCS box-independent manner. This interaction increases the polyubiquitylation of CKB and decreases total CKB levels within the cell. The targeting of CKB for degradation by Asb-9 was primarily SOCS box-dependent and suggests that Asb-9 acts as a specific ubiquitin ligase regulating levels of this evolutionarily conserved enzyme.

SIGNOR-271623

Q8IXL6

P10451

1

phosphorylation

down-regulates quantity

0.683

OPN phosphorylation by Fam20C decreased OPN secretion, and OPN neutralization reduced Fam20C-deficiency-induced osteoclast differentiation and bone metastasis.

SIGNOR-278936

Q9UL15

P0DMV9

1

binding

down-regulates activity

0.683

Here, we show that BAG5, a BAG domain-containing family member, interacts with both Hsp70 and parkin with deleterious functional consequences. Through these interactions, BAG5 inhibits Hsp70 chaperone activity and parkin E3 ubiquitin ligase activity; Thus, BAG5 interacts with Hsp70 in vitro and in vivo, and substitution of select residues within the BAG domains is sufficient to abolish this interaction.

SIGNOR-261197

Q86VP1

P21580

1

binding

up-regulates activity

0.683

Tx1bp1 appears to be a novel a20-binding protein which mediate the anti-apoptotic activity of a20; tax1bp1 phosphorylation was pivotal for cytokine-dependent interactions among tax1bp1, a20, itch and rnf11 and downregulation of signaling by the transcription factor nf-Kb.

SIGNOR-69921

Q8NFG4

Q9NQL2

1

gtpase-activating protein

up-regulates activity

0.683

The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1 [..} RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP-bound for the interaction to occur

SIGNOR-256504

Q15418

P17676

1

phosphorylation

up-regulates activity

0.683

13 The data presented support previous findings that C/EBPbeta can be a molecular target of RSK1, 16 but provide the first indication that RSK1 can phosphorylate and activate C/EBPbeta to mediate the IL-6 signalling events in cholangiocarcinoma.|As mentioned above, RSK1 has been shown to activate C/EBPbeta in hepatic stellate cells in an experimental model of liver fibrosis.

SIGNOR-280112

P19793

P10826

2

binding

up-regulates

0.682

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

SIGNOR-16668

P31751

P38936

1

binding

down-regulates activity

0.682

Whereas akt1 phosphorylates p21, inducing its release from cdk2 and cytoplasmic localization as previously described for akt, akt2 binds p21 in the region spanning the t145 site of p21, thus competing with phosphorylation by akt1 and inducing its accumulation in the nucleus. These distinct roles of akt/pkb isoforms in modulating proliferation and p21 have important implications for the development of drugs aimed at inhibiting cancer cell proliferation.

SIGNOR-149705

Q13131

P49815

1

phosphorylation

up-regulates activity

0.682

However, AMP-activated protein kinase (AMPK), an essential cellular energy sensor, phosphorylates and activates TSC2 [ xref ].

SIGNOR-278981

P26441

P40189

1

binding

up-regulates

0.682

Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. The dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. Some of these biological activities of il-6 are also often exerted by other cytokines, i.e. Il-11, lif, osm, cntf, and ct-2.

SIGNOR-47991

Q6PJG9

P78352

1

binding

up-regulates activity

0.682

SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. One possibility is that SALM3, which is capable of inducing presynaptic differentiation in contacting axons [19], recruits PSD-95 or SAP102 to the sites of early synaptic adhesion.

SIGNOR-264096

P10826

P19793

2

binding

up-regulates

0.682

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

SIGNOR-16519

Q9Y239

Q676U5

1

binding

up-regulates activity

0.681

By a mechanism independent of the adaptor RIP2 and transcription factor NF-kappaB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease.

SIGNOR-252406

O15297

Q00987

1

dephosphorylation

up-regulates

0.681

Wip1 interacts with and dephosphorylates mdm2 at serine 395, a site phosphorylated by the atm kinase. Dephosphorylated mdm2 has increased stability and affinity for p53, facilitating p53 ubiquitination and degradation.

SIGNOR-158328

Q07817

P55211

1

binding

down-regulates activity

0.681

Bcl2l1 associates with casp9 and apaf-1 in mammalian cells.Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation

SIGNOR-56402

P28562

P45984

1

dephosphorylation

down-regulates

0.681

We assayed the relative ability of mkp-2, pac1, and mkp-1 to dephosphorylate erk2 and the other related map kinases, jnk2 and p38. the dual specific phosphatases pac1 and mkp-1 previously have been implicated in the in vivo inactivation of erk or of erk and jnk, respectively.

SIGNOR-40879

P13497

P02452

1

cleavage

up-regulates activity

0.681

BMP-1myc Expressed in COS-7 Cells Exhibits Procollagen C-proteinase Activity. Bone morphogenetic protein (BMP)-1, which belongs to the tolloid subgroup of astacin-like zinc metalloproteinases, cleaves the C-propeptides of procollagen at the physiologic site and is, therefore, a procollagen C-proteinase (PCP). Cleavage occurs between a specific alanine or glycine residue (depending on the procollagen chain) and an invariant aspartic acid residue in each of the three chains of procollagen.

SIGNOR-256342

Q09472

P15172

1

acetylation

up-regulates

0.681

Our results provide direct evidence that myod acetylation functionally activates the protein and show that both pcaf and cbp/p300 are candidate enzymes for myod acetylation in vivo.

SIGNOR-81053

P28482

P49815

1

phosphorylation

down-regulates activity

0.681

Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. |Serine to alanine substitution at S664 or double S664A/S540A mutagenesis resulted in a marked reduction in TSC2 phosphorylation to a similar extent. In contrast, S540A substitution only moderately impaired TSC2 phosphorylation (Figure 3D), corroborating the notion that in vivo S664 is the most relevant residue for Erk-mediated phosphorylation.

SIGNOR-249454

P21675

P04637

1

phosphorylation

down-regulates

0.681

Phosphorylation on thr-55 by taf1 mediates degradation of p53

SIGNOR-123651

Q05086

P04637

1

ubiquitination

down-regulates quantity

0.681

E6-AP also directly ubiquitylated p53 in an in vitro ubiquitylation assay.|Our result suggests that E6-AP not only enhances the degradation of p53 but also regulates the neuronal cell growth.

SIGNOR-278681

Q13043

O43524

1

phosphorylation

up-regulates

0.681

Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity.

SIGNOR-178190

Q13627

Q52LA3

1

phosphorylation

up-regulates activity

0.681

Here we report that DYRK1A can specifically phosphorylate LIN52 on serine residue 28, and that this phosphorylation is required for DREAM assembly.

SIGNOR-262846

Q06124

P01112

1

dephosphorylation

up-regulates activity

0.681

Here we identify SHP2 as the ubiquitously expressed tyrosine phosphatase that preferentially binds to and dephosphorylates Ras to increase its association with Raf and activate downstream proliferative Ras/ERK/MAPK signalling.

SIGNOR-252094

P08631

P19174

1

phosphorylation

up-regulates activity

0.681

The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.

SIGNOR-249361

O14965

Q9NWT8

1

phosphorylation

up-regulates quantity by stabilization

0.681

AIP is phosphorylated on Serine 70 by Aurora‐A but not Aurora‐B and expression of phosphorylation mimic mutant of AIP results in prolonged protein stability compared to unphosphorylatable mutant. Phosphorylation of AIP Prolongs its Protein Stability

SIGNOR-262648

P12931

P35228

1

phosphorylation

up-regulates

0.681

We identify human inos residue tyr(1055) as a target for src-mediated phosphorylation. src kinase-mediated phosphorylation stabilizes inducible nitric-oxide synthase in normal cells and cancer cells.

SIGNOR-188974

P20338

Q96T51

1

binding

up-regulates activity

0.68

Here, we have demonstrated that Rab14 interacts with RUFY1, previously identified as a Rab4 effector, and is required for RUFY1 recruitment onto endosomes and efficient recycling of Tfn.|We also found that enlargement of early endosomes mediated by RUFY1 requires its interaction with Rab4

SIGNOR-261280

P68400

P60484

1

phosphorylation

down-regulates activity

0.68

The C-terminal tail of PTEN is also the target of mutations in tumors. As mentioned, this region contains the main phosphorylation sites mapped to residues Ser362, Thr366, Ser370, Ser380, Thr382, Thr383, and Ser385, and the kinases involved are casein kinase 2 (CK2), GSK3_, LKB1, and MAST.84,97-101 The phosphorylation of the tail has been shown to enhance PTEN stability but at the same time decrease its phosphatase activity

SIGNOR-89830

P84103

Q9UBU9

1

binding

up-regulates

0.68

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

SIGNOR-178111

Q13976

P41220

1

phosphorylation

up-regulates activity

0.68

Thus, PKGI-alpha binds to, phosphorylates and activates RGS-2, attenuating receptor-mediated vascular contraction.

SIGNOR-249241

P28482

Q9UQC2

1

phosphorylation

up-regulates

0.68

Phosphorylation of grb2-associated binder 2 on serine 623 by erk mapk regulates its association with the phosphatase shp-2 and decreases stat5 activation.We and others have demonstrated that il-2-induced tyrosine phosphorylation of gab2 and its interaction with its sh2 domain-containing partners, shp-2, p85 pi3k, and crkl (5, 26, 27). we report that pretreatment of kit 225 cells with the mek inhibitor u0126, strongly decreased the characteristic shift of gab2 in response to il-2 and increased gab2/shp-2 association, an effect that could be ascribed to erk phosphorylation of serine 623.

SIGNOR-128727

P28482

P35568

1

phosphorylation

down-regulates activity

0.68

Rin beta-cells exposed to high glucose exhibited increased c-jun n-terminal kinase (jnk) and erk1/2 activity, which was associated with increased irs-1 phosphorylation at serine (ser)(307) and ser(612), respectively, that inhibits coupling of irs-1 to the insulin receptor and is upstream of the inhibition of irs-1 tyrosine phosphorylation.

SIGNOR-123173

O00238

Q99717

1

phosphorylation

up-regulates activity

0.68

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-255260

P09619

P62993

1

binding

up-regulates

0.68

A pathway leading to activation of the gtp-binding protein ras involves the adaptor molecule grb2. Here we show that tyr-716, a novel autophosphorylation site in the pdgf beta-receptor kinase insert, mediates direct binding of grb2 in vitro and in vivo.

SIGNOR-34765

P06493

P49450

1

phosphorylation

down-regulates quantity by destabilization

0.68

Here, we report that the phosphorylation of CENP-A Ser68 primes the ubiquitin-proteasome-mediated proteolysis of CENP-A during mitotic phase in human cultured cells.the mitotic CENP-A degradation specifically depends on Cdk1 activity.

SIGNOR-277576

P62166

P14416

1

binding

down-regulates activity

0.68

Here we show that the neuronal calcium sensor-1 (NCS-1) can mediate desensitization of D2 dopamine receptors. Analysis of D2 receptors expressed in human embryonic kidney 293 cells indicates that NCS-1 attenuates agonist-induced receptor internalization via a mechanism that involves a reduction in D2 receptor phosphorylation. Coimmunoprecipitation experiments from striatal neurons reveal that NCS-1 is found in association with both the D2 receptor and G-protein-coupled receptor kinase 2, a regulator of D2 receptor desensitization.

SIGNOR-263964

Q13464

P35241

1

phosphorylation

up-regulates activity

0.68

A peak of the phosphopeptide, in which only T573 was phosphorylated, was not detected. Quantitative analyses revealed that _100% of T564, but at most _40% of T573, was phosphorylated when C-rad was incubated with Rho-Kc for 1 h. Then we concluded that the major and primary phosphorylation site of radixin by Rho-kinase was T564 and referred to the Rho-Kcphosphorylated C-rad as T564-phosphorylated C-rad. | In this study, we found that the T564 phosphorylation of radixin markedly suppressed its head-to-tail association. This suggests that the T564-phosphorylation of radixin (and probably also the phosphorylation of ezrin T567 and moesin T558) keeps them open and active.

SIGNOR-248994

P17948

P19174

1

binding

up-regulates

0.679

We conclude that both flt-1 and kdr have the potential to signal through plc gamma via phosphotyrosine residues located in juxta-membrane and carboxyl tail regions

SIGNOR-53743

Q16236

P09601

1

transcriptional regulation

up-regulates quantity by expression

0.679

In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).

SIGNOR-256276

Q15119

P08559

1

phosphorylation

down-regulates

0.679

Mammalian pyruvate dehydrogenase (?2_2) (e1) is regulated by phosphorylation-dephosphorylation, catalyzed by the e1-kinase and the phospho-e1-phosphatase.

SIGNOR-33141

P05362

P20702

1

binding

up-regulates

0.679

Using assays to quantify cd11c-mediated cell adhesion, we demonstrate that cd11c recognizes icam-2 and vcam-1. The cd11c-binding site on vcam-1 appears to be different from that used by the integrin alpha4.

SIGNOR-31388

P17706

P42226

1

dephosphorylation

down-regulates activity

0.679

These results identify TCPTP as a physiological regulator of STAT6 phosphorylation and suggest that specific increases in TCPTP expression in ABC-like DLBCLs may contribute to the different biological characteristics of these tumors

SIGNOR-235192

O15105

O75807

1

binding

up-regulates

0.679

We found smad7 interacts with growth arrest and dna damage protein, gadd34, a regulatory subunit of the protein phosphatase 1 (pp1) holoenzyme, which subsequently recruits catalytic subunit of pp1 (pp1c) to dephosphorylate t?RI.

SIGNOR-121280