• These accessory proteins play a fundamental role in regulating activities of RAS superfamily small GTPase via a conserved guanine binding (G)-domain, which consists of five G motifs. (nih.gov)
  • In 1998 a family of cAMP-sensitive proteins with guanine nucleotide exchange factor (GEF) activity was discovered. (wikipedia.org)
  • These are termed Exchange proteins activated by cAMP (Epac) and the family comprises Epac1 and Epac2 . (wikipedia.org)
  • The rationale of this organization may be related to important roles of these proteins as "exchange hubs" for the signaling proteins for their migration from the subcortical cytosol to the membrane. (frontiersin.org)
  • The normal rate of Ras catalytic GTPase (GTP hydrolysis) activity can be increased by proteins of the RasGAP family, which bind to Ras and increase its catalytic rate by a factor of one thousand - in effect, increasing the rate at which Ras is inactivated. (bionity.com)
  • Endoplasmic reticulum stress (ERS) might be stimulated by a dysfunctional activity of ER dealing with the misfolded or unfold proteins [ 1 ]. (hindawi.com)
  • Like the other Vav proteins, Vav3 is phosphorylated (activated) following ligand binding to a variety of receptor tyrosine kinases (TKs), including EGF receptor, PDGF receptor, insulin receptor, and insulin-like growth factor I receptor. (cytoskeleton.com)
  • The proteins encoded by members of the Dbl family share a common domain, presented in this entry, of about 200 residues (designated the Dbl homology or DH domain) that has been shown to encode a GEF activity specific for a number of Rho family members. (embl-heidelberg.de)
  • The guanine nucleotide exchange factor (GEF) Dbl targets Rho family proteins thereby stimulating their GDP/GTP exchange, and thus is believed to be involved in receptor-mediated regulation of the proteins. (embl-heidelberg.de)
  • Formins are multidomain proteins defined by a conserved FH2 (formin homology 2) domain with actin nucleation activity preceded by a proline-rich FH1 (formin homology 1) domain. (biomedcentral.com)
  • In vitro, the FH2 domain competes with barbed-end capping proteins and is necessary and sufficient to nucleate actin polymerization, but the FH1 domain, which interacts with profilin-actin, funnels actin to the nucleation vicinity and confers full activity to the molecule [ 1 ]. (biomedcentral.com)
  • In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization and growth-factor induced formation of membrane ruffles. (novusbio.com)
  • The active conformation is promoted by guanine-nucleotide exchange factors, and the inactive state by GTPase-activating proteins (GAPs) which stimulate the intrinsic GTPase activity of small G proteins. (embl-heidelberg.de)
  • By enhancing their GTPase activity, GAP proteins inactivate small Rho and Ras proteins, so inactivation of rhoGAP proteins might cause constitutive activation of their GTPase targets. (embl-heidelberg.de)
  • In particular, we propose that Arg 85 and Asn 194 are involved in binding G proteins and enhancing GTPase activity. (embl-heidelberg.de)
  • Proteins that regulate the signaling activity of GTP-BINDING PROTEINS . (nih.gov)
  • This process is usually regulated by guanine nucleotide-exchange factors GTPase-activating proteins and guanine nucleotide-dissociation inhibitors (1). (sciencepop.org)
  • The Rho proteins RhoA, RhoB, and RhoC are highly homologous and contain the consensus amino acid sequences necessary for GDP/GTP-binding and GTPase activity. (phosphosolutions.com)
  • The guanine nucleotide exchange factor Sos (Son-of-sevenless) is a complex multidomain protein that activates the small GTPase Ras (H-Ras, K-Ras, N-Ras, but not functionally distinct R-Ras) in response to receptor tyrosine kinase stimulation. (novusbio.com)
  • Ras superfamily GTPase activation and inactivation occur by canonical nucleotide exchange and GTP hydrolysis mechanisms. (elifesciences.org)
  • Thus, upon binding to GTP, the duration of Ras-GTPase activity is limited by the rate at which it hydrolyzes its bound GTP to GDP. (bionity.com)
  • Once released from SOS, the Ras-GTPase quickly binds fresh guanine nucleotide from the cytosol. (bionity.com)
  • Mutational analysis revealed that only the C1 and DH domains are essential for Vav3 GEF activity with the C1 region being involved in binding with the GTPase substrate. (cytoskeleton.com)
  • As a small membrane-associated GTPase, Cdc42 is well suited to designate where and when a particular activity should occur ( Etienne-Manneville, 2004 ). (rupress.org)
  • The distinctive presence of both Rab- and Rho-GTPase GEF activities suggests that C9orf72 may function as a dual exchange factor coupling physiological functions such as cytoskeleton modulation and autophagy with endocytosis. (bath.ac.uk)
  • There have been limited successes with molecules that disrupt the binding of guanine nucleotide exchange factors to RAC and CDC42 (7-10) as well as with molecules that disrupt GTPase membrane association (11). (sciencepop.org)
  • While efforts continue to develop direct small GTPase inhibitors a PLCG2 promising and more conventional Olmesartan medoxomil therapeutic approach has been to block the activities of RHO GTPase effectors. (sciencepop.org)
  • ARHGAP21 interacts with RhoA-GTP, and acts as a GAP to increase RhoA GTPase activity. (uth.edu)
  • By another (separable) guanine exchange factor domain domain Sos modulates activity of Rac/Rho GTPases. (novusbio.com)
  • Guanine nucleotide dissociation stimulators (GDSs, or exchange factors), such as RALGDS, are effectors of Ras-related GTPases (see MIM 190020) that participate in signaling for a variety of cellular processes. (cancerindex.org)
  • In cell signalling , Son of Sevenless , or SOS , is a gene encoding a guanine nucleotide exchange factor that acts on Ras - GTPases . (bionity.com)
  • As the name implies, Ras-GTPases possess intrinsic enzymatic activity that converts GTP to GDP plus phosphate. (bionity.com)
  • SOS (and other guanine nucleotide exchange factors) act by binding Ras-GTPases and forcing them to release of their bound nucleotide (usually GDP). (bionity.com)
  • The C9orf72 protein is predicted to be a differentially expressed in normal and neoplastic cells domain protein implying that C9orf72 functions as a guanine nucleotide exchange factor (GEF) to regulate specific Rab GTPases. (bath.ac.uk)
  • Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. (embl-heidelberg.de)
  • Our analysis allows some preliminary insight into the functionality of Dictyostelium formins: all isoforms might display actin nucleation activity and, with the exception of ForI, might also be susceptible to autoinhibition and to regulation by Rho GTPases. (biomedcentral.com)
  • However not much information is available that comprehensively expounds on the roles of insulin growth factor receptor (IGFR) and Rab GTPases may play in breast cancer. (fiu.edu)
  • RHO GTPases members of the RAS superfamily of small GTPases are adhesion and growth-factor activated molecular switches that play important roles in tumor development and progression. (sciencepop.org)
  • Upon activation GTP-bound RHO-GTPases interact with a wide spectrum of effectors to regulate various cellular pathways including cytoskeletal dynamics motility cytokinesis cell growth apoptosis and transcriptional activity. (sciencepop.org)
  • Structural analyses suggest that GTP hydrolysis of SMG9 would lead to a dramatic conformational change of SMG8-SMG9 and the KID would move away from the inhibitory position to restore SMG1 kinase activity. (nature.com)
  • Discovery of a new class of reversible TEA domain transcription factor inhibitors with a novel binding mode. (umassmed.edu)
  • Post-translational modification within the G4 and G5 motifs activates RAS by populating the GTP-bound "ON" state, either through enhancement of intrinsic guanine nucleotide exchange or impairing GAP-mediated down-regulation. (nih.gov)
  • This gene encodes a protein that has been shown to function as a guanine nucleotide release factor in mouse and to regulate the expression and function of the Nav1.5 cardiac sodium channel in human. (nih.gov)
  • Translation initiation factor eIF-2B subunit beta is a protein that in humans is encoded by the EIF2B2 gene. (wikipedia.org)
  • A rat gene, mss4, that encodes a guanine nucleotide exchange factor (GEF) for Sec4 was recently cloned by its ability to rescue defects in protein transport of a yeast temperature-sensitive (ts) mutant, sec4-8. (elsevierpure.com)
  • Vav3 GTP Exchange Factor (GEF) of Rac1, RhoA and Cdc42. (cytoskeleton.com)
  • At sites of polar growth, Cdc42 is activated by guanine nucleotide exchange factors. (rupress.org)
  • We next sought to gain mechanistic insight into actin-independent polarization, which requires both the guanine nucleotide dissociation inhibitor (GDI) Rdi1, which extracts Cdc42 from the peripheral membrane into a rapidly diffusing cytosolic complex, and the adaptor molecule Bem1, which binds both active Cdc42GTP and its guanine nucleotide exchange factor (GEF) or activator Cdc24. (ku.edu)
  • Using a Cdc42 activation biosensor, we found that Bem1 binding boosts Cdc24 GEF activity. (ku.edu)
  • Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. (rcsb.org)
  • Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. (rcsb.org)
  • Sperm intracellular cAMP levels depend on the activity of adenylyl cyclases, mostly SACY, though transmembrane-containing adenylyl cyclases are also present, and on the activity of cyclic nucleotide phosphodiesterases (PDE) whose role is to degrade cAMP into 5'-AMP. (plos.org)
  • Its activity is directed by intracellular signals mediated by various types of receptors such as G protein-coupled receptors. (embl-heidelberg.de)
  • In human cells, SMG1 forms a complex with two NMD effectors SMG8 and SMG9, which inhibit the kinase activity of SMG1 in vitro. (nature.com)
  • Guanine nucleotide exchange factor GEF115 specifically mediates activation of Rho and serum response factor by the G protein alpha subunit Galpha13. (umassmed.edu)
  • Eukaryotic initiation factor-2B (EIF2B) is a GTP exchange protein essential for protein synthesis. (wikipedia.org)
  • Mutations linked to leukoencephalopathy with vanishing white matter impair the function of the eukaryotic initiation factor 2B complex in diverse ways. (medlineplus.gov)
  • Mutations affecting the eukaryotic initiation factor 2B (eIF2B) cause one of the most common leukodystrophies, the autosomal recessive childhood ataxia with central nervous system hypomyelination (CACH), or vanishing white matter disease (VWM). (medlink.com)
  • The mammalian homologue similarly functions downstream of many growth factor and adhesion receptors. (bionity.com)
  • As the Drosophila homologue of mammalian DENN/MADD and Caenorhabditis elegans AEX-3, Rab3-GEF is a guanine nucleotide exchange factor (GEF) for Rab3 that stimulates GDP to GTP exchange. (eneuro.org)
  • Interestingly, we found that recombinant myostatin was sufficient to antagonize the hypertrophy activities of clenbuterol. (wada-ama.org)
  • Furthermore, our in vitro assay demonstrated that recombinant Mon2 did not promote guanine nucleotide exchange of Arl1. (a-star.edu.sg)
  • Here, it is demonstrated that TGFβ facilitates Tβ4 expression and leads to the activation of myocardin-related transcription factors (MRTF), which are coactivators of serum response factor (SRF) and regulate the expression of genes critical for the epithelial-mesenchymal transition (EMT) and tumor metastasis. (aacrjournals.org)
  • RhoA activity results in the assembly of myosin II and anti-parallel actin filaments into the structure of the contractile ring. (jove.com)
  • Post-translational regulation of Rho activity has been shown specifically for RhoA. (phosphosolutions.com)
  • Thus, Ser-188 is an important site for negative regulation of RhoA activity. (phosphosolutions.com)
  • We hypothesized that oxidative species increase arginase activity through PKC-activated RhoA/Rho kinase (ROCK) pathway. (elsevierpure.com)
  • Conclusions and Implications Our data indicate that the oxidative species ONOO - and H 2 O 2 increase arginase activity/expression through PKC-mediated activation of RhoA/Rho kinase pathway. (elsevierpure.com)
  • Suppression of glycogen synthase kinase activity is not sufficient for leukemia enhancer factor-1 activation. (umassmed.edu)
  • Therefore, our results suggest that Mon2 could be neither necessary nor sufficient for the guanine nucleotide exchange of Arl1. (a-star.edu.sg)
  • The eIF2 protein is called an initiation factor because it is involved in starting (initiating) protein synthesis. (medlineplus.gov)
  • For example, they may impair the ability of one of the protein subunits to form a complex with the others, or make it more difficult for the protein to attach to the initiation factor. (medlineplus.gov)
  • Under some conditions, eIF2B increases protein synthesis by helping to recycle molecules called GTP, which carry energy to the initiation factor. (medlineplus.gov)
  • Under other conditions, it slows protein synthesis by binding tightly to the initiation factor, which converts the eIF2B protein into an inactive form and prevents recycling of GTP. (medlineplus.gov)
  • Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. (rcsb.org)
  • Tβ4 levels are transcriptionally regulated via the novel cis -acting element AGACAAAG, which interacts with Smad and T-cell factor/lymphoid enhancer factor (TCF/LEF) to synergistically activate the Tβ4 promoter downstream of TGFβ. (aacrjournals.org)
  • PERK and ATF6 signaling pathways activate the downstream factor CHOP to downregulate the expression of Bcl-2, an antiapoptotic protein, and contribute to programmed cell death [ 5 ], which has been comprehensively reviewed [ 6 ]. (hindawi.com)
  • EIF2B activates its EIF2 (see MIM 603907) substrate by exchanging EIF2-bound GDP for GTP. (wikipedia.org)
  • There are many signaling pathways that lead to RHO activation including those initiated by physical stimuli (mechanical stress or cell-cell and cell-substrate adhesion) and chemical factors (growth factors and cytokines) (2). (sciencepop.org)
  • Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. (umassmed.edu)
  • Thus, our structural and biochemical analyses provide a mechanistic understanding of SMG1-SMG8-SMG9 complex assembly and the regulatory mechanism of SMG1 kinase activity. (nature.com)
  • We also reported that clenbuterol regulates negatively the expression of myostatin a master regulatory factor of muscle mass. (wada-ama.org)
  • Molecules that stabilize the eIF2B complex and normalize its activity are being developed. (medlink.com)
  • Crystal structure of C. elegans SMG8-SMG9 core complex reveals that SMG8-SMG9 heterodimer is formed through the contacts between a C-terminal guanine nucleotide-binding (G) domain of SMG9 and an N-terminal G-like domain of SMG8. (nature.com)
  • Our study determined the mechanism involved in peroxynitrite and hydrogen peroxide-induced enhancement in endothelial arginase activity. (elsevierpure.com)
  • These motifs are responsible for the recognition of the guanine moiety in GTP and GDP, and contain residues that undergo post-translational modifications that underlie new mechanisms of RAS regulation. (nih.gov)
  • The key event in NMD is the SMG1-mediated phosphorylation of an RNA helicase UPF1 and SMG1 kinase activity is inhibited by SMG8 and SMG9 in an unknown mechanism. (nature.com)
  • SMG8 has a C-terminal kinase inhibitory domain (KID), which covers the catalytic pocket and inhibits the kinase activity of SMG1. (nature.com)
  • SMG8-SMG9 heterodimer stably associates with SMG1 and the C-terminal region of SMG8 inhibits SMG1 kinase activity through covering the catalytic pocket. (nature.com)
  • The structural and biochemical analyses together provide structural insights into the assembly of SMG1C complex and the regulation of SMG1 kinase activity. (nature.com)
  • Nucleotide exchange activity of Sos is stimulated by allosteric Ras binding. (novusbio.com)
  • Dynein light chain LC8-nNOS from acto-myosin Va is possibly exchanged with shank, which thereafter facilitates transposition of nNOS for binding with palmitoyl-PSD95 at the nerve terminal membrane. (frontiersin.org)
  • Here, the results thus far, have shown that while activation of Rab5 may mediate increased cell proliferation, migration and invasion in breast cancer cells, the Rab5 GEF, RIN1 interacts with the IGFR thereby facilitating migration and invasion activities in breast cells. (fiu.edu)
  • The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. (umassmed.edu)
  • Specific requirement of Gli transcription factors in Hedgehog-mediated intestinal development. (umassmed.edu)
  • A predictive model of bifunctional transcription factor signaling during embryonic tissue patterning. (umassmed.edu)
  • furthermore, ectopic expression of constitutively active MRTF-A fully restores the diminished metastatic activity. (aacrjournals.org)
  • This activity pulls the anti-parallel actin, causing them to slide past one another, contracting the ring. (jove.com)
  • An analysis of RasGRP1 SNP variants led to the conclusion that the charge of His 212 in RasGRP1 alters signaling activity and plasma membrane recruitment, indicating that His 212 is a pH sensor that alters the balance between the inactive and active forms of RasGRP1. (rcsb.org)
  • Promotes the exchange of Ras-bound GDP by GTP. (cusabio.com)