• GEFs regulate the activity of members of the Ras superfamily of GTPases. (medscape.com)
  • RAS is a founding member of the RAS superfamily of GTPases. (nih.gov)
  • Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. (embl-heidelberg.de)
  • It does not share significant sequence homology with other subtypes of small G-protein GEF motifs such as the Cdc25 domain and the Sec7 domain, which specifically interact with Ras and ARF family small GTPases, respectively, nor with other Rho protein interactive motifs, indicating that the Dbl family proteins are evolutionarily unique. (embl-heidelberg.de)
  • Rho (A, B, & C) proteins are members of the Ras superfamily of GTPases. (phosphosolutions.com)
  • Rat sarcoma (Ras) family of small guanosine triphosphatases (GTPases). (umbc.edu)
  • Ras proteins are the founding members of the Ras superfamily of GTPases, which in humans is composed of more than 150 members [ 1 ] [ 2 ] . (encyclopedia.pub)
  • Ras proteins are membrane-bound small GTPases that act as molecular transducers, coupling cell surface receptors to intracellular effector pathways to regulate cellular processes such as cell proliferation, differentiation, migration, and apoptosis [ 3 ] [ 4 ] . (encyclopedia.pub)
  • Rem2 is a member of the RGK family of small Ras-like GTPases whose expression and function is regulated by neuronal activity in the brain. (health-ground.com)
  • Introduction The RGK (Ras, Rem, Rem2, Gem/Kir) protein family is a subclass of small Ras-like GTPases structurally distinct from canonical GTPases. (health-ground.com)
  • GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) regulate small GTPases, with GAPs promoting the GDP-bound (inactive) form, and GEFs promoting the GTP-bound (active) form. (generalrap.com)
  • First linked to human cancer in 1982 (1C3), members of the RAS family of GTPases (which comprises is the area in the yellow box enlarged, showing hydrogen bonds as thin dashed lines and cationC interaction as a thick dashed line. (niepokorny.org)
  • 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)
  • The exchange of GDP to GTP and thus the activation of Rho GTPases is catalyzed by guanine nucleotide exchange factors (GEFs), which act downstream of numerous growth factor receptors, integrins, cytokine receptors, and cadherins. (biomedcentral.com)
  • Rho GTPases are key integrating molecules from different extracellular signals, as they can be activated by different GEFs. (biomedcentral.com)
  • GEFs turn on (activate) proteins called GTPases, which play an important role in chemical signaling within cells. (medlineplus.gov)
  • EDTA enhances the GDP exchange and GTP hydrolysis of some GTPases. (bellbrooklabs.com)
  • 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)
  • Like all members of the Ras superfamily, the Rho proteins cycle between active GTP-bound and inactive GDP-bound conformational states. (embl-heidelberg.de)
  • Like other members of the RAS superfamily, ARF family proteins can be activated by guanine-nucleotide exchange factors (GEFs) and inactivated by GTPase-activating proteins (GAPs) [ 9 ]. (biomedcentral.com)
  • Ras superfamily GTPase activation and inactivation occur by canonical nucleotide exchange and GTP hydrolysis mechanisms. (elifesciences.org)
  • The Rab subfamily of proteins is part of the large Ras superfamily, and all members of this superfamily are activated and inactivated in a similar way, with the binding and unbinding of GDP and GTP taking place at a structure called the G-domain. (elifesciences.org)
  • These proteins are divided into families depending on their protein structure, and the most well studied is the Ras superfamily , of which Rap1 is a member. (generalrap.com)
  • Rho proteins belong to the Ras superfamily. (biomedcentral.com)
  • More recently interests have extended to the small G proteins of the Ras GTPase superfamily, in particular RhoA and its activators, i.e. the Guanine Exchange Factors (GEF) of the Dbl family. (unimore.it)
  • The product of this gene counteracts the mitogenic function of RAS because it can interact with RAS GAPs and RAF in a competitive manner. (wikipedia.org)
  • They play an important role in the recognition of regulatory factors (GEFs and GAPs) and effectors. (nih.gov)
  • The structure of alsin predicts that it functions as a guanine nucleotide exchange factor (GEF). (medscape.com)
  • 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)
  • Activation of Rho proteins through release of bound GDP and subsequent binding of GTP, is catalysed by guanine nucleotide exchange factors (GEFs) in the Dbl family. (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)
  • As a proangiogenic response effecter, the interaction of Sema4D with plexin-B1 is dependent on the COOH-terminal PDZ-binding motif of plexin-B1, which binds two guanine nucleotide exchange factors (GEFs) for Rho and is mediated by the activation of Rho-initiated (Ras homolog gene family) pathways ( 4 - 8 ). (jcancer.org)
  • The present invention relates to diagnosing abnormal cell proliferation in biological samples and screening for drugs which inhibit, reduce or abolish cell growth, especially tumorigenic cell growth, by detecting a phosphovariant isoform of a guanine nucleotide exchange factor biomarker, such as the novel GEF-H1S. (justia.com)
  • Guanine nucleotide exchange factors ("GEFs") stimulate the dissociation of the GTP hydrolytic product, GDP, from small GTP-binding proteins, to promote the binding of a new GTP molecule. (justia.com)
  • Proteins called guanine nucleotide exchange factors, or GEFs for short, activate the Rab protein by promoting the release of GDP and the binding of GTP. (elifesciences.org)
  • Ras is activated by guanine nucleotide exchange factors (GEFs) that release GDP and allow GTP binding. (umbc.edu)
  • In tumors, RAC1 is usually hyper-activated and RAC1 inhibitors such as EHop-016 aim at blocking the interaction of RAC1 with several of its known guanine nucleotide exchange factors (GEFs). (broadinstitute.org)
  • Jackson, C. L. & Casanova, J. E. Turning on ARF: the Sec7 family of guanine-nucleotide-exchange factors. (nature.com)
  • Donaldson, J. G., Finazzi, D. & Klausner, R. D. Brefeldin A inhibits Golgi membrane-catalysed exchange of guanine nucleotide onto ARF protein. (nature.com)
  • Helms, J. B. & Rothman, J. E. Inhibition by brefeldin A of a Golgi membrane enzyme that catalyses exchange of guanine nucleotide bound to ARF. (nature.com)
  • Morinaga, N., Tsai, S.-C., Moss, J. & Vaughan, M. Isolation of a brefeldin A-inhibited guanine nucleotide-exchange protein for ADP ribosylation factor (ARF) 1 and ARF3 that contains a Sec7-like domain. (nature.com)
  • We determine through siRNA screening of a guanine nucleotide exchange element (GEF) library candidate GEFs that contribute to the rules of Cdc42 specifically in the Golgi but remarkably none of these is definitely involved in regulating the GM130-Cdc42 axis. (researchatlanta.org)
  • Evidence for a novel nucleotide exchange factor. (embl-heidelberg.de)
  • These include four regions participating in guanine nucleotide binding, and effector region corresponding to the effector region in Ras, and a CXC prenylation motif at the C-terminal (45). (pancreapedia.org)
  • One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. (niepokorny.org)
  • TARP functions by binding two distinct Rac guanine nucleotide exchange factors (GEFs), Sos1 and Vav2, in a phosphotyrosine-dependent manner. (elsevierpure.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)
  • The proteins in this family act as guanine nucleotide exchange factors (GEFs). (medlineplus.gov)
  • Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. (umbc.edu)
  • The RAS family consists of three proteins all sharing a highly conserved N-terminus region: Harvey RAS (HRAS), Kirsten RAS (KRAS) and neuroblastoma RAS (NRAS). (biomedcentral.com)
  • The targeting motif of Ras is part of the COOH-terminal hypervariable region, which significantly differs amongst the otherwise highly conserved Ras isoforms. (rupress.org)
  • When GTP is bound, for instance, Ras proteins can interact with effectors and other molecules to affect cell proliferation, differentiation and apoptosis. (justia.com)
  • Ras proteins regulate cell growth, proliferation and differentiation. (umbc.edu)
  • In addition to an essential role in regulating cell growth and differentiation, Ras signaling has more recently been linked to a wide range of neuronal functions including synaptic and behavioral plasticity (for review see Thomas and Huganir, 2004 ). (rupress.org)
  • These guanosine triphosphatases bind GTP causing the activation of mitogen activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K) and Ras-like (RAL) pathways [ 1 ]. (biomedcentral.com)
  • R-Ras proteins function distinctly from classic Ras proteins by regulating distinct signaling pathways that promote MPNST tumorigenesis by mediating migration and invasion. (biomedcentral.com)
  • We have previously shown that three related Ras proteins (the classic Ras proteins) are highly activated in malignant peripheral nerve sheath tumor (MPNST) cells with neurofibromin loss and that they drive cancer cell proliferation and survival by activating multiple cellular signaling pathways. (biomedcentral.com)
  • We examined the activation of cytoplasmic signaling pathways in the presence and absence of R-Ras signaling and found that R-Ras proteins regulated 13 signaling pathways distinct from those regulated by classic Ras proteins. (biomedcentral.com)
  • It has been hypothesized that inactivation of the RASSF1A tumor suppressor facilitates K-RAS-mediated transformation by uncoupling it from apoptotic pathways such as the Hippo pathway. (cancerindex.org)
  • RAS is activated by GTP loading and deactivated upon GTP hydrolysis to GDP. (nih.gov)
  • All NSP proteins contain an NH 2 -terminal SH2 (Src homology domain 2) domain, a central proline/serine-rich domain, and a COOH-terminal domain with modest homology to Ras subfamily GDP-exchange factors (GEFs). (molvis.org)
  • Neurofibromin loss potentially hyperactivates classic Ras (H-Ras, N-Ras, K-Ras), M-Ras, and R-Ras (R-Ras, R-Ras2/TC21) subfamily proteins. (biomedcentral.com)
  • Cells were transfected with doxycycline-inducible vectors expressing either a pan-inhibitor of the R-Ras subfamily [dominant negative (DN) R-Ras] or enhanced green fluorescent protein (eGFP). (biomedcentral.com)
  • The multi-component Nox2 has both trans-membrane and cytosolic proteins, and the small G-protein, Ras-related C3 botulinum toxin substrate 1 (Rac1), is an integral cytosolic component for its activation 8 . (nature.com)
  • Transcreener GDP Assay directly measures GDP produced by Rac1 (Ras-related C3 botulinum toxin substrate 1). (bellbrooklabs.com)
  • GTP binding to Ras induces changes in conformation, mainly in two regions named switch I and switch II, that greatly increase the affinity of Ras for its downstream effectors [ 14 ] [ 15 ] . (encyclopedia.pub)
  • Mutant K-RAS has been shown to have both tumor-promoting and -suppressing functions, and growing evidence suggests that the RASSF family of tumor suppressors can act as RAS apoptosis and senescence effectors. (cancerindex.org)
  • These four Ras isoforms are ubiquitously expressed and are highly similar in primary sequence, structure, and biochemical properties [ 5 ] [ 6 ] . (encyclopedia.pub)
  • All three Ras isoforms have a CAAX sequence at the COOH terminus that specifies farnesylation and further processing of the COOH-terminal cysteine residue. (rupress.org)
  • There are no known GEFs specific for individual Rab3 isoforms such as Rab3D. (pancreapedia.org)
  • Gain-of-function variants in the three RAS genes have been found in 27 % of human cancers [ 3 ]. (biomedcentral.com)
  • The degree of activation and the underlying biochemical mechanism differs between variants in the three RAS genes, with the KRAS isoform being the most commonly disrupted in human carcinomas [ 6 ]. (biomedcentral.com)
  • In humans, three Ras genes ( H-ras , N-ras, and K-ras ) encode four distinct Ras proteins: H-Ras, N-Ras, K-Ras4A, and K-RasS4B, the latter 2 resulting from alternative RNA splicing of the K-ras gen. (encyclopedia.pub)
  • Additionally, Ras proteins are recognized as major oncogenes, as mutations in all three Ras genes occur in approximately 30% of human cancers [ 10 ] . (encyclopedia.pub)
  • In human lung tumors, combined activation of K-RAS and inactivation of RASSF1A is closely associated with the development of the most aggressive and worst prognosis tumors. (cancerindex.org)
  • Inhibition of R-Ras/R-Ras2 and ROCK1 signaling also triggered the accumulation of abnormal intracellular vesicles, indicating that these signaling molecules regulate the movement of proteins and other molecules in the cellular interior. (biomedcentral.com)
  • A novel small molecular weight GTP-binding protein with the same putative effector domain as the ras proteins in bovine brain membranes. (wikipedia.org)
  • Active GTP-bound Ras interacts with several effector proteins: among the best characterized are the Raf kinases, phosphatidylinositol 3-kinase (PI3K), RalGEFs and NORE/MST1. (umbc.edu)
  • Closer study of an R-Ras regulated pathway containing the signaling protein ROCK1 showed that inhibition of either R-Ras, R-Ras2 or ROCK1 similarly impaired cellular migration and invasion and altered cellular morphology. (biomedcentral.com)
  • Loss of GM130 releases RasGRF allowing it to inhibit Cdc42 and activate Ras leading to alterations in cell polarity and hyperactivity of the Ras-ERK pathway. (researchatlanta.org)
  • The Ras/MAPK pathway regulates synaptic plasticity and cell survival in neurons of the central nervous system. (rupress.org)
  • Mutations of the NF1 gene potentially results in the activation of multiple Ras proteins, which are key regulators of many biologic effects. (biomedcentral.com)
  • 29% of melanomas are driven by mutations in N-Ras, while H-Ras mutations appears mutated in 5% of head and neck squamous cell carcinoma and 6% of bladder cancers [ 11 ] . (encyclopedia.pub)
  • KRAS is one of the most highly mutated proteins in cancer accounting for nearly 30% of cancer related mutations, and 86% of all RAS related mutations (reviewed in (1, 2)) . (cytoskeleton.com)
  • We have shown that classic Ras proteins promote proliferation and survival, but not migration, in malignant peripheral nerve sheath tumor (MPNST) cells. (biomedcentral.com)
  • Consistent with classical Ras inhibition, DN R-Ras and R-Ras2 knockdown inhibited proliferation. (biomedcentral.com)
  • Inhibition of R-Ras action inhibited proliferation, migration and invasion but not survival. (biomedcentral.com)
  • Treatment with EP3 antagonists induced upregulation of estrogen receptor β and decreased activity of Ras and led to attenuated proliferation and migration of RL95-2 cells. (oncotarget.com)
  • Whereas Ras is known for its role in cell proliferation and survival, Rap1 is predominantly involved in cell adhesion and cell junction formation. (generalrap.com)
  • Ras signaling is activated by cellular receptors including receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs), cytokines receptors, and extracellular matrix receptors [ 12 ] . (encyclopedia.pub)
  • Indeed, covalent KRASG12C inhibitors are known to require GDP-bound inactive KRASG12C for binding, and potential combination therapies by upstream inhibition of RAS activation (e.g., by inhibition of receptor tyrosine kinase or RASGEF activity) have been discussed (11C13). (niepokorny.org)
  • Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. (niepokorny.org)
  • Most Ras proteins contain a lipid modification site at the C-terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. (umbc.edu)
  • Ras activity relies on proper anchoring to the cytoplasmic leaflet of the plasma membrane (PM) by means of a lipid-based PM targeting motif. (rupress.org)
  • Ras-related protein Rap-1A is a protein that in humans is encoded by the RAP1A gene. (wikipedia.org)
  • The product of this gene belongs to the family of Ras-related proteins. (wikipedia.org)
  • 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)
  • Here, we provide a comprehensive review of post-translational modifications in the RAS G4 and G5 motifs, and describe the role of these modifications in RAS activation as well as potential applications for cancer therapy. (nih.gov)
  • Although the recent Food and Drug Administration (FDA) approval of the first Ras G12C inhibitor is an important milestone, only a small percentage of patients will benefit from it. (encyclopedia.pub)
  • Recently, a drug that targets mutant RAS G12C specifically has shown promising clinical results and is now the first FDA approved RAS-targeting drug for the treatment of NSCLC, read on for a summary of this drugs journey from discovery to approval, and roadblocks that still lie ahead. (cytoskeleton.com)
  • Non-malignant somatic KRAS variants underlie a subset of RAS-associated autoimmune leukoproliferative disorders (RALD). (biomedcentral.com)
  • This case of idiopathic splenomegaly in childhood due to a somatic variant in KRAS expands our understanding of the clinical spectrum of RAS-associated autoimmune leukoproliferative disorder and emphasizes the value of securing a molecular diagnosis in children with unusual early-onset presentations with a suspected monogenic origin. (biomedcentral.com)
  • These are sequestered in the cytosol until activation by growth factors triggers recruitment to the plasma membrane or Golgi, where the GEF colocalizes with Ras. (umbc.edu)
  • Lipid binding is essential for membrane attachment, a key feature of most Ras proteins. (umbc.edu)
  • Rab proteins constitute the largest family of Ras-related small G proteins and play a role in regulating the specificity of membrane trafficking (63, 78). (pancreapedia.org)
  • Alterations in Ras signaling are implicated in the development of different diseases, such as neurological disorders, developmental disorders, and autism. (encyclopedia.pub)
  • Together, the data presented here indicate that inhibition of GEFs DprE1-IN-2 may represent a viable approach for targeting RAS-driven tumors. (niepokorny.org)
  • The experiments showed that different amino acids in the active site of the Rab protein are involved when the GEFs mediate the release of the GDP during the activation process. (elifesciences.org)
  • For example, the amino acid glutamine is involved when the Listeria GEF and one of the human GEFs activate the protein, whereas a different amino acid-aspartate-is involved when one of the other human GEFs is responsible for the activation. (elifesciences.org)
  • Here, we examined the expression, activation and action of R-Ras proteins in MPNST cells that have lost neurofibromin. (biomedcentral.com)
  • Cherfils, J. & Chardin, P. GEFs: structural basis for their activation of small GTP-binding proteins. (nature.com)
  • Here, we describe the first transgenic mouse model for activation of K-RAS in the lung in a RASSF1A-defective background. (cancerindex.org)
  • However, DN R-Ras inhibition impaired migration and invasion but not survival. (biomedcentral.com)
  • Members of the RAS family of oncogenes are the most frequently mutated in human cancer. (broadinstitute.org)
  • In general, K-Ras is the most frequently mutated isoform (accounting for 75% of Ras mutation in cancer), followed by N-Ras (17%) and H-Ras (7%) [ 10 ] . (encyclopedia.pub)
  • These proteins share approximately 50% amino acid identity with the classical RAS proteins and have numerous structural features in common. (wikipedia.org)
  • In doing so, this GEF-facilitated exchange of GDP for GTP is associated with structural changes in the GTP-binding protein which influence the degree to which the GTP-binding protein can interact with other molecules. (justia.com)
  • Mutant Ras is a driver both in tumor initiation and tumor maintenance [ 5 ] [ 7 ] . (encyclopedia.pub)
  • tRNAs interact these reactions through signaling with the complex complex cofactors( GEFs) ATG16L1-positive as fibrinopeptide and mark. (familie-vos.de)
  • R-Ras2 was uniformly expressed in MPNST cells, with R-Ras present in a major subset. (biomedcentral.com)
  • Ras proteins act as molecular switches that cycle between two conformational states: an active GTP-bound state and an inactive GDP-bound state. (encyclopedia.pub)
  • The structure of the Rabs changes upon binding GTP and mutant Rab3 species have been described similar to Ras that are locked into active and inactive configurations (6). (pancreapedia.org)
  • Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. (nature.com)
  • Mass spectrometry-based phosphoproteomics identified thirteen protein networks distinctly regulated by DN R-Ras, including multiple networks regulating cellular movement and morphology. (biomedcentral.com)
  • Ras proteins are essential mediators of a multitude of cellular processes, and its deregulation is frequently associated with cancer appearance, progression, and metastasis. (encyclopedia.pub)
  • Targeting RAS directly is difficult because of the absence of known allosteric regulatory sites, as well as the fact that it has picomolar affinity to GTP/GDP (3) . (cytoskeleton.com)