• These findings highlight plasticity in the activation mechanisms of closely related Rab GTPases. (elifesciences.org)
  • Most Rab GTPases contain a lipid modification site at the C-terminus, with sequence motifs CC, CXC, or CCX. (umbc.edu)
  • Small GTPases act as molecular switches in signaling pathways, which act to regulate functions of other proteins. (wikipedia.org)
  • Activation and deactivation of small GTPases can be regarded as occurring in a cycle, between the GTP-bound and GDP-bound form, regulated by other regulatory proteins. (wikipedia.org)
  • The inactive form of GTPases (GDP-form) are activated by a class of proteins called Guanosine nucleotide exchange factors (GEFs). (wikipedia.org)
  • The rate of GTP hydrolysis for small GTPases is generally too slow to create physiologically relevant transient signals, and thus requires another class of regulatory proteins to accelerate this activity, the GTPase activating proteins (GAPs). (wikipedia.org)
  • Another class of regulatory proteins, the Guanosine nucleotide dissociation inhibitors (GDIs), bind to the GDP-bound form of Rho and Rab small GTPases and not only prevent exchange (maintaining the small GTPase in an off-state), but also prevent the small GTPase from localizing at the membrane, which is their place of action. (wikipedia.org)
  • Widespread domain present in Gyp6 and Gyp7, thereby giving rise to the notion that it performs a GTP-activator activity on Rab-like GTPases. (embl.de)
  • We focus on the Rab GTPases that are master regulators of membrane trafficking. (stanford.edu)
  • Activating mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) cause Parkinson's disease and previously we showed that activated LRRK2 phosphorylates a subset of Rab GTPases (Steger et al. (stanford.edu)
  • Rab GTPases are implicated in vesicle trafficking. (embl.de)
  • Vesicular transport: how many Ypt/Rab-GTPases make a eukaryotic cell? (embl.de)
  • Small G-proteins, monomeric GTPases, or the RAS (Rat sarcoma) superfamily are a large family of small guanine nucleotide-binding proteins with molecular weights ranging from 20 to 30 kDa [ 1 , 2 ]. (oncotarget.com)
  • 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)
  • EDTA enhances the GDP exchange and GTP hydrolysis of some GTPases. (bellbrooklabs.com)
  • Ras superfamily GTPase activation and inactivation occur by canonical nucleotide exchange and GTP hydrolysis mechanisms. (elifesciences.org)
  • GTPase activating proteins (GAPs) interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. (umbc.edu)
  • Inactivation of the active small GTPase is achieved through hydrolysis of the GTP by the small GTPase's intrinsic GTP hydrolytic activity. (wikipedia.org)
  • They are regulated by a diverse group of structurally unrelated GDP-GTP exchange factors (GEFs), and a family of GTP-hydrolysis activating proteins (GAPs) containing the conserved TBC domain. (ox.ac.uk)
  • Members of the Rab protein family are nontransforming monomeric GTP-binding proteins of theRas superfamily that contain 4 highly conserved regions involved in GTP binding and hydrolysis.Rabs are prenylated, membrane-bound proteins involved in vesicular fusion and trafficking. (technuc.com)
  • They cycle between inactive GDP-bound and activated GTP-bound states, which is controlled by GTP hydrolysis-activating proteins (GAPs). (nih.gov)
  • The 70 or so members of the Rab subfamily of proteins perform a wide range of important tasks inside cells. (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)
  • As a result we hypothesized that EPI64 subfamily proteins(s) would have potential Rab27B-Difference activity in pancreatic acinar cells. (research-in-field.com)
  • ATP binding cassette subfamily D membe. (gsea-msigdb.org)
  • Despite conservation of active-site residues, the Ras-related Rab GTPase activation pathway differs from Ras and between different Rabs. (elifesciences.org)
  • Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. (umbc.edu)
  • Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. (umbc.edu)
  • Rabs are GTP-binding proteins with conserved functions in membrane trafficking. (ox.ac.uk)
  • 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)
  • There is no known specific Rab3 GDI, but rather a common family of Rab GDI isoforms which bind prenylated Rabs in the cytoplasm and participates in insertion and removal from membranes (75). (pancreapedia.org)
  • This gene encodes a small GTP-binding protein that belongs to the largest family within the Ras superfamily. (nih.gov)
  • 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)
  • 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)
  • Rab GEFs and GAPs. (ox.ac.uk)
  • Similar to other small G proteins, the guanine binding state of Rab3 proteins is regulated by guanine nucleotide exchange proteins or factors (GEPs or GEFs) and GTPase activating proteins (GAPs). (pancreapedia.org)
  • Individual transport steps are regulated by Ras-like guanine nucleotide-binding proteins, termed Ypt in yeast or Rab in mammals. (embl.de)
  • Amino acid sequences typical for guanine nucleotide-binding proteins and characteristic for ypt proteins are perfectly conserved in the mouse ypt1 protein. (embl.de)
  • GTP-bound Rab10 could recruit a variety of Rab effectors to facilitate the transport of GLUT4 storage vesicles towards PM [8 9 32 33 Apparent colocalization of GLUT4 and Rab10 exposed in the present study is consistent with the statement by Sano et al. (colinsbraincancer.com)
  • Recent findings, however, indicate that their function in vesicle trafficking can go beyond this role, and a number of proteins, unrelated to each other, have been identified as putative Rab effectors. (embl.de)
  • 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)
  • Other proteins-known as GAPs-lead to the inactivation of the Rab protein. (elifesciences.org)
  • Rab functions are accompanied by cyclical activation and inactivation of GTP-bound and GDP-bound forms between the cytosol and plasma membrane that are regulated by upstream regulators ( 15 ) . (researchsquare.com)
  • Conserved active-site residues in the Rab switch II region stabilising the nucleotide-free form differentiate these pathways. (elifesciences.org)
  • The YPT1 gene of the yeast Saccharomyces cerevisiae codes for a guanine nucleotide-binding protein which is essential for cell viability. (embl.de)
  • 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)
  • 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)
  • microRNA (miR) is a highly conserved non-coding small RNA widely distributed in eukaryotic cells, 18-25 nucleotides long, being capable of affecting the biological functions of other genes by binding to the 3'UTR end of its target gene ( 4 , 5 ) . (researchsquare.com)
  • Although the GTPase switch of Rab proteins is highly conserved, functional mechanisms may be highly diversified among members of the Rab family. (embl.de)
  • Rab26 belongs to the Rab functional group III, which are considered key regulators of intracellular vesicle transport during exocytosis. (umbc.edu)
  • The diversity of Rab proteins in vesicle transport. (embl.de)
  • A yeast open reading frame sharing homology with the two known yeast Rab GTPase-activating proteins (GAPs), Gyp6p and Gyp7p, was found in a data base search. (embl.de)
  • The Rab-GTPase-activating proteins (GAPs) TBC1D1 and TBC1D4 play important roles in the insulin-stimulated translocation of the glucose transporter GLUT4 from intracellular vesicles to the plasma membrane in muscle cells and adipocytes. (bath.ac.uk)
  • AS160, a novel Akt substrate of 160 kDa, contains a Rab GTP aseactivating protein (GAP) domain. (johnshopkins.edu)
  • We identified Rab28 as a substrate for the GAP domains of both TBC1D1 and TBC1D4 in vitro. (bath.ac.uk)
  • 2017). Moreover, Golgi-associated Rab29 can recruit LRRK2 to the surface of the Golgi and activate it there for both auto- and Rab substrate phosphorylation. (stanford.edu)
  • In Dictyostelium, GTP-bound Rab21, together with two novel LIM domain proteins, LimF and ChLim, has been shown to regulate phagocytosis. (umbc.edu)
  • GTP-binding protein regulators regulate G proteins in several different ways. (wikipedia.org)
  • Proteins that regulate vesicle exocytosis cluster at AZs, composing the cytomatrix at the active zone (CAZ). (eneuro.org)
  • Our results suggest that although Rab3-GEF acts upstream of Rab3 to control Rab3 localization and likely GTP-binding, it also acts downstream to regulate CAZ development, potentially as a Rab3 effector at the synapse. (eneuro.org)
  • Although it did not regulate Rab 2, Rab 5, Rab 10 or Rab 11, a recent study indicates it can act on Rab 27A and 27B (23). (pancreapedia.org)
  • Patrick A. Lewis ABSTRACT Leucine-rich repeat kinase 2 (LRRK2) is a multidomain scaffolding protein with dual guanosine triphosphatase ( GTPase ) and kinase enzymatic activities, providing this protein with the capacity to regulate a multitude of signalling pathways. (biologists.com)
  • The combination of growth factors and RTKs can activate the PI3K/AKT signaling pathway and negatively regulate TSC1/2, promoting Rheb to become GTP loaded, which can activate mTORC1. (biomedcentral.com)
  • Rab40c is a SOCS box-containing protein which binds Cullin5 to form a ubiquitin E3 ligase complex (Rab40c/CRL5) to regulate protein ubiquitylation. (life-science-alliance.org)
  • This study tested this hypothesis by determining the effect of the PCAIs on the levels of RAS and related monomeric G-proteins. (oncotarget.com)
  • These findings implicate the potential role of PCAIs as anticancer agents through their direct interaction with monomeric G-proteins. (oncotarget.com)
  • Together these proteins form a molecular switch that can be turned on and off. (elifesciences.org)
  • The long term goal of our research is to elucidate the molecular mechanisms by which proteins are targeted to specific and distinct compartments. (stanford.edu)
  • As a molecular mechanism, we identified the Rab35 GAP EPI64B as an effector of ARF6 in negatively regulating Rab35 activation. (pasteur.fr)
  • The present study unravels a new molecular system for vesicle-based axonal transport of proteins in male and female flies (Drosophila melanogaster). (sdbonline.org)
  • Our studies reveal that Rab3 and Rab3-GEF act within the same molecular mechanism and support a model wherein Rab3-GEF serves as a Rab3 effector to control active zone protein composition. (eneuro.org)
  • 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)
  • Thus, an effector of an ARF protein is a GAP for a downstream Rab protein, and we propose that this hierarchical ARF/Rab GTPase cascade controls the proper activation of a common endocytic pathway essential for cytokinesis. (pasteur.fr)
  • Rab proteins are known to be important participants in insulin secretion by pancreatic β cells. (researchsquare.com)
  • Themammalian RAB proteins show striking similarities to the S. cerevisiae YPT1 and SEC4 proteins,Ras-related GTP-binding proteins involved in the regulation of secretion. (technuc.com)
  • Because of its localization and homology to the yeast protein Sec4, it was believed to play a role in the terminal steps of secretion. (pancreapedia.org)
  • The tiny GTPase Rab27B localizes to the zymogen granule membranes and plays an important role in regulating protein secretion by pancreatic acinar cells as does Rab3D. (research-in-field.com)
  • Overexpression of EPI64B in isolated mouse acini specifically inhibited the activation of exogenous and endogenous Rab27B but not Rab3D or additional closely related small G proteins involved in secretion. (research-in-field.com)
  • In eukaryotic cells, protein transport through the secretory and endocytic pathways is mediated by vesicular intermediates. (embl.de)
  • O-linked found in mucous fluids, but can also be present in membrane and secretory proteins, 3 or more sugars linked by N-acetylglalactosamine (GalNAc)--connected to serine, theronine. (freezingblue.com)
  • The contractile ring is made up of structural proteins, including actin filaments and myosin II filaments. (jove.com)
  • Loss of Pcs impairs Rab11 localization on the trans-side of Golgi units and induces the cytoplasmic accumulation of post-Golgi vesicles bearing rhabdomere proteins, as observed in Rab11-deficiency. (sdbonline.org)
  • Human cells expressing a constitutively activated, GTP-bound ARF6 mutant display identical endocytic recycling and cytokinesis defects as those observed upon overexpression of the inactivated, GDP-bound Rab35 mutant. (pasteur.fr)
  • A Rab protein is always bound to another molecule, which determines whether it is inactive or active. (elifesciences.org)
  • Binding to a molecule called GDP makes the Rab protein inactive, while binding to GTP makes it active. (elifesciences.org)
  • They are active or 'ON' when it is bound to GTP and inactive or 'OFF' when bound to GDP. (wikipedia.org)
  • Rab GTPase family 26 (Rab26). (umbc.edu)
  • Rab GTPase family 21 (Rab21). (umbc.edu)
  • Identification of a Sec4p GTPase-activating protein (GAP) as a novel member of a Rab GAP family. (embl.de)
  • The finding that yeast Rab GAPs share homology with proteins in other species, such as Caenorhabditis elegans and human, suggests the existence of a conserved Rab GAP family. (embl.de)
  • The Rab family of small GTP-binding proteins has long been implicated in the docking and fusion of transport vesicles with their target membranes. (embl.de)
  • 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)
  • This family member can be activated by the GAP protein RN-Tre, and it is localized to the Golgi complex. (nih.gov)
  • Evolution of the Rab family of small GTP-binding proteins. (nih.gov)
  • A transgenically expressed GTP-locked variant of Rab3 accumulates at the NMJ at wild-type levels and fully rescues the rab3 mutant but is unable to rescue the rab3-GEF mutant. (eneuro.org)
  • Finding effective therapies against cancers driven by mutant and/or overexpressed hyperactive G-proteins remains an area of active research. (oncotarget.com)
  • ARHGAP21 interacts with RhoA-GTP, and acts as a GAP to increase RhoA GTPase activity. (uth.edu)
  • A protein called RhoA is the chief regulator of contractile ring assembly and function. (jove.com)
  • By showing that different Rab proteins are activated by different mechanisms, and that a single Rab protein can be activated by more than one mechanism, the work of Langemeyer et al. (elifesciences.org)
  • Recent structural and cell biological studies shed new light on the mechanisms of Rab GEF and GAP action, and the cellular trafficking pathways they act in. (ox.ac.uk)
  • The cytoskeleton is a highly dynamic network of filamentous proteins that enables the active transport of cellular cargo, transduces force, and when assembled into higher-order structures, forms the basis for motile cellular structures that promote cell movement. (mechanobio.info)
  • We discuss how recent chemical proteomic approaches have delivered the first global overviews of protein lipidation in these organisms, contributing to our understanding of the role of this PTM in critical metabolic and cellular functions. (imperial.ac.uk)
  • 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)
  • 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)
  • The p53 interacting partner protein NUMB (homology of numb protein) preserves this intrinsic cellular asymmetry by preventing ubiquitin-mediated proteolysis of p53 catalyzed by the MDM2 E3 ubiquitin ligase 11 . (nature.com)
  • Here we define the precise Rab29 binding region of the LRRK2 Armadillo domain between residues 360-450 and show that this domain, termed 'Site #1', can also bind additional LRRK2 substrates, Rab8A and Rab10. (stanford.edu)
  • These proteins share a core structure, the conserved G-box (GDP/GTP) binding domain, of approximately 170 residues [ 3 ]. (oncotarget.com)
  • Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) make up the core machinery that mediates membrane fusion. (bvsalud.org)
  • In the trans-Golgi network (TGN), phosphorylated lysosomal enzymes bind to M-6-P receptors, which direct the enzymes into clathrin-coated vesicles. (biomedcentral.com)
  • This domain occurred 99 times on human genes ( 176 proteins). (umbc.edu)
  • 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)
  • So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes. (wikidoc.org)
  • Gyp1p also stimulated the GTPase activity of several other yeast Rab proteins including Ypt1p, Ypt7p, and Ypt51p but showed no GAP activity on Ypt6p and Ypt32p. (embl.de)
  • The ras-related ypt protein is an ubiquitous eukaryotic protein: isolation and sequence analysis of mouse cDNA clones highly homologous to the yeast YPT1 gene. (embl.de)
  • The cDNAs were derived from a gene, designated ypt1, which codes for a protein of 205 amino acids with 71% homology to the yeast YPT1 gene product. (embl.de)
  • A monoclonal antibody specifically recognizing the 23.5-kd yeast YPT1 protein cross-reacted with a protein of identical size on protein blots of mouse, rat, pig, bovine and human cell lines. (embl.de)
  • A yeast gene encoding a protein homologous to the human c-has/bas proto-oncogene product. (embl.de)
  • With similar manifestation levels of FLAG-Rab4A(S27N) the mutation favouring the GDP-bound form [30] and HA-GDIs more GDI-2 was immunoprecipitated with Rab4A (Numbers 7A and ?and7B).7B). (colinsbraincancer.com)
  • Recombinant Gyp1p showed GAP activity on Sec4p, increasing both its steady-state rate and single turnover GTPase activity. (embl.de)
  • This effect is probably due to the increase in GAP activity, which can be observed in a lysate from cells overexpressing Gyp1p. (embl.de)
  • The second Rab3 GEF, known as GRAB, interacts with inositol hexakisphosphate kinase and Rab3A and its protein expression is primarily in brain (41). (pancreapedia.org)
  • For DENND1-Rab35 and DrrA-Rab1 the Rab active-site glutamine, often mutated to create constitutively active forms, is involved in GEF mediated GDP-release. (elifesciences.org)
  • Macropinocytosis GTPase Rab Phosphatase Phosphoinositide EGF Ruffling Macropinocytosis is an actin-driven process that involves the formation and extension of plasma membrane ruffles and the eventual closure of large (≥0.2 to 5.0. (biologists.com)
  • Mechanistically, we found that Rab40c binds the protein phosphatase 6 (PP6) complex and ubiquitylates one of its subunits, ankyrin repeat domain 28 (ANKRD28), thus leading to its lysosomal degradation. (life-science-alliance.org)
  • The extracellular signaling protein Sonic hedgehog (Shh) requires dual lipidation for functional signaling, whereby N-terminal palmitoylation is performed by the enzyme Hedgehog acyltransferase (Hhat). (imperial.ac.uk)
  • It is hypothesized that PCAIs work as anticancer agents by disrupting polyisoprenylation-dependent functional interactions of the G-Proteins. (oncotarget.com)
  • Resolution of the 3D structure of the TBC/rab GAP domain of GYP1 has shown that it is a fully alpha-helical V-shaped molecule. (embl.de)
  • Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) is overexpressed and contributes to p53 degradation in TICs. (nature.com)
  • Our results indicate that loss of Rab3-GEF results in the development of NMJs that are structurally and functionally indistinguishable from NMJs that lack the protein Rab3. (eneuro.org)
  • The ~200 amino acid TBC/rab GTPase-activating protein (GAP) domain is well conserved across species and has been found in a wide range of different proteins from plant adhesion molecules to mammalian oncogenes. (embl.de)
  • The conserved arginine residue probably functions as a catalytic arginine finger analogous to that seen in ras and Rho-GAPs. (embl.de)
  • However, the exact functions of Rab40c remain to be determined, and what proteins are the targets of Rab40c-Cullin5-mediated ubiquitylation in mammalian cells are unknown. (life-science-alliance.org)
  • EPI64B almost completely abolished the GTP-bound form of Rab27B without influencing GTP-Rab3D. (research-in-field.com)
  • Mutations that block the Space activity decreased the inhibitory effect of EPI64B within the GTP-bound state of Rab27B and abolished the enhancing effect of EPI64B within the amylase launch. (research-in-field.com)
  • Two TBC proteins EPI64/TBC1D10A and EPI64B/TBC1D10B/FLJ13130 have already been identified as Spaces for Rab27A in melanocytes (28). (research-in-field.com)