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FLASH GENE
Symbol RABGEF1 contributors: mct/npt - updated : 28-02-2015
HGNC name RAB guanine nucleotide exchange factor (GEF) 1
HGNC id 17676
Location 7q11.21      Physical location : 66.205.642 - 66.276.446
Synonym name
  • putative Rab5 GDP/GTP exchange factor homolog
  • rabaptin-5-associated exchange factor for Rab5
  • Rabex5
  • Synonym symbol(s) RABEX5, FLJ32302, RAP1, RAP-1
    DNA
    TYPE functioning gene
    STRUCTURE 70.81 kb     9 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 - 3832 56.7 491 - 2004 15339665
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveesophagus   highly
    Nervousbrain    
    Reproductivemale systemtestis  highly
    Respiratoryrespiratory tracttrachea  highly
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Connectiveadipose  highly
    Muscularstriatumskeletal  
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N-terminal zinc finger domain, and contains tandem ubiquitin binding domains: A20_ZF and MIU
  • a VPS9 domain, that would be sufficient for directing RAB5A to mitochondria
  • a heptad repeat
  • two ubiquitin binding domains (UBDs)
  • a MIU domain
  • a separate early endosomal targeting domain that localizes the protein to early endosomes
  • a proline-rich C-terminus, Rabaptin-5-binding site within the C-terminal coiled-coil domain at the C terminus that mediates the interaction with endosomally localized RABGEF1
  • HOMOLOGY
    interspecies ortholog to murine Rab5ef-pending
    homolog to Drosophila CG9139
    homolog to yeast S.pombe spbc29a10.11c
    Homologene
    FAMILY
    CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    text
  • enriched in the cytosol
  • localization to endosomes, mediated by three different domains: a motif interacting with ubiquitin, an early endosomal targeting domain, and a coiled-coil domain at the C terminus that mediates the interaction with endosomally localized RABGEF1
  • basic FUNCTION
  • guanine nucleotide exchange factor for RAB5, involved in vacuolar protein sorting
  • required for the consumption of transport vesicles containing vacuolar protein precursors
  • recruited to early endosomes by interaction of its UBD with transmembrane ubiquitinated cargo (or ubiquitinated adaptors bound to this cargo)
  • RABGEF1-mediated RAS ubiquitination promotes RAS endosomal localization and leads to the suppression of ERK activation
  • regulates the endocytic trafficking pathway of ubiquitinated neural cell adhesion molecule L1CAM
  • its GEF activity acts as an intramolecular switch for spatiotemporal trafficking of the ubiquitinated cargos
  • regulates ITGB2 adhesiveness through one of its effectors, RABGEF1-interacting adapter molecule (APBB1IP)
  • catalytic activity of RABGEF1 is an essential component for specific spatial and temporal recruitment of cognate RAB proteins
  • is critical for platelet activation and thrombus formation
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    RAB22A-RABGEF1-RAB5A cascade is functionally important for the endocytosis and degradation of epidermal growth factor
    a component
  • forms a complex with RABEP1
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binding to RAB GTPase (such as VPS21)
  • binding to ubiquitin (Ub binding is necessary for the recruitment of RABGEF1 to early endosomes, and this recruitment is independent of its GEF activity and of its partners, RAB5 and RABEP1)
  • RAB22A is a binding site on early endosomes for direct recruitment of RABGEF1 and activation of RAB5A, establishing a RAB22A-RAB5A signaling relay to promote early endosome fusion
  • positive feedback activation of RAB5A by RABGEF1 and RABEP1 in endocytosis with a delayed onset
  • functions as an E3 ligase for RAS
  • interaction of RABGEF1 with RAB5A depends specifically on interaction of the MIU domain with the ubiquitinated L1 to drive its internalization
  • GEF activity of RABGEF1 is crucial for recruiting RAB5A
  • corecruitment of RAB5A to the same structures to which RABGEF1 is mistargeted offers strong support for the idea that RABGEF1 localization determines RAB5A membrane localization
  • APBB1IP is a critical component of the phagocytosis machinery downstream of RABGEF1 and mediates its function by recruiting talin to the phagocytic complement receptors
  • in the absence of F11R, the exchange factors RABGEF3 and RAPGEF4 are down-regulated, which prevents the activation of the small GTPase RABGEF1
  • RASA3 targets RAS and RABGEF1
  • P2RY12 signaling is required to inhibit RASA3 and enable sustained RABGEF1-dependent platelet activation and thrombus formation at sites of vascular injury
  • RABEP1 is recruited by both RABGEF1 recognizing ubiquitylated cargo and by RAB4A to activate RAB5A in a feed-forward manner
  • role of the RABGEF1-APBB1IP, in leukocyte integrin activation and consequently in leukocyte trafficking
  • TBC1D21 may likely interact with and potentially regulate RABGEF1 during spermatogenesis
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neuromuscularmyopathy 
    pharmacological inhibition of RABGEF1 increases mesoangioblasts (MABs) engraftment in dystrophic muscle, which results into a significant improvement of muscle function offering a novel strategy for stem cell-based therapies
    ANIMAL & CELL MODELS