title: The Rab GTPase-activating protein TBC1D4/AS160 contains an atypical phosphotyrosine-binding domain that interacts with plasma membrane phospholipids to facilitate GLUT4 trafficking in adipocytes.
abstract: The Rab GTPase-activating protein TBC1D4/AS160 regulates GLUT4 trafficking in adipocytes. Nonphosphorylated AS160 binds to GLUT4 vesicles and inhibits GLUT4 translocation, and AS160 phosphorylation overcomes this inhibitory effect. In the present study we detected several new functional features of AS160. The second phosphotyrosine-binding domain in AS160 encodes a phospholipid-binding domain that facilitates plasma membrane (PM) targeting of AS160, and this function is conserved in other related RabGAP/Tre-2/Bub2/Cdc16 (TBC) proteins and an AS160 ortholog in Drosophila. This region also contains a nonoverlapping intracellular GLUT4-containing storage vesicle (GSV) cargo-binding site. The interaction of AS160 with GSVs and not with the PM confers the inhibitory effect of AS160 on insulin-dependent GLUT4 translocation. Constitutive targeting of AS160 to the PM increased the surface GLUT4 levels, and this was attributed to both enhanced AS160 phosphorylation and 14-3-3 binding and inhibition of AS160 GAP activity. We propose a model wherein AS160 acts as a regulatory switch in the docking and/or fusion of GSVs with the PM.
authors.affiliation: Diabetes and Obesity Research Program, The Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors.forename: Shi-Xiong
authors.initials: SX
authors.lastname: Tan
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ng
authors.forename: James G
authors.initials: JG
authors.lastname: Burchfield
authors.forename: Georg
authors.initials: G
authors.lastname: Ramm
authors.forename: David G
authors.initials: DG
authors.lastname: Lambright
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Stöckli
authors.forename: David E
authors.initials: DE
authors.lastname: James
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001693:Biological Transport, Active; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D020691:rab GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D008563:Membrane Lipids; D050505:Mutant Proteins; D010743:Phospholipids; D011993:Recombinant Fusion Proteins; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; D019000:Phosphotyrosine; D020691:rab GTP-Binding Proteins