title: Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles.
abstract: The poly(ADP-ribose) polymerase tankyrase was originally described as a telomeric protein whose catalytic activity was proposed to regulate telomere function. Subsequent studies revealed that most tankyrase is actually extranuclear, but a discordant pattern of cytoplasmic targeting was reported. Here we used fractionation and immunofluorescence to show in 3T3-L1 fibroblasts that tankyrase is a peripheral membrane protein associated with the Golgi. We further colocalized tankyrase with GLUT4 storage vesicles in the juxtanuclear region of adipocytes. Consistent with this colocalization, we found that tankyrase binds specifically to a resident protein of GLUT4 vesicles, IRAP (insulin-responsive amino peptidase). The binding of tankyrase to IRAP involves the ankyrin repeats of tankyrase and a defined sequence ((96)RQSPDG(101)) in the IRAP cytosolic domain (IRAP(1-109)). Tankyrase is a novel signaling target of mitogen-activated protein kinase (MAPK); it is stoichiometrically phosphorylated upon insulin stimulation. Phosphorylation enhances the poly(ADP-ribose) polymerase activity of tankyrase but apparently does not mediate the acute effect of insulin on GLUT4 targeting. Taken together, tankyrase is a novel target of MAPK signaling in the Golgi, where it is tethered to GLUT4 vesicles by binding to IRAP. We speculate that tankyrase may be involved in the long term effect of the MAPK cascade on the metabolism of GLUT4 vesicles.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
authors.forename: N W
authors.initials: NW
authors.lastname: Chi
authors.forename: H F
authors.initials: HF
authors.lastname: Lodish
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism*; D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D010122:Cystinyl Aminopeptidase; D051275:Glucose Transporter Type 4; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D038501:Tankyrases; D014162:Transfection
chemical_list: D000626:Aminopeptidases; D010122:Cystinyl Aminopeptidase; D051275:Glucose Transporter Type 4; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011065:Poly(ADP-ribose) Polymerases; D011993:Recombinant Fusion Proteins; D038501:Tankyrases; C495692:SLC2A4 protein, human; C495693:Slc2a4 protein, mouse; C498822:Tnks protein, mouse; C418109:TNKS protein, human; C105964:leucyl-cystinyl aminopeptidase