Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking

Mark Larance, Georg Ramm, Jacqueline Stöckli, Ellen M. van Dam, Stephanie Winata, Valerie Wasinger, Fiona Simpson, Michael Graham, Jagath R. Junutula, Michael Guilhaus, David E. James (Lead / Corresponding author)

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    294 Citations (Scopus)

    Abstract

    Insulin stimulates the translocation of the glucose transporter GLUT4 from intracellular vesicles to the plasma membrane. In the present study we have conducted a comprehensive proteomic analysis of affinity-purified GLUT4 vesicles from 3T3-L1 adipocytes to discover potential regulators of GLUT4 trafficking. In addition to previously identified components of GLUT4 storage vesicles including the insulin-regulated aminopeptidase insulin-regulated aminopeptidase and the vesicle soluble N-ethylmaleimide factor attachment protein (v-SNARE) VAMP2, we have identified three new Rab proteins, Rab10, Rab11, and Rab14, on GLUT4 vesicles. We have also found that the putative Rab GTPase-activating protein AS160 (Akt substrate of 160 kDa) is associated with GLUT4 vesicles in the basal state and dissociates in response to insulin. This association is likely to be mediated by the cytosolic tail of insulin-regulated aminopeptidase, which interacted both in vitro and in vivo with AS160. Consistent with an inhibitory role of AS160 in the basal state, reduced expression of AS160 in adipocytes using short hairpin RNA increased plasma membrane levels of GLUT4 in an insulin-independent manner. These findings support an important role for AS160 in the insulin regulated trafficking of GLUT4.
    Original languageEnglish
    Pages (from-to)37803-37813
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume280
    Issue number45
    DOIs
    Publication statusPublished - 11 Nov 2005

    Keywords

    • Secretory Vesicles
    • Animals
    • Cystinyl Aminopeptidase
    • GTPase-Activating Proteins
    • Mice
    • 3T3-L1 Cells
    • Aminopeptidases
    • Glucose Transporter Type 4
    • Insulin
    • Fibroblasts
    • Gene Expression Profiling
    • Adipocytes
    • Gene Expression Regulation
    • RNA Interference
    • Cell Line
    • Protein Transport
    • Cricetinae

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  • Cite this

    Larance, M., Ramm, G., Stöckli, J., van Dam, E. M., Winata, S., Wasinger, V., Simpson, F., Graham, M., Junutula, J. R., Guilhaus, M., & James, D. E. (2005). Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. Journal of Biological Chemistry, 280(45), 37803-37813. https://doi.org/10.1074/jbc.M503897200