A role for 14-3-3 in insulin-stimulated GLUT4 translocation through its interaction with the RabGAP AS160

Georg Ramm (Lead / Corresponding author), Mark Larance, Michael Guilhaus, David E. James (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    152 Citations (Scopus)

    Abstract

    Translocation of the insulin-regulated glucose transporter GLUT4 to the cell surface is dependent on the phosphatidylinositol 3-kinase/Akt pathway. The RabGAP (Rab GTPase-activating protein) AS160 (Akt substrate of 160 kDa) is a direct substrate of Akt and plays an essential role in the regulation of GLUT4 trafficking. We have used liquid chromatography tandem mass spectrometry to identify several 14-3-3 isoforms as AS160-interacting proteins. 14-3-3 proteins interact with AS160 in an insulin- and Akt-dependent manner via an Akt phosphorylation site, Thr-642. This correlates with the dominant negative effect of both the AS160(T642A) and the AS160(4P) mutants on insulin-stimulated GLUT4 translocation. Introduction of a constitutive 14-3-3 binding site into AS160(4P) restored 14-3-3 binding without disrupting AS160-IRAP (insulin-responsive amino peptidase) interaction and reversed the inhibitory effect of AS160(4P) on GLUT4 translocation. These data show that the insulin-dependent association of 14-3-3 with AS160 plays an important role in GLUT4 trafficking in adipocytes.
    Original languageEnglish
    Pages (from-to)29174-29180
    Number of pages7
    JournalJournal of Biological Chemistry
    Volume281
    Issue number39
    DOIs
    Publication statusPublished - 29 Sep 2006

    Keywords

    • Animals
    • 14-3-3 Proteins
    • GTPase-Activating Proteins
    • Glucose
    • Proto-Oncogene Proteins c-akt
    • 3T3-L1 Cells
    • Mice
    • Glucose Transporter Type 4
    • Insulin
    • rab GTP-Binding Proteins
    • CHO Cells
    • Protein Kinases
    • Cricetinae
    • Protein Transport

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