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J. Biol. Chem., Vol. 281, Issue 39, 29174-29180, September 29, 2006

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A Role for 14-3-3 in Insulin-stimulated GLUT4 Translocation through Its Interaction with the RabGAP AS160^*

Georg Ramm¹, Mark Larance, Michael Guilhaus, and David E. James²

From the Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, NSW 2010 and the Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW 2052 Australia

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.

Received for publication, April 6, 2006 , and in revised form, July 24, 2006.

^* This work was supported by grants from the National Health and Medical Research Council of Australia (to D. E. J.), and Diabetes Australia Research Trust (to G. R. and D. E. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Diabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia. Tel.: 61-2-9295-8229; Fax: 61-2-9295-8201; E-mail: g.ramm{at}garvan.org.au.

² An National Health and Medical Research Council senior principle research fellow. To whom correspondence may be addressed: Diabetes and Obesity Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, NSW 2010, Australia. Tel.: 61-2-9295-8210; Fax: 61-2-9295-8201; E-mail: d.james{at}garvan.org.au.

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