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J. Biol. Chem., Vol. 283, Issue 40, 27208-27219, October 3, 2008

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GLUT4 Vesicle Recruitment and Fusion Are Differentially Regulated by Rac, AS160, and Rab8A in Muscle Cells^*

Varinder K. Randhawa¹, Shuhei Ishikura², Ilana Talior-Volodarsky², Alex W. P. Cheng³, Nish Patel⁴, John H. Hartwig^¶, and Amira Klip⁵

From the Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and ^¶Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

Insulin increases glucose uptake into muscle by enhancing the surface recycling of GLUT4 transporters. In myoblasts, insulin signals bifurcate downstream of phosphatidylinositol 3-kinase into separate Akt and Rac/actin arms. Akt-mediated Rab-GAP AS160 phosphorylation and Rac/actin are required for net insulin gain of GLUT4, but the specific steps (vesicle recruitment, docking or fusion) regulated by Rac, actin dynamics, and AS160 target Rab8A are unknown. In L6 myoblasts expressing GLUT4myc, blocking vesicle fusion by tetanus toxin cleavage of VAMP2 impeded GLUT4myc membrane insertion without diminishing its build-up at the cell periphery. Conversely, actin disruption by dominant negative Rac or Latrunculin B abolished insulin-induced surface and submembrane GLUT4myc accumulation. Expression of non-phosphorylatable AS160 (AS160-4P) abrogated membrane insertion of GLUT4myc and partially reduced its cortical build-up, an effect magnified by selective Rab8A knockdown. We propose that insulin-induced actin dynamics participates in GLUT4myc vesicle retention beneath the membrane, whereas AS160 phosphorylation is essential for GLUT4myc vesicle-membrane docking/fusion and also contributes to GLUT4myc cortical availability through Rab8A.

Received for publication, June 3, 2008 , and in revised form, July 17, 2008.

^* This study was supported by Grant MOP-7307 (to A. K.) from the Canadian Institutes of Health Research (CIHR). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ Supported by doctoral awards from CIHR, Banting and Best Diabetes Centre (BBDC)-Novo Nordisk-University of Toronto, and an Ontario Graduate Scholarship; recipient of the Joe Connolly Award.

² Supported by fellowships from BBDC and the Hospital for Sick Children.

³ Supported by a BBDC studentship.

⁴ Supported by a CIHR doctoral award.

⁵ To whom correspondence should be addressed: Program in Cell Biology, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada. Tel.: 416-813-6392; Fax: 416-813-5028; E-mail: amira{at}sickkids.ca.

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