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J. Biol. Chem., Vol. 283, Issue 37, 25115-25123, September 12, 2008

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-Actinin-4 Is Selectively Required for Insulin-induced GLUT4 Translocation^*

Ilana Talior-Volodarsky¹, Varinder K. Randhawa², Hilal Zaid, and Amira Klip³

From the Program in Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8 and Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Insulin induces GLUT4 translocation to the muscle cell surface. Using differential amino acid labeling and mass spectrometry, we observed insulin-dependent co-precipitation of actinin-4 (ACTN4) with GLUT4 (Foster, L. J., Rudich, A., Talior, I., Patel, N., Huang, X., Furtado, L. M., Bilan, P. J., Mann, M., and Klip, A. (2006) J. Proteome Res. 5, 64–75). ACTN4 links F-actin to membrane proteins, and actin dynamics are essential for GLUT4 translocation. We hypothesized that ACTN4 may contribute to insulin-regulated GLUT4 traffic. In L6 muscle cells insulin, but not platelet-derived growth factor, increased co-precipitation of ACTN4 with GLUT4. Small interfering RNA-mediated ACTN4 knockdown abolished the gain in surface-exposed GLUT4 elicited by insulin but not by platelet-derived growth factor, membrane depolarization, or mitochondrial uncoupling. In contrast, knockdown of -actinin-1 (ACTN1) did not prevent GLUT4 translocation by insulin. GLUT4 colocalized with ACTN4 along the insulin-induced cortical actin mesh and ACTN4 knockdown prevented GLUT4-actin colocalization without impeding actin remodeling or Akt phosphorylation, maintaining GLUT4 in a tight perinuclear location. We propose that ACTN4 contributes to GLUT4 traffic, likely by tethering GLUT4 vesicles to the cortical actin cytoskeleton.

Received for publication, March 4, 2008 , and in revised form, May 16, 2008.

^* This work was supported by Canadian Institutes of Health Research Grant MT 7307 (to A. K.). 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. 1 and 2.

¹ Supported by research fellowship awards from the Banting and Best Diabetes Center and the Hospital for Sick Children Research Training Centre.

² Supported by doctoral awards from Canadian Institutes of Health Research, Banting and Best Diabetes Center, Research Training Centre, and Ontario Graduate Scholarship.

³ To whom correspondence should be addressed: Program in Cell Biology, The 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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