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J. Biol. Chem., Vol. 280, Issue 18, 17978-17985, May 6, 2005

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Expression of Constitutively Active Akt/Protein Kinase B Signals GLUT4 Translocation in the Absence of an Intact Actin Cytoskeleton^*

Craig A. Eyster, Quwanza S. Duggins, and Ann Louise Olson

From the Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190

The actin cytoskeleton has been shown to be required for insulin-dependent GLUT4 translocation; however, the role that the actin network plays is unknown. Actin may play a role in formation of an active signaling complex, or actin may be required for movement of vesicles to the plasma membrane surface. To distinguish between these possibilities, we examined the ability of myr-Akt, a constitutively active form of Akt that signals GLUT4 translocation to the plasma membrane in the absence of insulin, to signal translocation of an HA-GLUT4-GFP reporter protein in the presence or absence of an intact cytoskeleton in 3T3-L1 adipocytes. Expression of myr-Akt signaled the redistribution of the GLUT4 reporter protein to the cell surface in the absence or presence of 10 µM latrunculin B, a concentration sufficient to completely inhibit insulin-dependent redistribution of the GLUT4 reporter to the cell surface. These data suggest that the actin network plays a primary role in organization of the insulin-signaling complex. To further support this conclusion, we measured the activation of known signaling proteins using a saturating concentration of insulin in cells pretreated without or with 10 µM latrunculin B. We found that latrunculin treatment did not affect insulin-dependent tyrosine phosphorylation of the insulin receptor -subunit and IRS-1 but completely inhibited activation of Akt/PKB enzymatic activity. Phosphorylation of Akt/PKB at Ser-473 and Thr-308 was inhibited by latrunculin B treatment, indicating that the defect in signaling lies prior to Akt/PKB activation. In summary, our data support the hypothesis that the actin network plays a role in organization of the insulin-signaling complex but is not required for vesicle trafficking and/or fusion.

Received for publication, August 26, 2004 , and in revised form, February 23, 2005.

^* This work was supported by grants from the Oklahoma Center for the Advancement of Science and Technology (OCAST), National Institutes of Health Grants DK62341 and DK68438, and grants from the American Diabetes Association. 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.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, P. O. Box 26901, Rm. 853-BMSB, Oklahoma City, OK 73190. Tel.: 405-271-2227 (ext. 1252); Fax: 405-271-3092; E-mail: ann-olson{at}ouhsc.edu.

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