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J. Biol. Chem., Vol. 281, Issue 38, 27982-27990, September 22, 2006

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Insulin-stimulated Interaction between Insulin Receptor Substrate 1 and p85 and Activation of Protein Kinase B/Akt Require Rab5^*

Xiong Su, Irfan J. Lodhi, Alan R. Saltiel, and Philip D. Stahl¹

From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and Life Sciences Institute, Departments of Internal Medicine and Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109

Binding of insulin to the insulin receptor initiates a cascade of protein phosphorylation and effector recruitment events leading to the activation of multiple distinct signaling pathways. Previous studies suggested that the diversity and specificity of insulin signal transduction are accomplished by both subcellular localization of receptor and the selective activation of downstream signaling molecules. The small GTPase Rab5 is a key regulator of endocytosis. Three Rab5 isoforms (Rab5a, -5b, and -5c) have been identified. Here we exploited the RNA interference technique to specifically knock down individual Rab5 isoforms to determine the cellular function of Rab5 in distinct insulin signaling pathways. Small interference RNA against a single Rab5 isoform had no effect on protein kinase B (PKB)/Akt or MAPK activation by insulin in NIH3T3 cells overexpressing human insulin receptor. However, simultaneous knockdown of all three Rab5 isoforms dramatically attenuated PKB/Akt activation by insulin without affecting MAPK activation. This inhibition of PKB/Akt activation was because of the impaired interaction between insulin receptor substrate 1 and the p85 subunit of phosphatidylinositol 3-kinase. These results indicate a requirement of Rab5 in presenting p85 to insulin receptor substrate 1. Additional evidence supporting a role for Rab5 was suggested by studies with GAPex-5, a vps9 domain containing exchange factor. Down-regulation of GAPex-5 impaired insulin-stimulated PKB/Akt activation. Collectively, this study indicates the involvement of Rab5 in insulin signaling.

Received for publication, March 27, 2006 , and in revised form, June 26, 2006.

^* This work was supported by National Institutes of Health Grants 2R01GM42259-33, 5R21DK065844-02, and R01DK061618-04. 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 should be addressed: Dept. of Cell Biology and Physiology, Washington University School of Medicine, Campus Box 8228, 660 S. Euclid, St. Louis, MO 63110. Tel.: 314-361-6950; Fax: 314-361-1490; E-mail: pstahl{at}cellbiology.wustl.edu.

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