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Vol. 19, Issue 7, 2718-2728, July 2008

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Insulin Stimulates Phosphatidylinositol 3-Phosphate Production via the Activation of Rab5

Irfan J. Lodhi^*,, Dave Bridges^*,, Shian-Huey Chiang^*, Yanling Zhang^*,, Alan Cheng^*, Lynn M. Geletka^*, Lois S. Weisman^*,, and Alan R. Saltiel^*,

*Life Sciences Institute, Departments of Internal Medicine and Molecular and Integrative Physiology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109

Submitted February 1, 2008; Revised March 24, 2008; Accepted April 14, 2008
Monitoring Editor: Francis Barr

Phosphatidylinositol 3-phosphate (PI(3)P) plays an important role in insulin-stimulated glucose uptake. Insulin promotes the production of PI(3)P at the plasma membrane by a process dependent on TC10 activation. Here, we report that insulin-stimulated PI(3)P production requires the activation of Rab5, a small GTPase that plays a critical role in phosphoinositide synthesis and turnover. This activation occurs at the plasma membrane and is downstream of TC10. TC10 stimulates Rab5 activity via the recruitment of GAPEX-5, a VPS9 domain–containing guanyl nucleotide exchange factor that forms a complex with TC10. Although overexpression of plasma membrane-localized GAPEX-5 or constitutively active Rab5 promotes PI(3)P formation, knockdown of GAPEX-5 or overexpression of a dominant negative Rab5 mutant blocks the effects of insulin or TC10 on this process. Concomitant with its effect on PI(3)P levels, the knockdown of GAPEX-5 blocks insulin-stimulated Glut4 translocation and glucose uptake. Together, these studies suggest that the TC10/GAPEX-5/Rab5 axis mediates insulin-stimulated production of PI(3)P, which regulates trafficking of Glut4 vesicles.

These authors contributed equally to this work.

Address correspondence to: Alan R. Saltiel (saltiel{at}lsi.umich.edu)