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MBC in Press, published online ahead of print April 30, 2008
Mol. Biol. Cell 10.1091/mbc.E08-01-0105

A more recent version of this article appeared on July 1, 2008 Originally published as MBC in Press, 10.1091/mbc.E08-01-0105 on April 23, 2008
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Submitted on February 1, 2008
Revised on March 24, 2008
Accepted on April 14, 2008

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

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

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

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. While 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.

{dagger}These authors contributed equally to this work.

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






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