Insulin stimulates phosphatidylinositol 3-phosphate production via the activation of Rab5 |
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Authors: | Lodhi Irfan J Bridges Dave Chiang Shian-Huey Zhang Yanling Cheng Alan Geletka Lynn M Weisman Lois S Saltiel Alan R |
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Affiliation: | *Life Sciences Institute, Departments of Internal Medicine and Molecular and Integrative Physiology and Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109. |
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Abstract: | 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. |
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