Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 19, Issue 7, Pages 2718-2728Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E08-01-0105
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- American Diabetes Association Mentor
- National Institutes of Health [R01DK061618-06]
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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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