Insulin stimulates phosphatidylinositol 3-phosphate production via the activation of Rab5.
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.
Lodhi
Irfan J
IJ
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Bridges
Dave
D
Chiang
Shian-Huey
SH
Zhang
Yanling
Y
Cheng
Alan
A
Geletka
Lynn M
LM
Weisman
Lois S
LS
Saltiel
Alan R
AR
D041721:3T3-L1 Cells; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D004815:Epidermal Growth Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
C529585:Gapex-5 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D004815:Epidermal Growth Factor; C503260:Rhoq protein, mouse; D020696:rab5 GTP-Binding Proteins; D020741:rho GTP-Binding Proteins