Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10

Shian-Huey Chiang, Christian A. Baumann, Makoto Kanzaki, Debbie C. Thurmond, Robert T. Watson, Cheryl L. Neudauer, Ian G. Macara, Jeffrey E. Pessin and Alan R. Saltiel ()
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Shian-Huey Chiang: Cellular and Molecular Biology Graduate Program, University of Michigan
Christian A. Baumann: University of Michigan School of Medicine
Makoto Kanzaki: The University of Iowa
Debbie C. Thurmond: The University of Iowa
Robert T. Watson: The University of Iowa
Cheryl L. Neudauer: Center for Cell Signaling, University of Virginia
Ian G. Macara: Center for Cell Signaling, University of Virginia
Jeffrey E. Pessin: The University of Iowa
Alan R. Saltiel: University of Michigan School of Medicine

Nature, 2001, vol. 410, issue 6831, 944-948

Abstract: Abstract The stimulation of glucose uptake by insulin in muscle and adipose tissue requires translocation of the GLUT4 glucose transporter protein from intracellular storage sites to the cell surface1,2,3,4,5,6. Although the cellular dynamics of GLUT4 vesicle trafficking are well described, the signalling pathways that link the insulin receptor to GLUT4 translocation remain poorly understood. Activation of phosphatidylinositol-3-OH kinase (PI(3)K) is required for this trafficking event, but it is not sufficient to produce GLUT4 translocation7. We previously described a pathway involving the insulin-stimulated tyrosine phosphorylation of Cbl, which is recruited to the insulin receptor by the adapter protein CAP8,9. On phosphorylation, Cbl is translocated to lipid rafts. Blocking this step completely inhibits the stimulation of GLUT4 translocation by insulin10. Here we show that phosphorylated Cbl recruits the CrkII–C3G complex to lipid rafts, where C3G specifically activates the small GTP-binding protein TC10. This process is independent of PI(3)K, but requires the translocation of Cbl, Crk and C3G to the lipid raft. The activation of TC10 is essential for insulin-stimulated glucose uptake and GLUT4 translocation. The TC10 pathway functions in parallel with PI(3)K to stimulate fully GLUT4 translocation in response to insulin.

Date: 2001
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DOI: 10.1038/35073608

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