Insulin CAP Involvement in Glucose Transport

Insulin-mediated glucose transport depends on the activation of phosphatidylinositol-3 kinase (PI3K) and other uncharacterized intracellular signaling pathways. Now a new piece of the transport puzzle has fallen into place. Baumann et al. present evidence that Cbl and the Cbl-associated protein, CAP, work to increase glucose uptake. Using the yeast two-hybrid method, the authors identified flotillin as a protein that associated with CAP. GST-flotillin fusion proteins also existed in a tripartite complex with CAP and Cbl from cell lysates. In insulin-treated cells, Cbl translocated to flotillin-rich lipid rafts in the plasma membranes, in a manner coincident with Cbl tyrosine phosphorylation. Overexpression of SH3 domain-deleted CAP mutants (CAPSH3) prevented translocation of phospho-Cbl to the lipid rafts. Coexpression of Glut4, a glucose transporter, and CAPSH3 also blocked insulin-stimulated but not basal translocation of Glut4. Additionally, CAP-mediated Glut4 translocation was resistant to wortmannin, a PI3K inhibitor. Thus, the data suggest that CAP may have a role in insulin-mediated glucose uptake. A News & Views article by Czech describes the glucose transport pathway mediated by PI3K, and also reviews the evidence given by Baumann et al. for the existence of a CAP pathway that regulates glucose transporter translocation.

Baumann, C.A., Ribon, V., Kanzaki, M., Thurmond, D.C., Mora, S., Shigematsu, S., Bickel, P.E., Pessin, J.E., and Saltiel, A.R. (2000) CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 407: 202-207. [Online Journal]

Czech, M.P. (2000) Signal transduction: Lipid rafts and insulin action. Nature 407: 147-148. [Online Journal]