Insulin stimulates the transport of glucose into fat and muscle cells. Although the precise molecular mechanisms involved in this process remain uncertain, insulin initiates its actions by binding to its tyrosine kinase receptor, leading to the phosphorylation of intracellular substrates. One such substrate is the Cbl protooncogene product1. Cbl is recruited to the insulin receptor by interaction with the adapter protein CAP, through one of three adjacent SH3 domains in the carboxy terminus of CAP2. Upon phosphorylation of Cbl, the CAP–Cbl complex dissociates from the insulin receptor and moves to a caveolin-enriched, triton-insoluble membrane fraction3. Here, to identify a molecular mechanism underlying this subcellular redistribution, we screened a yeast two-hybrid library using the amino-terminal region of CAP and identified the caveolar protein flotillin. Flotillin forms a ternary complex with CAP and Cbl, directing the localization of the CAP–Cbl complex to a lipid raft subdomain of the plasma membrane. Expression of the N-terminal domain of CAP in 3T3-L1 adipocytes blocks the stimulation of glucose transport by insulin, without affecting signalling events that depend on phosphatidylinositol-3-OH kinase. Thus, localization of the Cbl–CAP complex to lipid rafts generates a pathway that is crucial in the regulation of glucose uptake.
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J.E.P. is supported by the NIH. P.E.B. is supported by the American Diabetes Association and awards from the Washington University Clinical Nutrition Research Unit and Diabetes Research Training Center.
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Baumann, C., Ribon, V., Kanzaki, M. et al. CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 407, 202–207 (2000). https://doi.org/10.1038/35025089
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