The Caveolins are not Direct Substrates of the Insulin Receptor

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Insulin binding to its receptor at the cell surface causes a conformational change in the intracellular domain of the receptor, leading to auto-transphosphorylation of the receptor. This autophosphorylation in turn activates the kinase domain, leading to the phosphorylation of direct substrates, including insulin receptor sub-strate-1 (IRS-1). Since the insulin receptor is associated with caveolae [14,57,58], it was possible that caveolin was a direct substrate of the insulin receptor itself. Several lines of evidence indicate that this is not the case, however [14,15]. First, although caveolin co-fractionates with the insulin receptor, caveolin is phosphory-lated in vitro under conditions where the insulin receptor in these fractions is completely inactive (i.e., in the absence of insulin). Therefore, caveolin co-purifies with a caveolin-tyrosine kinase that is not the insulin receptor. A second line of evidence comes from the differentiation dependence of caveolin phosphorylation. Both adipocytes and preadipocytes express caveolin-1, and caveolin-1 co-purifies with caveolin-directed tyrosine kinase activity in both cell types. Adipocytes and preadipocytes both express active insulin receptors that phosphorylate direct substrates such as IRS-1 equally well. The insulin receptor co-fractionates with cav-eolins in both cell types. However, insulin stimulates caveolin phosphorylation only in adipocytes, not in preadipocytes. The cell type dependence of caveolin phosphorylation strongly indicates that the insulin receptor is not the insulin-stimulated caveolin tyrosine kinase, and that differentiation leads to the expression of signaling molecules that lie downstream of the insulin receptor and couple activation of the insulin receptor to activation of the caveolin tyrosine kinase.

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