CAVEOLIN IS AN ACTIVATOR OF INSULIN-RECEPTOR SIGNALING

Recent data have demonstrated that caveolin, a major structural protei n of caveolae, negatively regulates signaling molecules localized to c aveolae, The interaction of caveolin with several caveolae-associated signaling proteins is mediated by the binding of the scaffolding regio n of caveolin to a hydrophobic amino acid-containing region within the regulated proteins. The presence of a similar motif within the insuli n receptor kinase prompted us to investigate the caveolar localization and regulation of the insulin receptor by caveolin, We found that ove rexpression of caveolin-3 augmented insulin-stimulated phosphorylation of insulin receptor substrate-1 in 293T cells but not the phosphoryla tion of insulin receptor. Peptides corresponding to the scaffolding do main of caveolin potently stimulated insulin receptor kinase activity toward insulin receptor substrate-1 or a Src-derived peptide in vitro and in a caveolin subtype-dependent fashion. Peptides from caveolin-2 exhibited no effect, whereas caveolin-1 and -3 stimulated activity 10- and 17-fold, respectively. Peptides which increased insulin receptor kinase activity did so without affecting insulin receptor auto-phospho rylation. Furthermore, the insulin receptor bound to immobilized caveo lin peptides, and this binding was inhibited in the presence of free c aveolin-3 peptides. Thus, we have identified a novel mechanism by whic h the insulin receptor is bound and activated by specific caveolin sub types, Furthermore, these data define a new role for caveolin as an ac tivator of signaling.