Caveolin is an inhibitor of platelet-derived growth factor receptor signaling

Caveolin is a major structural component of caveolae and has been implicate d in the regulation of the function of several caveolae-associated signalin g molecules. Platelet-derived growth factor (PDGF) receptors and caveolin w ere colocalized in the same subcellular fraction after sucrose density grad ient fractionation of fibroblasts. Additionally, we found that the PDGF rec eptors interacted with caveolin in NIH3T3 fibroblast cells. We then examine d whether caveolin directly binds to PDGF receptors and inhibits kinase act ivity using a recombinant PDGF receptor overexpressed in insect cells and p eptides derived from the scaffolding domain of caveolin subtypes. We found the peptide from caveolin-1 and -3, but not -2, inhibited the autophosphory lation of PDGF receptors in a dose-dependent manner. Similarly, caveolin-1 and -3 peptides directly bound to PDGF receptors. Mutational analysis using a series of truncated caveolin-3 peptides (20-, 17-, 14-, and 11-mer pepti des) revealed that at least 17 amino acid residues of the peptide were requ ired to inhibit and directly bind to PDGF receptors. Thus, our findings sug gest that PDGF receptors directly interact with caveolin subtypes, leading to the inhibition of kinase activity. Caveolin may be another regulating fa ctor of PDGF-mediated tyrosine kinase signaling. (C) 1999 Academic Press.