Identification of pY19-caveolin-2 as a positive regulator of insulin-stimulated actin cytoskeleton-dependent mitogenesis

Abstract

Mitogenic regulation by caveolin-2 in response to insulin was investigated. Insulin triggered phosphorylation of caveolin-2 on tyrosine 19. Insulin increased the interaction between pY19-caveolin-2 and phospho-ERK, and that interaction was inhibited by a MEK inhibitor U0126. Insulin-induced interaction of caveolin-2 with phospho-ERK was prevented when tyrosine 19 is mutated to alanine. Insulin relocalized phospho-ERK and pY19-caveolin-2 to the nucleus and their nuclear co-localization was impaired by U0126. Down-regulation of caveolin-2 by caveolin-2 siRNA arrested the insulin-induced nuclear localization of ERK with no change in the insulin-stimulated ERK activation. Of consequence, the caveolin-2 siRNA attenuated the ERK-mediated c-Jun and cyclinD1 expression and DNA synthesis by insulin. In addition, actin cytoskeleton influenced the nuclear translocation of caveolin-2-ERK complex. Collectively, our findings underscore the importance of pY19-caveolin-2 with the spatial coordination by insulin in ERK-mediated mitogenic regulation of insulin signalling and indicate that the phosphorylation of pY19-caveolin-2 is required for actin cytoskeleton-dependent ERK nuclear import.