Caveolin-2 regulation of STAT3 transcriptional activation in response to insulin.

The regulatory function of caveolin-2 in signal transducer and activator of transcription 3 (STAT3) signaling by insulin was investigated. Insulin-induced increase in phosphorylation of STAT3 was reduced by caveolin-2 siRNA. Mutagenesis studies identified that phosphorylation of tyrosines 19 and 27 on caveolin-2 is required for the STAT3 activation. Caveolin-2 Y27A mutation decreased insulin-induced phosphorylation of STAT3 interacting with caveolin-2. pY27-Caveolin-2 was required for nuclear translocation of pY705-STAT3 in response to insulin. In contrast, caveolin-2 Y19A mutation influenced neither the phosphorylation of STAT3 nor nuclear translocation of pY705-STAT3. pY19-Caveolin-2, however, was essential for insulin-induced DNA binding of pS727-STAT3 and STAT3-targeted gene induction in the nucleus. Finally, insulin-induced transcriptional activation of STAT3 depended on phosphorylation of both 19 and 27 tyrosines. Together, our data reveal that phosphotyrosine-caveolin-2 is a novel regulator for transcriptional activation of STAT3 in response to insulin.