Prolonged tyrosine kinase activation of insulin receptor by pY27-caveolin-2

Caveolin-2 regulation of insulin receptor (IR) tyrosine kinase activity was investigated. An insulin time course revealed that rapidly induced tyrosine phosphorylation of IR was steadily maintained over a 180 min time period. In parallel, insulin-exerted IR interaction with caveolin-2 was detected as early as 5 min throughout until 180 min. Down-regulation of caveolin-2 by caveolin-2 siRNA arrested specifically a long term activation of IR. The attenuation of IR activation resulted in retardation of rapamycin-sensitive pS727-STAT3 activation. As caveolin-2 tyrosine mutants were examined, Y27A-caveolin-2 explicitly impeded the long term IR activation by insulin, enhanced tyrosine dephosphorylation of IR, impaired tyrosine phosphorylation of IRS-1, and exerted the interaction between activated IR and SOCS-3. Together, we propose that pY27-caveolin-2 prolongs IR activation by its interaction with IR, thereby preventing IR interaction with SOCS-3.