A novel actin cytoskeleton-dependent noncaveolar microdomain composed of homo-oligomeric caveolin-2 for activation of insulin signaling.

Abstract The role of caveolin-2 (cav-2), independently of caveolin-1 (cav-1) and caveolae, has remained elusive. Our data show that cav-2 exists in the plasma membrane (PM) in cells lacking cav-1 and forms homo-oligomeric complexes. Cav-2 did not interact with cavin-1 and cavin-2 in the PM. Rab6-GTP was required for the microtubule-dependent exocytic transport of cav-2 from the Golgi to the PM independently of cav-1. The cav-2-oligomerized noncaveolar microdomain was unaffected by cholesterol depletion and protected from shearing of silica-coated PM. Activation of insulin receptor (IR) was processed in the microdomain. Actin depolymerization affected the formation and sustenance of cav-2-oligomerized noncaveolar microdomain and attenuated IR recruitment to the microdomain thereby inhibiting IR signaling activation. Cav-2 shRNA stable cells and the cells ectopically expressing an oligomerization domain truncation mutant, cav-2 ∆47–86 exhibited retardation of IR signaling activation via the noncaveolar microdomain. Elevation in status of cav-2 expression rendered the noncaveolar activation of IR signaling in cav-1 down-regulated or/and cholesterol-depleted cells. Our findings reveal a novel homo-oligomeric cav-2 microdomain responsible for regulating activation of IR signaling in the PM.