RaIA-Exocyst Complex Regulates Integrin-Dependent Membrane Raft Exocytosis and Growth Signaling

Anchorage dependence of cell growth is a key metastasis-suppression mechanism that is mediated by effects of integrins on growth signaling pathways [1]. The small GTPase RaIA is activated in metastatic cancers through multiple mechanisms and specifically induces anchorage independence [2-4]. Loss of integrin-mediated adhesion triggers caveolin-dependent internalization of cholesterol- and sphingolipid-rich lipid raft microdomains to the recycling endosomes; these domains serve as platforms for many signaling pathways, and their clearance from the plasma membrane (PM) after cell detachment suppresses growth signaling [5, 6]. Conversely, readhesion triggers their return to the PM and restores growth signaling. Activation of Arf6 by integrins mediates exit of raft markers from the recycling endosomes but is not sufficient for return to the PM. We now show that RaIA but not RaIB mediates integrin-dependent membrane raft exocytosis through the exocyst complex. Constitutively active RaIA restores membrane raft targeting to promote anchorage-independent growth signaling. Ras-transformed pancreatic cancer cells also show RaIA-dependent constitutive PM raft targeting. These results identify RaIA as a key determinant of integrin-dependent membrane raft trafficking and regulation of growth signaling. They therefore define a mechanism by which RaIA regulates anchorage dependence and provide a new link between integrin signaling and cancer.