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Abstract
Anchorage dependence of cell growth is a key metastasis-suppression mechanism that
is mediated by effects of integrins on growth signaling pathways. The small GTPase
RalA is activated in metastatic cancers through multiple mechanisms and specifically
induces anchorage independence. 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. 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
RalA but not RalB mediates integrin-dependent membrane raft exocytosis through the
exocyst complex. Constitutively active RalA restores membrane raft targeting to promote
anchorage-independent growth signaling. Ras-transformed pancreatic cancer cells also
show RalA-dependent constitutive PM raft targeting. These results identify RalA as
a key determinant of integrin-dependent membrane raft trafficking and regulation of
growth signaling. They therefore define a mechanism by which RalA regulates anchorage
dependence and provide a new link between integrin signaling and cancer.
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