Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss.

We aimed to understand how spatial compartmentalization in the plasma membrane might contribute to the functions of the ubiquitous class IA phosphoinositide 3-kinase (PI3K) isoforms, p110 alpha and p110 beta. We found that p110 beta localizes to membrane rafts in a Rac1-dependent manner. This localization potentiates Akt activation by G-protein-coupled receptors (GPCRs). Thus genetic targeting of a Rac1 binding-deficient allele of p110 beta to rafts alleviated the requirement for p110 beta-Rac1 association for GPCR signaling, cell growth and migration. In contrast, p110 alpha, which does not play a physiological role in GPCR signaling, is found to reside in nonraft regions of the plasma membrane. Raft targeting of p110 alpha allowed its EGFR-mediated activation by GPCRs. Notably, p110 beta dependent, PTEN null tumor cells critically rely upon raft-associated PI3K activity. Collectively, our findings provide a mechanistic account of how membrane raft localization regulates differential activation of distinct PI3K isoforms and offer insight into why PTEN-deficient cancers depend on p110 beta.