TY - JOUR TI - Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss AU - Cizmecioglu, Onur AU - Ni, Jing AU - Xie, Shaozhen AU - Zhao, Jean J AU - Roberts, Thomas M A2 - Alitalo, Kari VL - 5 PY - 2016 DA - 2016/10/04 SP - e17635 C1 - eLife 2016;5:e17635 DO - 10.7554/eLife.17635 UR - https://doi.org/10.7554/eLife.17635 AB - 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, p110α and p110β. We found that p110β 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 p110β to rafts alleviated the requirement for p110β-Rac1 association for GPCR signaling, cell growth and migration. In contrast, p110α, which does not play a physiological role in GPCR signaling, is found to reside in nonraft regions of the plasma membrane. Raft targeting of p110α allowed its EGFR-mediated activation by GPCRs. Notably, p110β 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 p110β. KW - PI3K signaling KW - Rac1 KW - PTEN loss KW - GPCR signaling KW - membrane microdomains JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -