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- Title
Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss.
- Authors
Cizmecioglu, Onur; Jing Ni; Shaozhen Xie; Zhao, Jean J.; Roberts, Thomas M.
- Abstract
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, p110a 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, p110a, which does not play a physiological role in GPCR signaling, is found to reside in nonraft regions of the plasma membrane. Raft targeting of p110a 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.
- Subjects
G protein coupled receptors; RAP1 proteins; PROTEIN kinase B; PHOSPHOINOSITIDES; CELLULAR signal transduction
- Publication
eLife, 2016, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.17635