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

• Published in: eLife Vol. 5
• Main Authors: Cizmecioglu, Onur, Ni, Jing, Xie, Shaozhen, Zhao, Jean J, Roberts, Thomas M
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 04.10.2016; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: 1-Phosphatidylinositol 3-kinase; Acids; AKT protein; Animals; Cancer; Cancer Biology; Cell adhesion & migration; Cell Biology; Cell Membrane - enzymology; Cells, Cultured; Class I Phosphatidylinositol 3-Kinases - metabolism; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Epidermal growth factor receptors; Ethanol; Experiments; Fibroblasts - physiology; G protein-coupled receptors; G proteins; GPCR signaling; Isoforms; Kinases; Lipid rafts; Localization; membrane microdomains; Membrane Microdomains - enzymology; Membrane proteins; Mice; Neuropeptides - metabolism; Observations; Phosphatase; Phosphorylation; Physiological aspects; PI3K signaling; Plasma; Protein-protein interactions; Proto-Oncogene Proteins c-akt - metabolism; PTEN loss; PTEN Phosphohydrolase - deficiency; PTEN protein; Rac1; rac1 GTP-Binding Protein - metabolism; Rac1 protein; Signal Transduction; Standard deviation; Tumor cells; Tumors; mouse; PI3K signaling; cell biology; membrane microdomains; PTEN loss; cancer biology; Rac1; human; GPCR signaling
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.17635

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.