title: Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss.
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, 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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
authors.forename: Onur
authors.initials: O
authors.lastname: Cizmecioglu
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Ni
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
authors.forename: Shaozhen
authors.initials: S
authors.lastname: Xie
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
authors.forename: Thomas M
authors.identifier: 0000-0001-6453-3955
authors.initials: TM
authors.lastname: Roberts
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000201:enzymology*; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D005347:Fibroblasts / Q000502:physiology; D021962:Membrane Microdomains / Q000201:enzymology*; D051379:Mice; D009479:Neuropeptides / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020830:rac1 GTP-Binding Protein
keywords: GPCR signaling; PI3K signaling; PTEN loss; Rac1; cancer biology; cell biology; human; membrane microdomains; mouse