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

Elife. 2016 Oct 4;5:e17635. doi: 10.7554/eLife.17635.

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.

Keywords: GPCR signaling; PI3K signaling; PTEN loss; Rac1; cancer biology; cell biology; human; membrane microdomains; mouse.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Membrane / enzymology*
  • Cells, Cultured
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism*
  • Fibroblasts / physiology
  • Membrane Microdomains / enzymology*
  • Mice
  • Neuropeptides / metabolism*
  • PTEN Phosphohydrolase / deficiency*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Neuropeptides
  • Rac1 protein, mouse
  • 1-phosphatidylinositol 3-kinase p110 subunit, mouse
  • Class I Phosphatidylinositol 3-Kinases
  • Class Ia Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • rac1 GTP-Binding Protein