Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium

Elife. 2015 Jul 29:4:e06866. doi: 10.7554/eLife.06866.

Abstract

The canonical action of the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is to associate with the p110α catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. We elucidate a p110α-independent role of homodimerized p85α in the positive regulation of PTEN stability and activity. p110α-free p85α homodimerizes via two intermolecular interactions (SH3:proline-rich region and BH:BH) to selectively bind unphosphorylated activated PTEN. As a consequence, homodimeric but not monomeric p85α suppresses the PI3K pathway by protecting PTEN from E3 ligase WWP2-mediated proteasomal degradation. Further, the p85α homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Strikingly, we identified cancer patient-derived oncogenic p85α mutations that target the homodimerization or PTEN interaction surface. Collectively, our data suggest the equilibrium of p85α monomer-dimers regulates the PI3K pathway and disrupting this equilibrium could lead to disease development.

Keywords: PI3K; PTEN; cancer; cell biology; human; mouse; mutation; p85.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Class Ia Phosphatidylinositol 3-Kinase / chemistry
  • Class Ia Phosphatidylinositol 3-Kinase / genetics
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Models, Biological
  • Models, Molecular
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • PTEN Phosphohydrolase / metabolism*
  • Protein Binding
  • Protein Multimerization*
  • Signal Transduction*

Substances

  • Mutant Proteins
  • Class Ia Phosphatidylinositol 3-Kinase
  • PTEN Phosphohydrolase
  • PTEN protein, human