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

Abstract

The canonical action of the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is mediated by association with the p110 catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. Although the best-characterized role of p85α is p110-dependent, intermolecular interactions of p85α protomers have been suggested to result in p85α homodimerization. However, the function of the p85α homodimer remains to be elucidated. Through structural modeling and biochemical analyses, we demonstrate the p110α-independent role of homodimerized p85α in the positive regulation of PTEN. p110α-free p85α homodimerizes via SH3:proline rich domain and BH:BH intermolecular interactions to selectively bind unphosphorylated activated PTEN. p85α homodimer competes for PTEN binding with the E3 ligase WWP2. As a consequence, homodimeric but not monomeric p85α suppresses the PI3K pathway by protecting PTEN from WWP2-mediated proteasomal degradation. Further, p85α homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Importantly, the homodimerization surface and the PTEN-interaction interface are targeted in cancer patient-derived p85α mutants, providing a plausible mechanism for tumor development. These p85α mutants are oncogenic by destabilizing PTEN and inducing PI3K pathway activation. Together, we provide a mechanistic model of how p85α plays a dual role in regulating the PI3K pathway through forming p85α homodimer or p110-bound heterodimer. Our data suggest that the monomer-dimer equilibrium of p85α regulates the PI3K pathway and thereby associates with cancer development.