Abstract
The canonical action of the p85 alpha regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is to associate with the p110 alpha catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. We elucidate a p110 alpha-independent role of homodimerized p85 alpha in the positive regulation of PTEN stability and activity. p110 alpha-free p85 alpha 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 p85 alpha suppresses the PI3K pathway by protecting PTEN from E3 ligase WWP2-mediated proteasomal degradation. Further, the p85 alpha homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Strikingly, we identified cancer patient-derived oncogenic p85 alpha mutations that target the homodimerization or PTEN interaction surface. Collectively, our data suggest the equilibrium of p85 alpha monomer-dimers regulates the PI3K pathway and disrupting this equilibrium could lead to disease development.