Regulation of the PI3K pathway through a p85? monomer-homodimer equilibrium.

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

SUBMITTER: Cheung LW 

PROVIDER: S-EPMC4518712 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature