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

Lydia W.T. Cheung, Katarzyna W. Walkiewicz, Tabot Md Besong, Huifang Guo, David H. Hawke, Stefan T. Arold, Gordon B. Mills

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    31 Scopus citations


    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 monomerdimers regulates the PI3K pathway and disrupting this equilibrium could lead to disease development.

    Original languageEnglish (US)
    Article numbere06866
    Issue numberJULY 2015
    StatePublished - Jul 29 2015

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Immunology and Microbiology(all)
    • Biochemistry, Genetics and Molecular Biology(all)

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    Cheung, L. W. T., Walkiewicz, K. W., Besong, T. M., Guo, H., Hawke, D. H., Arold, S. T., & Mills, G. B. (2015). Regulation of the PI3K pathway through a p85α monomer–homodimer equilibrium. eLife, 4(JULY 2015), [e06866].