Regulation of the PI3K pathway through a p85α monomer–homodimer equilibrium
Lydia WT Cheung,
Katarzyna W Walkiewicz,
Tabot MD Besong,
Huifang Guo,
David H Hawke,
Stefan T Arold,
Gordon B Mills
Affiliations
Lydia WT Cheung
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, United States
Katarzyna W Walkiewicz
Computational Bioscience Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
Tabot MD Besong
Division of Physical Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
Huifang Guo
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, United States
David H Hawke
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, United States
Stefan T Arold
Computational Bioscience Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
Gordon B Mills
Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, United States
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.
