title: 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 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.
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Lydia W T
authors.initials: LW
authors.lastname: Cheung
authors.affiliation: Computational Bioscience Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
authors.forename: Katarzyna W
authors.initials: KW
authors.lastname: Walkiewicz
authors.affiliation: Division of Physical Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
authors.forename: Tabot M D
authors.initials: TM
authors.lastname: Besong
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Huifang
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: David H
authors.initials: DH
authors.lastname: Hawke
authors.affiliation: Computational Bioscience Research Center, Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Arold
authors.affiliation: Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, United States.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
mesh_terms: D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D015398:Signal Transduction
chemical_list: D050505:Mutant Proteins; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PI3K; PTEN; cancer; cell biology; human; mouse; mutation; p85