| First Author | Cheung LW | Year | 2015 |
| Journal | Elife | Volume | 4 |
| Pages | e06866 | PubMed ID | 26222500 |
| Mgi Jnum | J:226575 | Mgi Id | MGI:5697775 |
| Doi | 10.7554/eLife.06866 | Citation | Cheung LW, et al. (2015) Regulation of the PI3K pathway through a p85alpha monomer-homodimer equilibrium. Elife 4:e06866 |
| abstractText | The canonical action of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is to associate with the p110alpha catalytic subunit to allow stimuli-dependent activation of the PI3K pathway. We elucidate a p110alpha-independent role of homodimerized p85alpha in the positive regulation of PTEN stability and activity. p110alpha-free p85alpha 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 p85alpha suppresses the PI3K pathway by protecting PTEN from E3 ligase WWP2-mediated proteasomal degradation. Further, the p85alpha homodimer enhances the lipid phosphatase activity and membrane association of PTEN. Strikingly, we identified cancer patient-derived oncogenic p85alpha mutations that target the homodimerization or PTEN interaction surface. Collectively, our data suggest the equilibrium of p85alpha monomer-dimers regulates the PI3K pathway and disrupting this equilibrium could lead to disease development. |
