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Regulation of the PI3K pathway through a p85α monomer-homodimer equilibrium.
- Source :
-
ELife [Elife] 2015 Jul 29; Vol. 4, pp. e06866. Date of Electronic Publication: 2015 Jul 29. - Publication Year :
- 2015
-
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.
- Subjects :
- Class Ia Phosphatidylinositol 3-Kinase chemistry
Class Ia Phosphatidylinositol 3-Kinase genetics
Humans
Models, Biological
Models, Molecular
Mutant Proteins genetics
Mutant Proteins metabolism
Protein Binding
Class Ia Phosphatidylinositol 3-Kinase metabolism
Gene Expression Regulation
PTEN Phosphohydrolase metabolism
Protein Multimerization
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 4
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 26222500
- Full Text :
- https://doi.org/10.7554/eLife.06866