Regulation of the PI3K pathway through a p85α monomer–homodimer equilibrium
AuthorsCheung, Lydia W T
Walkiewicz, Katarzyna Wiktoria
Besong, Tabot M.D.
Hawke, David H.
Arold, Stefan T.
Mills, Gordon B.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
KAUST Solar Center (KSC)
Physical Science and Engineering (PSE) Division
Structural Biology and Engineering
Permanent link to this recordhttp://hdl.handle.net/10754/566025
MetadataShow full item record
AbstractThe 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. © Cheung et al.
PublishereLife Sciences Publications, Ltd
- Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase.
- Authors: Chagpar RB, Links PH, Pastor MC, Furber LA, Hawrysh AD, Chamberlain MD, Anderson DH
- Issue date: 2010 Mar 23
- Multiple roles for the p85α isoform in the regulation and function of PI3K signalling and receptor trafficking.
- Authors: Mellor P, Furber LA, Nyarko JN, Anderson DH
- Issue date: 2012 Jan 1
- Impact of p85α Alterations in Cancer.
- Authors: Marshall JDS, Whitecross DE, Mellor P, Anderson DH
- Issue date: 2019 Jan 15
- Activation of PI3K/Akt signaling by n-terminal SH2 domain mutants of the p85α regulatory subunit of PI3K is enhanced by deletion of its c-terminal SH2 domain.
- Authors: Hofmann BT, Jücker M
- Issue date: 2012 Oct
- A beta version of life: p110β takes center stage.
- Authors: Dbouk HA, Backer JM
- Issue date: 2010 Dec