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.

journal_name

Elife

journal_title

eLife

authors

Cheung LW,Walkiewicz KW,Besong TM,Guo H,Hawke DH,Arold ST,Mills GB

doi

10.7554/eLife.06866

subject

Has Abstract

pub_date

2015-07-29 00:00:00

pages

e06866

issn

2050-084X

journal_volume

4

pub_type

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