Regulation of the PI3K pathway through a p85α monomer–homodimer equilibrium

Handle URI:
http://hdl.handle.net/10754/566025
Title:
Regulation of the PI3K pathway through a p85α monomer–homodimer equilibrium
Authors:
Cheung, Lydia W T; Walkiewicz, Katarzyna Wiktoria; Besong, Tabot M.D. ( 0000-0002-3572-1428 ) ; Guo, Huifang; Hawke, David H.; Arold, Stefan T. ( 0000-0001-5278-0668 ) ; Mills, Gordon B.
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 monomerdimers regulates the PI3K pathway and disrupting this equilibrium could lead to disease development. © Cheung et al.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Computational Bioscience Research Center (CBRC); Physical Sciences and Engineering (PSE) Division; Bioscience Program; Structural Biology and Engineering
Publisher:
eLife Sciences Organisation, Ltd.
Journal:
eLife
Issue Date:
29-Jul-2015
DOI:
10.7554/eLife.06866
Type:
Article
ISSN:
2050-084X
Appears in Collections:
Articles; Bioscience Program; Physical Sciences and Engineering (PSE) Division; Computational Bioscience Research Center (CBRC); Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorCheung, Lydia W Ten
dc.contributor.authorWalkiewicz, Katarzyna Wiktoriaen
dc.contributor.authorBesong, Tabot M.D.en
dc.contributor.authorGuo, Huifangen
dc.contributor.authorHawke, David H.en
dc.contributor.authorArold, Stefan T.en
dc.contributor.authorMills, Gordon B.en
dc.date.accessioned2015-08-12T09:00:00Zen
dc.date.available2015-08-12T09:00:00Zen
dc.date.issued2015-07-29en
dc.identifier.issn2050-084Xen
dc.identifier.doi10.7554/eLife.06866en
dc.identifier.urihttp://hdl.handle.net/10754/566025en
dc.description.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.en
dc.publishereLife Sciences Organisation, Ltd.en
dc.titleRegulation of the PI3K pathway through a p85α monomer–homodimer equilibriumen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.contributor.departmentPhysical Sciences and Engineering (PSE) Divisionen
dc.contributor.departmentBioscience Programen
dc.contributor.departmentStructural Biology and Engineeringen
dc.identifier.journaleLifeen
kaust.authorArold, Stefan T.en
kaust.authorWalkiewicz, Katarzyna Wiktoriaen
kaust.authorBesong, Tabot M.D.en
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