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dc.contributor.authorOwen, Darerca
dc.contributor.authorClayton, natasha
dc.contributor.authorFox, millie
dc.contributor.authorVicenté-Garcia, Jose
dc.contributor.authorSchroeder, Courtney
dc.contributor.authorLittlewood, Trevor
dc.contributor.authorWilde, Jonathon
dc.contributor.authorKrishnan, Kadalmani
dc.contributor.authorBrown, Murray
dc.contributor.authorCrafter, Claire
dc.contributor.authorMott, Helen
dc.date.accessioned2022-04-08T23:30:19Z
dc.date.available2022-04-08T23:30:19Z
dc.identifier.issn0021-9258
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/335930
dc.description.abstractActivated Cdc42-associated kinase (ACK) is an oncogenic non-receptor tyrosine kinase associated with poor prognosis in several human cancers. ACK promotes proliferation, in part by contributing to the activation of Akt, the major effector of class 1A phosphoinositide 3-kinases (PI3Ks), which transduce signals via membrane phosphoinositol lipids. We now show that ACK also interacts with other key components of class 1A PI3K signaling, the PI3K regulatory subunits. We demonstrate ACK binds to all five PI3K regulatory subunit isoforms and directly phosphorylates p85α, p85β, p50α, and p55α on Tyr607 (or analogous residues). We found that phosphorylation of p85β promotes cell proliferation in HEK293T cells. We demonstrate that ACK interacts with p85α exclusively in nuclear-enriched cell fractions, where p85α phosphorylated at Tyr607 (pTyr607) also resides, and identify an interaction between pTyr607 and the N-terminal SH2 domain that supports dimerization of the regulatory subunits. We infer from this that ACK targets p110-independent p85, and further postulate that these regulatory subunit dimers undertake novel nuclear functions underpinning ACK activity. We conclude that these dimers represent a previously undescribed mode of regulation for the class1A PI3K regulatory subunits and potentially reveal additional avenues for therapeutic intervention.
dc.description.sponsorshipThis research was supported by: BBSRC DTG/A studentships (BB/F017464/1 and BB/A517685/1) to NSC and JV-G; an MRC iCASE (MR/N018354/1) to DO and CC; a Churchill Scholarship (awarded by the Winston Churchill Foundation of the United States) to CS; a CR-UK (C4750/A19013) programme grant to TDL; a National Overseas Scholarship, Government of India and a Cambridge Commonwealth Scholarship to KK and a CR-UK project grant (C11309/A5148) to DO and HRM.
dc.publisherAmerican Society for Biochemistry and Molecular Biology
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleAssembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK
dc.typeArticle
dc.publisher.departmentDepartment of Biochemistry
dc.date.updated2022-04-08T09:25:57Z
prism.publicationNameJournal of Biological Chemistry
dc.identifier.doi10.17863/CAM.83362
dcterms.dateAccepted2022-04-06
rioxxterms.versionAM
dc.contributor.orcidOwen, Darerca [0000-0003-0978-5425]
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMRC (MR/N08354/1)
pubs.funder-project-idMedical Research Council (1789868)
cam.orpheus.counter24*
cam.depositDate2022-04-08
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2025-04-08


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International