Assembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK
View / Open Files
Authors
Clayton, natasha
Fox, millie
Vicenté-Garcia, Jose
Schroeder, Courtney
Littlewood, Trevor
Wilde, Jonathon
Krishnan, Kadalmani
Brown, Murray
Crafter, Claire
Mott, Helen
Journal Title
Journal of Biological Chemistry
ISSN
0021-9258
Publisher
American Society for Biochemistry and Molecular Biology
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Owen, D., Clayton, n., Fox, m., Vicenté-Garcia, J., Schroeder, C., Littlewood, T., Wilde, J., et al. Assembly of nuclear dimers of PI3K regulatory subunits is regulated by the Cdc42-activated tyrosine kinase ACK. Journal of Biological Chemistry https://doi.org/10.17863/CAM.83362
Abstract
Activated 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.
Sponsorship
This 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.
Funder references
MRC (MR/N08354/1)
Medical Research Council (1789868)
Embargo Lift Date
2025-04-08
Identifiers
This record's DOI: https://doi.org/10.17863/CAM.83362
This record's URL: https://www.repository.cam.ac.uk/handle/1810/335930
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.