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Assembly of novel, nuclear dimers of the PI3-Kinase regulatory subunits underpins the pro-proliferative activity of the Cdc42-activated tyrosine kinase, ACK

Natasha S. Clayton, Millie Fox, Jose J. Vicenté-Garcia, Courtney M. Schroeder, Trevor D. Littlewood, Jonathan I. Wilde, Jessica Corry, Kadalmani Krishnan, Qifeng Zhang, Michael J. O. Wakelam, Murray J. B. Brown, Claire Crafter, Helen R. Mott, Darerca Owen
doi: https://doi.org/10.1101/791277
Natasha S. Clayton
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, U.K
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Millie Fox
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, U.K
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Jose J. Vicenté-Garcia
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, U.K
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Courtney M. Schroeder
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, U.K
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Trevor D. Littlewood
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, U.K
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Jonathan I. Wilde
2GlaxoSmithKline Medicines Research Centre, Gunnels Wood Rd., Stevenage, Herts, SG1 2NY, U.K
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Jessica Corry
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, U.K
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Kadalmani Krishnan
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, U.K
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Qifeng Zhang
3The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, U.K
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Michael J. O. Wakelam
3The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, U.K
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Murray J. B. Brown
2GlaxoSmithKline Medicines Research Centre, Gunnels Wood Rd., Stevenage, Herts, SG1 2NY, U.K
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Claire Crafter
4Bioscience, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, U.K
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Helen R. Mott
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, U.K
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  • For correspondence: do202@cam.ac.uk hrm28@cam.ac.uk
Darerca Owen
1Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, U.K
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  • For correspondence: do202@cam.ac.uk hrm28@cam.ac.uk
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Abstract

The tyrosine kinase ACK is an oncogene associated with poor prognosis in human cancers. ACK promotes proliferation, in part, by contributing to the activation of Akt, the major PI3-Kinase effector. We show that ACK also regulates PI3-Kinase directly, via interactions with the PI3-Kinase regulatory subunits. ACK interacts with all five regulatory subunit isoforms and directly phosphorylates p85α, p85β, p55α and p50α on Tyr607 (or equivalent). Phosphorylation of p85β at this residue promotes cell proliferation but, counterintuitively, ACK does not stimulate PI3-Kinase catalytic activity. We show that ACK stabilizes p85α levels by promoting an interaction between the p85 nSH2 domain and pTyr607, protecting p85 from ubiquitination. We demonstrate that ACK interacts with p85α exclusively in nuclear-enriched cell fractions where the increased levels of the regulatory subunits, together with the nSH2-pTyr607 interaction, promote formation of dimeric p85. We postulate that these novel dimers undertake nuclear functions that contribute to Cdc42-ACK driven oncogenesis. We propose that ACK shapes PI3-Kinase signalling by dampening the PIP3 response, whilst continuing to drive cell proliferation through Akt activation and hereto unexplored but crucial functions of nuclear dimeric p85. These new regulatory subunit dimers represent a previously undescribed mode of regulation for PI3-Kinase and potentially reveal additional avenues for therapeutic intervention.

  • Abbreviations

    BH
    Bcr homology
    CRIB
    Cdc42/Rac interactive binding
    EBD
    EGFR binding domain
    EGF
    epidermal growth factor
    GAP
    GTPase activating protein
    NES
    Nuclear export signal
    PIP2
    phosphatidylinositol 4,5-bisphosphate
    PIP3
    phosphatidylinositol (3,4,5)-trisphosphate
    RTK
    receptor tyrosine kinase
    SAM
    sterile alpha motif
    SH2
    Src homology 2 domain
    SH3
    Src homology 3 domain
    UBA
    ubiquitin association
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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    Posted October 04, 2019.
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    Assembly of novel, nuclear dimers of the PI3-Kinase regulatory subunits underpins the pro-proliferative activity of the Cdc42-activated tyrosine kinase, ACK
    Natasha S. Clayton, Millie Fox, Jose J. Vicenté-Garcia, Courtney M. Schroeder, Trevor D. Littlewood, Jonathan I. Wilde, Jessica Corry, Kadalmani Krishnan, Qifeng Zhang, Michael J. O. Wakelam, Murray J. B. Brown, Claire Crafter, Helen R. Mott, Darerca Owen
    bioRxiv 791277; doi: https://doi.org/10.1101/791277
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    Assembly of novel, nuclear dimers of the PI3-Kinase regulatory subunits underpins the pro-proliferative activity of the Cdc42-activated tyrosine kinase, ACK
    Natasha S. Clayton, Millie Fox, Jose J. Vicenté-Garcia, Courtney M. Schroeder, Trevor D. Littlewood, Jonathan I. Wilde, Jessica Corry, Kadalmani Krishnan, Qifeng Zhang, Michael J. O. Wakelam, Murray J. B. Brown, Claire Crafter, Helen R. Mott, Darerca Owen
    bioRxiv 791277; doi: https://doi.org/10.1101/791277

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