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A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells

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  • Evelyne Lima-Fernandes

    (Metabolism and Diabetes, Inserm, U1016, Institut Cochin, 27 rue du Faubourg St Jaques, Paris 75014, France
    CNRS, UMR8104
    University Paris Descartes, Sorbonne Paris Cité
    Present address: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada M5G 1L7)

  • Stanislas Misticone

    (Metabolism and Diabetes, Inserm, U1016, Institut Cochin, 27 rue du Faubourg St Jaques, Paris 75014, France
    CNRS, UMR8104
    University Paris Descartes, Sorbonne Paris Cité)

  • Cédric Boularan

    (Metabolism and Diabetes, Inserm, U1016, Institut Cochin, 27 rue du Faubourg St Jaques, Paris 75014, France
    CNRS, UMR8104
    University Paris Descartes, Sorbonne Paris Cité)

  • Justine S. Paradis

    (Molecular Biology Program, Institute for Research in Immunology and Cancer, Université de Montréal
    Institute for Research in Immunology and Cancer, Université de Montréal)

  • Hervé Enslen

    (Metabolism and Diabetes, Inserm, U1016, Institut Cochin, 27 rue du Faubourg St Jaques, Paris 75014, France
    CNRS, UMR8104
    University Paris Descartes, Sorbonne Paris Cité)

  • Philippe P. Roux

    (Molecular Biology Program, Institute for Research in Immunology and Cancer, Université de Montréal
    Institute for Research in Immunology and Cancer, Université de Montréal)

  • Michel Bouvier

    (Molecular Biology Program, Institute for Research in Immunology and Cancer, Université de Montréal
    Institute for Research in Immunology and Cancer, Université de Montréal)

  • George S. Baillie

    (Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow)

  • Stefano Marullo

    (Metabolism and Diabetes, Inserm, U1016, Institut Cochin, 27 rue du Faubourg St Jaques, Paris 75014, France
    CNRS, UMR8104
    University Paris Descartes, Sorbonne Paris Cité)

  • Mark G.H. Scott

    (Metabolism and Diabetes, Inserm, U1016, Institut Cochin, 27 rue du Faubourg St Jaques, Paris 75014, France
    CNRS, UMR8104
    University Paris Descartes, Sorbonne Paris Cité)

Abstract

Tumour suppressor PTEN is a phosphatase that negatively regulates the PI3K/AKT pathway. The ability to directly monitor PTEN conformation and function in a rapid, sensitive manner is a key step towards developing anti-cancer drugs aimed at enhancing or restoring PTEN-dependent pathways. Here we developed an intramolecular bioluminescence resonance energy transfer (BRET)-based biosensor, capable of detecting signal-dependent PTEN conformational changes in live cells. The biosensor retains intrinsic properties of PTEN, enabling structure–function and kinetic analyses. BRET shifts, indicating conformational change, were detected following mutations that disrupt intramolecular PTEN interactions, promoting plasma membrane targeting and also following physiological PTEN activation. Using the biosensor as a reporter, we uncovered PTEN activation by several G protein-coupled receptors, previously unknown as PTEN regulators. Trastuzumab, used to treat ERBB2-overexpressing breast cancers also elicited activation-associated PTEN conformational rearrangement. We propose the biosensor can be used to identify pathways regulating PTEN or molecules that enhance its anti-tumour activity.

Suggested Citation

  • Evelyne Lima-Fernandes & Stanislas Misticone & Cédric Boularan & Justine S. Paradis & Hervé Enslen & Philippe P. Roux & Michel Bouvier & George S. Baillie & Stefano Marullo & Mark G.H. Scott, 2014. "A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5431
    DOI: 10.1038/ncomms5431
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