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

Evelyne Lima-Fernandes, Stanislas Misticone, Cédric Boularan, Justine S. Paradis, Hervé Enslen, Philippe P. Roux, Michel Bouvier, George S. Baillie, Stefano Marullo and Mark G.H. Scott ()
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Evelyne Lima-Fernandes: Metabolism and Diabetes, Inserm, U1016, Institut Cochin, 27 rue du Faubourg St Jaques, Paris 75014, France
Stanislas Misticone: Metabolism and Diabetes, Inserm, U1016, Institut Cochin, 27 rue du Faubourg St Jaques, Paris 75014, France
Cédric Boularan: Metabolism and Diabetes, Inserm, U1016, Institut Cochin, 27 rue du Faubourg St Jaques, Paris 75014, France
Justine S. Paradis: Molecular Biology Program, 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
Philippe P. Roux: Molecular Biology Program, 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
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
Mark G.H. Scott: Metabolism and Diabetes, Inserm, U1016, Institut Cochin, 27 rue du Faubourg St Jaques, Paris 75014, France

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5431

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