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Article Dans Une Revue Nature Communications Année : 2014

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

Evelyne Lima-Fernandes
Cédric Boularan
  • Fonction : Auteur
Hervé Enslen
Michel Bouvier
Stefano Marullo
Mark G.H. Scott
  • Fonction : Auteur

Résumé

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 conforma-tional rearrangement. We propose the biosensor can be used to identify pathways regulating PTEN or molecules that enhance its anti-tumour activity.
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Dates et versions

hal-01142351 , version 1 (20-02-2020)

Identifiants

Citer

Evelyne Lima-Fernandes, Stanislas Misticone, Cédric Boularan, Justine Paradis, Hervé Enslen, et al.. A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells. Nature Communications, 2014, 5, pp.4431. ⟨10.1038/ncomms5431⟩. ⟨hal-01142351⟩

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