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

Lima-Fernandes, E., Misticone, S., Boularan, C., Paradis, J. S., Enslen, H., Roux, P. P., Bouvier, M., Baillie, G. S. , Marullo, S. and Scott, M. G.H. (2014) A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells. Nature Communications, 5(4431), (doi:10.1038/ncomms5431) (PMID:25028204)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George
Authors: Lima-Fernandes, E., Misticone, S., Boularan, C., Paradis, J. S., Enslen, H., Roux, P. P., Bouvier, M., Baillie, G. S., Marullo, S., and Scott, M. G.H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723

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