A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity

Conde-Perez, A. et al. (2015) A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity. Nature Communications, 6, 8093. (doi: 10.1038/ncomms9093) (PMID:26307673) (PMCID:PMC4560817)

Abstract

Loss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K–AKT–GSK3β axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent β-catenin transcriptional modulation in vitro, cooperates with NRASQ61K to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-β–catenin axis is mediated by a feedback loop in which β-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of β-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sansom, Professor Owen and Campbell, Dr Andrew
• Authors: Conde-Perez, A., Gros, G., Longvert, C., Pedersen, M., Petit, V., Aktary, Z., Viros, A., Gesbert, F., Delmas, V., Rambow, F., Bastian, B. C., Campbell, A. D., Colombo, S., Puig, I., Bellacosa, A., Sansom, O., Marais, R., Van Kempen, L. C.L.T., and Larue, L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Publishing Group
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2015 Macmillan Publishers Limited
• First Published: First published in Nature Communications 6:8093
• Publisher Policy: Reproduced under a Creative Commons License