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

Alejandro Conde-Perez, Gwendoline Gros, Christine Longvert, Malin Pedersen, Valérie Petit, Zackie Aktary, Amaya Viros, Franck Gesbert, Véronique Delmas, Florian Rambow, Boris C. Bastian, Andrew D. Campbell, Sophie Colombo, Isabel Puig, Alfonso Bellacosa, Owen Sansom, Richard Marais, Leon C. L. T. Van Kempen and Lionel Larue ()
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Alejandro Conde-Perez: Normal and Pathological Development of Melanocytes, Institut Curie
Gwendoline Gros: Normal and Pathological Development of Melanocytes, Institut Curie
Christine Longvert: Normal and Pathological Development of Melanocytes, Institut Curie
Malin Pedersen: Targeted Therapy Team, The Institute of Cancer Research
Valérie Petit: Normal and Pathological Development of Melanocytes, Institut Curie
Zackie Aktary: Normal and Pathological Development of Melanocytes, Institut Curie
Amaya Viros: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester
Franck Gesbert: Normal and Pathological Development of Melanocytes, Institut Curie
Véronique Delmas: Normal and Pathological Development of Melanocytes, Institut Curie
Florian Rambow: Normal and Pathological Development of Melanocytes, Institut Curie
Boris C. Bastian: University of California San Francisco
Andrew D. Campbell: The Beatson Institute for Cancer Research
Sophie Colombo: Normal and Pathological Development of Melanocytes, Institut Curie
Isabel Puig: Normal and Pathological Development of Melanocytes, Institut Curie
Alfonso Bellacosa: Fox Chase Cancer Center
Owen Sansom: The Beatson Institute for Cancer Research
Richard Marais: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester
Leon C. L. T. Van Kempen: Radboud University Nijmegen Medical Centre
Lionel Larue: Normal and Pathological Development of Melanocytes, Institut Curie

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9093

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