title: A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity.
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 NRAS(Q61K) 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.
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Alejandro
authors: A
authors: Conde-Perez
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Gwendoline
authors: G
authors: Gros
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Christine
authors: C
authors: Longvert
authors: Targeted Therapy Team, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors: Malin
authors: M
authors: Pedersen
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Valérie
authors: V
authors: Petit
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Zackie
authors: Z
authors: Aktary
authors: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors: Amaya
authors: A
authors: Viros
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Franck
authors: F
authors: Gesbert
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Véronique
authors: V
authors: Delmas
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Florian
authors: F
authors: Rambow
authors: Departments of Dermatology and Pathology and UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94143, USA.
authors: Boris C
authors: BC
authors: Bastian
authors: The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Andrew D
authors: AD
authors: Campbell
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Sophie
authors: S
authors: Colombo
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Isabel
authors: I
authors: Puig
authors: Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors: Alfonso
authors: A
authors: Bellacosa
authors: The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
authors: Owen
authors: O
authors: Sansom
authors: Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors: Richard
authors: R
authors: Marais
authors: Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands.|Jewish General Hospital, Lady Davis Institute for Medical Research, Montreal, Quebec QC H3T 1E2, Canada.|Department of Pathology, McGill University, Montreal, Quebec QC H3T 1E2, Canada.
authors: Leon C L T
authors: LC
authors: Van Kempen
authors: Normal and Pathological Development of Melanocytes, Institut Curie, Orsay 91405, France.|CNRS, UMR3347 Bat. 110, Orsay Cedex 91405, France.|INSERM U1021, Orsay Cedex 91405, France.|Equipe labellisée-Ligue Nationale contre le Cancer, Orsay Cedex 91405, France.
authors: Lionel
authors: L
authors: Larue
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics*; D045744:Cell Line, Tumor; D025461:Feedback, Physiological; D020558:GTP Phosphohydrolases / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D008544:Melanocytes / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs; D008856:Microscopy, Fluorescence; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015820:Cadherins; D051242:Caveolin 1; C546703:MIRN203 microRNA, human; C575934:MIRN203 microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; D051176:beta Catenin; C531408:mirn199 microRNA, human; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human