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

• Published in: Nature communications Vol. 6; no. 1; p. 8093
• Main Authors: Conde-Perez, Alejandro, Gros, Gwendoline, Longvert, Christine, Pedersen, Malin, Petit, Valérie, Aktary, Zackie, Viros, Amaya, Gesbert, Franck, Delmas, Véronique, Rambow, Florian, Bastian, Boris C., Campbell, Andrew D., Colombo, Sophie, Puig, Isabel, Bellacosa, Alfonso, Sansom, Owen, Marais, Richard, Van Kempen, Leon C. L. T., Larue, Lionel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-08-2015; Nature Pub. Group
• Subjects: 13; 13/106; 14/19; 38/35; 631/337/572; 631/67/1813/1634; 631/80/86; 64; 64/60; 96; 96/95; Animals; beta Catenin - metabolism; Blotting, Western; Cadherins - metabolism; Caveolin 1 - genetics; Cell Line, Tumor; Feedback, Physiological; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; GTP Phosphohydrolases - genetics; Humanities and Social Sciences; Humans; Immunohistochemistry; Melanocytes - metabolism; Melanoma - genetics; Melanoma - metabolism; Membrane Proteins - genetics; Mice; Mice, Transgenic; MicroRNAs; Microscopy, Fluorescence; multidisciplinary; Phosphatidylinositol 3-Kinases - metabolism; Prognosis; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - genetics; Science; Science (multidisciplinary); Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Transcriptional Activation - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms9093

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.
The mechanism by which PTEN mutation is melanomagenic is complicated by different PTEN functions in different cellular locations. Here, the authors identify an alternative to membrane PI3K–AKT signalling, a caveolin-1-dependent PTEN pathway that induces nuclear localization and activation of β-catenin.