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

0301 basic medicine Skin Neoplasms Caveolin 1 Transgenic GTP Phosphohydrolases Glycogen Synthase Kinase 3 Mice Phosphatidylinositol 3-Kinases 2.1 Biological and endogenous factors Aetiology Melanoma beta Catenin Cancer Feedback, Physiological Microscopy 0303 health sciences Tumor Blotting Biological Sciences Prognosis Cadherins Immunohistochemistry 3. Good health Melanocytes Western Transcriptional Activation 570 Physiological Blotting, Western 610 Mice, Transgenic 612 Fluorescence Article Cell Line Feedback 03 medical and health sciences Cell Line, Tumor Genetics Animals Humans Glycogen Synthase Kinase 3 beta Biomedical and Clinical Sciences PTEN Phosphohydrolase Membrane Proteins ResearchInstitutes_Networks_Beacons/mcrc; name=Manchester Cancer Research Centre MicroRNAs Microscopy, Fluorescence Biochemistry and Cell Biology PRIMARY CUTANEOUS MELANOMA TUMOR-SUPPRESSOR GENE METASTATIC MELANOMA CELL-MIGRATION CANCER CELLS ACTIVATION SENESCENCE EXPRESSION PROLIFERATION INVASION Proto-Oncogene Proteins c-akt
DOI: 10.1038/ncomms9093 Publication Date: 2015-08-26T10:27:09Z
ABSTRACT
AbstractLoss 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.
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