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

Nat Commun. 2015 Aug 26:6:8093. doi: 10.1038/ncomms9093.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cadherins / metabolism*
  • Caveolin 1 / genetics*
  • Cell Line, Tumor
  • Feedback, Physiological
  • GTP Phosphohydrolases / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Immunohistochemistry
  • Melanocytes / metabolism*
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Membrane Proteins / genetics
  • Mice
  • Mice, Transgenic
  • MicroRNAs
  • Microscopy, Fluorescence
  • PTEN Phosphohydrolase / genetics*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prognosis
  • Proto-Oncogene Proteins c-akt / metabolism
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism
  • Transcriptional Activation / genetics*
  • beta Catenin / metabolism*

Substances

  • Cadherins
  • Caveolin 1
  • MIRN203 microRNA, human
  • MIRN203 microRNA, mouse
  • Membrane Proteins
  • MicroRNAs
  • Mirn199 microRNA, mouse
  • beta Catenin
  • mirn199 microRNA, human
  • Phosphatidylinositol 3-Kinases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • PTEN Phosphohydrolase
  • GTP Phosphohydrolases
  • NRAS protein, human