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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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TGFbeta-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN

Roger Vogelmann1, Marc-Daniel Nguyen-Tat, Klaudia Giehl

  • 1Department of Internal Medicine I, University of Ulm, Robert-Koch-Strasse 8, 89070 Ulm, Germany.

Journal of Cell Science
|October 13, 2005
PubMed

Insights

Transforming growth factor beta (TGFbeta) triggers epithelial dedifferentiation and cell migration by destabilizing E-cadherin adhesion. This process involves beta-catenin phosphorylation regulated by PI3-kinase and PTEN.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Transforming growth factor beta (TGFbeta) paradoxically suppresses normal epithelial cell growth but promotes tumor metastasis.
  • TGFbeta(1) induces epithelial dedifferentiation, characterized by reduced cell aggregation and increased migration in epithelial tumor cells.

Purpose of the Study:

  • To investigate the molecular mechanisms by which TGFbeta(1) induces epithelial dedifferentiation and dissociation of the E-cadherin adhesion complex.
  • To identify the key signaling pathways and proteins involved in TGFbeta(1)-mediated destabilization of cell-cell adhesion.

Main Methods:

  • Analysis of PANC-1 and Smad4-deficient BxPC-3 pancreatic carcinoma cells.
  • Investigating the roles of phosphatidylinositol 3-kinase (PI3-kinase) and phosphatase PTEN in TGFbeta(1) signaling.
  • Assessing the tyrosine phosphorylation of alpha- and beta-catenin and their association with the E-cadherin complex.
  • Evaluating the impact of PTEN expression and PI3-kinase/Ras activity on TGFbeta(1) effects.

Main Results:

  • TGFbeta(1) treatment induced epithelial dedifferentiation and E-cadherin complex dissociation, dependent on PI3-kinase and PTEN.
  • TGFbeta(1) enhanced tyrosine phosphorylation of beta-catenin, leading to E-cadherin/catenin complex dissociation from the actin cytoskeleton and reduced cell adhesion.
  • PI3-kinase and PTEN were associated with the E-cadherin/catenin complex via beta-catenin; TGFbeta(1) reduced PTEN binding and increased beta-catenin phosphorylation.
  • Forced PTEN expression inhibited TGFbeta(1)-induced beta-catenin phosphorylation, highlighting PTEN's regulatory role.
  • These effects were independent of Smad4, indicating an alternative signaling pathway.

Conclusions:

  • TGFbeta(1)-induced destabilization of E-cadherin-mediated cell-cell adhesion is mediated by beta-catenin phosphorylation.
  • The phosphorylation of beta-catenin is regulated by PI3-kinase and PTEN associated with the E-cadherin adhesion complex.
  • These findings elucidate a novel mechanism for TGFbeta(1) in promoting tumor cell migration and metastasis.

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