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First published online October 11, 2005
doi: 10.1242/10.1242/jcs.02594

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TGFß-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN

Roger Vogelmann^1,*, Marc-Daniel Nguyen-tat¹, Klaudia Giehl², Guido Adler¹, Doris Wedlich³ and Andre Menke^1,

¹ Department of Internal Medicine I, University of Ulm, Robert-Koch-Strasse 8, 89070 Ulm, Germany
² Department of Pharmacology and Toxicology, University of Ulm, Robert-Koch-Strasse 8, 89070 Ulm, Germany
³ Institute of Zoology II, University of Karlsruhe, 76131 Karlsruhe, Germany

Author for correspondence (e-mail: andre.menke{at}uni-ulm.de)

Accepted 19 July 2005

Transforming growth factor beta (TGFß) has profound growth-suppressive effects on normal epithelial cells, but supports metastasis formation in many tumour types. In most epithelial tumour cells TGFß₁ treatment results in epithelial dedifferentiation with reduced cell aggregation and enhanced cellular migration. Here we show that the epithelial dedifferentiation, accompanied by dissociation of the E-cadherin adhesion complex, induced by TGFß₁ depended on phosphatidylinositol 3-kinase (PI3-kinase) and the phosphatase PTEN as analysed in PANC-1 and Smad4-deficient BxPC-3 pancreatic carcinoma cells. TGFß₁ treatment enhanced tyrosine phosphorylation of - and ß-catenin, which resulted in dissociation of the E-cadherin/catenin complex from the actin cytoskeleton and reduced cell-cell adhesion. The PI3-kinase and PTEN were found associated with the E-cadherin/catenin complex via ß-catenin. TGFß₁ treatment reduced the amount of PTEN bound to ß-catenin and markedly increased the tyrosine phosphorylation of ß-catenin. By contrast, forced expression of PTEN clearly reduced the TGFß₁-induced phosphorylation of ß-catenin. The TGFß₁-induced ß-catenin phosphorylation was also dependent on PI3-kinase and Ras activity. The described effects of TGFß₁ were independent of Smad4, which is homozygous deleted in BxPC-3 cells. Collectively, these data show that the TGFß₁-induced destabilisation of E-cadherin-mediated cell-cell adhesion involves phosphorylation of ß-catenin, which is regulated by E-cadherin adhesion complex-associated PI3-kinase and PTEN.

Key words: Transforming growth factor beta, E-cadherin, Cell-cell adhesion, ß-catenin tyrosine phosphorylation, Epithelial cells, Pancreatic cancer, Invasion, Cell migration

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