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

Abstract

Transforming growth factor beta (TGFβ) has profound growth-suppressive effects on normal epithelial cells, but supports metastasis formation in many tumour types. In most epithelial tumour cells TGFβ₁ 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 TGFβ₁ depended on phosphatidylinositol 3-kinase (PI3-kinase) and the phosphatase PTEN as analysed in PANC-1 and Smad4-deficient BxPC-3 pancreatic carcinoma cells. TGFβ₁ treatment enhanced tyrosine phosphorylation of α- and β-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 β-catenin. TGFβ₁ treatment reduced the amount of PTEN bound to β-catenin and markedly increased the tyrosine phosphorylation of β-catenin. By contrast, forced expression of PTEN clearly reduced the TGFβ₁-induced phosphorylation of β-catenin. The TGFβ₁-induced β-catenin phosphorylation was also dependent on PI3-kinase and Ras activity. The described effects of TGFβ₁ were independent of Smad4, which is homozygous deleted in BxPC-3 cells. Collectively, these data show that the TGFβ₁-induced destabilisation of E-cadherin-mediated cell-cell adhesion involves phosphorylation of β-catenin, which is regulated by E-cadherin adhesion complex-associated PI3-kinase and PTEN.