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

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