Truncation of the extracellular region abrogrates cell contact but retainsthe growth-suppressive activity of E-cadherin

E-cadherin has been demonstrated to induce growth suppression and decrease the invasiveness of cancer cells and thus has been proposed to be a tumor s uppressor gene. The ability of E-cadherin to mediate cell-cell contact and contact inhibition presumably accounts for its antitumor effects, which are attributed to the extracellular domain of the protein, Here we report that blocking the ability of E-cadherin to mediate contact inhibition by either antagonistic antibodies or expression of a mutant form of E-cadherin with the extracellular region deleted does not abrogate growth suppression. Tran sfection of the E-cadherin gene into the human prostate cancer cell line TS U.Pr-1 induced cell-cell contact formation, growth suppression, and redistr ibution of beta -catenin to the cell membrane. Treatment of the E-cadherin transfectant (CAD) with blocking antibodies disrupted cell-cell contact for mation but did not influence the growth rate, suggesting that cell-cell int eraction is not required for E-cadherin-mediated growth suppression, Simila rly, transfection of an E-cadherin construct in which the NH2-terminal (ext racellular) region was deleted did not allow cell-cell contact formation bu t induced growth suppression. In contrast, transfection of an E-cadherin co nstruct in which the COOH-terminal (cytoplasmic) region was deleted did not induce suppression but promoted cell contact formation. In cells expressin g E-cadherin lacking the cytoplasmic region, beta -catenin was evenly distr ibuted in the cytoplasm, By contrast, in cells expressing E-cadherin lackin g the extracellular region, beta -catenin was cell membrane associated. Gro wth suppression was always associated with the localization of beta -cateni n to the cell membrane, The redistribution of beta -catenin from the cytopl asm to the cell membrane initially suggested the Involvement of the Wnt sig naling pathway in regulating cell growth. However, only small differences i n beta -catenin/T-cell factor signaling were detected in control and E-cadh erin-expressing cells, suggesting that the Wnt pathway is not involved. Tak en together, these findings suggest that E-cadherin-induced growth inhibiti on may not be solely attributed to contact inhibition but may involve the r edistribution of beta -catenin from the cytoplasm to the cell membrane, and this redistribution may affect growth pathways independent of T-cell facto r.