Regulation of cadherin function and turnover byp120 catenin: Evidence for a tumor supressive role

Cadherins are transmembrane glycoproteins that mediate cell-cell adhesion through calcium dependent homotypic interactions. The association of β- and α-catenin with the cadherin cytoplasmic domain creates strong adhesion by connecting the cadherin to the actin cytoskeleton. By binding both cadherin and α-catenin, β-catenin serves as a link between the cadherin cytoplasmic tail and F-actin-associated α-catenin. In contrast, p120 catenin binds to the juxtamembrane domain of cadherin and has a controversial role in adhesion. Indirect evidence suggests p120 can have positive and negative adhesive effects, leaving the role of p120 in adhesion unclear.; Here, I used p120 deficient cell lines to examine the effects of p120 loss upon cadherin mediated cell adhesion. I have characterized the p120 deficiency in SW48 colon carcinoma cells and have shown that cadherin adhesion is impaired as a direct consequence of p120-insufficiency. Restoring normal p120 levels caused a striking adhesive rescue, demonstrating a crucial role for p120 in reactivation of E-cadherin function. The ability of p120 to rescue adhesion varied between isoforms and was also dependent on p120 expression levels and its ability to bind E-cadherin. p120 increased E-cadherin expression in the SW48 cells by a posttranscriptional mechanism, indicating that p120 modulates adhesion by regulating cadherin stability. I broadened my study on the adhesive effects of p120 loss by using p120 siRNA to knockdown p120 in a variety of cell lines. Using these cells, I show that p120 acts at the cell surface to control cadherin turnover, thereby regulating cadherin levels. p120 knockdown resulted in dose-dependant elimination of E-, P-, N-, and VE-cadherins, and complete loss of cell-cell adhesion. ARVCF and δ-catenin were functionally redundant, suggesting that proper cadherin-dependant adhesion requires the presence of at least one p120 family member.; These data assign a definite role for p120 in adhesion and establish that the core function of p120 in the cadherin complex is to regulate cadherin surface expression. Clearly, the in vitro consequence of p120 loss is cadherin downregulation, suggesting that p120 downregulation in tumors leads to reduced levels of E-cadherin. Thus, p120 may have a tumor suppressive role in cancer by maintaining E-cadherin expression.