Here, we provide evidence that the core function of p120 in cadherin complexes is to regulate cadherin turnover. Previously, we showed that the stabilizing effect of p120 on E-cadherin in a p120-deficient SW48 cell line involved a post-transcriptional mechanism and required direct p120–E-cadherin interaction (Ireton et al., 2002). However, it was not clear whether this phenomenon was generally applicable beyond SW48 cells, nor could we determine the underlying mechanism. Here, using siRNA and/or p120 reconstitution, we show that E-cadherin levels depend absolutely on p120 expression. Importantly, this set point mechanism is common to other (probably all) p120-binding cadherins because p120 knockdown also induced significant down-regulation of P-, VE-, and N-cadherins. The timing and location of p120 action argue strongly that p120 regulates adhesion via controlling cadherin turnover at the cell surface. These observations have crucial implications for roles of p120 in cadherin function and cancer.
