Under normal circumstances, cadherin turnover is constitutive and endocytosis is a crucial mechanism for down-regulating cadherin adhesiveness (Le et al., 1999, 2002; Xiao et al., 2003). Previously, we postulated that p120 acts as a switch, inducing the assembly or disassembly of cadherin complexes through transient signaling events (probably tyrosine and serine phosphorylation), which in turn might regulate cadherin clustering. Our new data strongly favor a mechanism whereby dynamic assembly and disassembly of cadherin complexes is driven primarily by regulation of cadherin turnover rather than physical clustering (Fig. 7). A plausible explanation is that the rate of cadherin turnover is dictated by events at the cell surface that transiently increase or decrease p120 affinity for cadherins. The off state favors internalization/degradation, whereas the on state favors retention/recycling. The low affinity of p120 for cadherins, as judged by coimmunoprecipitation experiments (Thoreson et al., 2000), probably reflects the ability of p120 to rapidly alternate between cadherin-bound and -unbound states. It is worth noting that α- and β-catenins are largely passive players in this model. Because their stability is controlled by cadherin binding, their
