Figure 7.

Model for p120 function in regulating cadherin turnover. The low affinity of p120 for cadherins, as judged by coimmunoprecipitation experiments, probably reflects the ability of p120 to rapidly alternate between cadherin-bound and -unbound states. (1) Our data suggest that the rate of cadherin turnover is controlled by cell surface events that transiently increase or decrease p120 affinity for cadherins. Thus, cadherin complexes exist in a dynamic equilibrium between p120-bound and -unbound states, which in turn may be regulated by p120 phosphorylation (not depicted). (2) Unbound cadherin is targeted for internalization, possibly via a Hakai-like ubiquitination mechanism (see Discussion). (3) We cannot yet rule out an alternative pathway where p120 binding is irrelevant for internalization, but mediates a sorting decision that recycles internalized cadherin back to the membrane. (4) Regardless of the exact decision point, unbound cadherin is targeted for degradation by the proteosome and/or lysosome. Considerable evidence indicates that signaling events at the cell surface modulate phosphorylation of the cadherin-bound pool of p120. The simplest interpretation of these observations is that p120 phosphorylation regulates its steady-state affinity for cadherins, which in turn regulates adhesion by controlling the rate of cadherin turnover. Note that α- and β-catenin are passive players in this model. They likely participate in clustering and certainly mediate the cytoskeletal interaction (not depicted), but their role may be secondary to regulating surface cadherin levels, which is almost completely determined by p120.