Regulation of Complexed and Free Catenin Pools by Distinct Mechanisms

Abstract

Cadherins are transmembrane receptors with an extracellular domain that participates in homophilic cell to cell adhesion and a cytoplasmic domain that associates with proteins called catenins. Cadherin-mediated adhesion as well as adhesion-independent functions for catenins play important roles in differentiation, development, and malignant transformation. Mechanisms that regulate steady-state catenin levels and cadherin-catenin complex stability are poorly understood, but activities of both the Wnt-1 proto-oncogene and tyrosine kinases are implicated. Here I define, at the biochemical level, distinct mechanisms that modulate steady-state catenin levels. Increased cadherin expression, providing more catenin binding sites, leads to selective stabilization of the cadherin-associated population of α- and β-catenin, but not p120^cas. In contrast, expression of Wnt-1 leads primarily to increased stability of the uncomplexed pool of β-catenin without effect on p120^cas. Significantly, the Wnt-1-induced stabilization of uncomplexed β-catenin is independent of cadherin expression. Transformation by v-Src does not disrupt the catenin-cadherin complex despite the phosphorylation of E-cadherin and β-catenin on tyrosine. In contrast to the effects of Wnt-1, v-Src does not modulate the uncomplexed population of β-catenin. p120^cas is phosphorylated on tyrosine by v-Src, and this is accompanied by a significant decrease in the level of uncomplexed p120^cas as well as a change in behavior of p120^cas upon biochemical fractionation. Taken together these data suggest that p120^cas and β-catenin are regulated independently.