WNT-1 REGULATES FREE POOLS OF CATENINS AND STABILIZES APC-CATENIN COMPLEXES

The Wnt-1 proto-oncogene induces the accumulation of beta-catenin and plakoglobin, two related proteins that associate with and functionally modulate the cadherin cell adhesion proteins, Here we have investigat ed the effects of Wnt-1 expression on the tumor suppressor protein APC , which also associates with catenins. Expression of Wnt-1 in two diff erent cell lines greatly increased the stability of APC-catenin comple xes. The steady-state levels of both catenins and APC were elevated by Wnt-1, and the half-lives of both beta-catenin and plakoglobin associ ated with APC were also markedly increased, The stabilization of caten ins by Wnt-1 was primarily the result of a selective increase in the a mount of uncomplexed, monomeric beta-catenin and plakoglobin, detected both by affinity precipitation and size-exclusion chromatography of c ell extracts, Exogenous expression of beta-catenin was possible in cel ls already responding to Wnt-1 but not in the parental cells, suggesti ng that Wnt-1 inhibits an essential regulatory mechanism for beta-cate nin turnover, APC has the capacity to oppose this Wnt-1 effect in expe riments in which overexpression of the central region of APC significa ntly reduced the size of the monomeric pool of beta-catenin induced by Wnt-1. Thus, the Wnt-1 signal transduction pathway leads to the accum ulation of monomeric catenins and stabilization of catenin complex for mation with both APC and cadherins.