Targeted inactivation of CTNNB1 reveals unexpected effects of [beta]-catenin mutation

Inactivating mutations of the adenomatous polyposis coli gene (APC) or activating mutations of the [beta]-catenin gene (CTNNB1) initiate colorectal neoplasia. To address the biochemical and physiologic effects of mutant [beta]-catenin, we disrupted either the mutant or wild-type CTNNB1 allele in a human colorectal cancer cell line. Cells with only wild-type [beta]-catenin had decreased colony-forming ability when plated at low density, although their growth was similar to that of parental cells when passaged under routine conditions. Immunohistochemistry and cell-fractionation studies suggested that mutant [beta]-catenin activity was distinguished primarily by cellular localization and not by protein degradation. Surprisingly, we found mutant [beta]-catenin bound less well to Ecadherin than did wild-type [beta]-catenin, and the membranous localization of wild-type and mutant [beta]-catenin was accordingly distinct. These findings pose several challenges to current models of APC/[beta]-catenin function.