Adenomatous polyposis coli (APC) differentially regulates β-catenin phosphorylation and ubiquitination in colon cancer cells

Abstract

Most colorectal cancers have mutations of the adenomatous polyposis coli (APC) gene or the β-catenin gene that stabilize β-catenin and activate β-catenin target genes, leading ultimately to cancer. The molecular mechanisms of APC function in β-catenin degradation are not completely known. APC binds β-catenin and is involved in the Axin complex, suggesting that APC regulates β-catenin phosphorylation. Some evidence also suggests that APC regulates β-catenin nuclear export. Here, we examine the effects of APC mutations on β-catenin phosphorylation, ubiquitination, and degradation in the colon cancer cell lines SW480, DLD-1, and HT29, each of which contains a different APC truncation. Although the current models suggest that β-catenin phosphorylation should be inhibited by APC mutations, we detected significant β-catenin phosphorylation in these cells. However, β-catenin ubiquitination and degradation were inhibited in SW480 but not in DLD-1 and HT29 cells. The ubiquitination of β-catenin in SW480 cells can be rescued by exogenous expression of APC. The APC domains required for β-catenin ubiquitination were analyzed. Our results suggest that APC regulates β-catenin phosphorylation and ubiquitination by distinct domains and by separate molecular mechanisms. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.