Modeling the Effect of APC Truncation on Destruction Complex Function in Colorectal Cancer Cells

In colorectal cancer cells, APC, a tumor suppressor protein, is commonly expressed in truncated form. Truncation of APC is believed to disrupt degradation of β—catenin , which is regulated by a multiprotein complex called the destruction complex. The destruction complex comprises APC, Axin, β—catenin , serine/threonine kinases, and other proteins. The kinasesand, which are recruited by Axin, mediate phosphorylation of β—catenin , which initiates its ubiquitination and proteosomal degradation. The mechanism of regulation of β—catenindegradation by the destruction complex and the role of truncation of APC in colorectal cancer are not entirely understood. Through formulation and analysis of a rule-based computational model, we investigated the regulation of β—cateninphosphorylation and degradation by APC and the effect of APC truncation on function of the destruction complex. The model integrates available mechanistic knowledge about site-specific interactions and phosphorylation of destruction complex components and is consistent with an array of published data. We find that the phosphorylated truncated form of APC can outcompete Axin for binding to β—catenin , provided that Axin is limiting, and thereby sequester β—cateninaway from Axin and the Axin-recruited kinasesand. Full-length APC also competes with Axin for binding to β—catenin ; however, full-length APC is able, through its SAMP repeats, which bind Axin and which are missing in truncated oncogenic forms of APC, to bring β—catenininto indirect association with Axin and Axin-recruited kinases. Because our model indicates that the positive effects of truncated APC on β—cateninlevels depend on phosphorylation of APC, at the first 20-amino acid repeat, and because phosphorylation of this site is mediated by, we suggest thatis a potential target for therapeutic intervention in colorectal cancer. Specific inhibition ofis predicted to limit binding of β—cateninto truncated APC and thereby to reverse the effect of APC truncation.