Paper Info
Title
Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells.
Abstract
In colorectal cancer cells, APC, a tumor suppressor protein, is commonly expressed in truncated form. Truncation of APC is believed to disrupt degradation of beta-catenin, which is regulated by a multiprotein complex called the destruction complex. The destruction complex comprises APC, Axin, beta-catenin, serine/ threonine kinases, and other proteins. The kinases CK1 alpha and GSK-3 beta, which are recruited by Axin, mediate phosphorylation of b-catenin, which initiates its ubiquitination and proteosomal degradation. The mechanism of regulation of beta-catenin degradation 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 beta-catenin phosphorylation 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 beta-catenin, provided that Axin is limiting, and thereby sequester beta-catenin away from Axin and the Axin-recruited kinases CK1 alpha and GSK-3 beta. Full-length APC also competes with Axin for binding to beta-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 beta-catenin into indirect association with Axin and Axin-recruited kinases. Because our model indicates that the positive effects of truncated APC on beta-catenin levels depend on phosphorylation of APC, at the first 20-amino acid repeat, and because phosphorylation of this site is mediated by CK1E, we suggest that CK1E is a potential target for therapeutic intervention in colorectal cancer. Specific inhibition of CK1E is predicted to limit binding of beta-catenin to truncated APC and thereby to reverse the effect of APC truncation.
Year
DOI
Venue
2013
10.1371/journal.pcbi.1003217
PLOS COMPUTATIONAL BIOLOGY
Keywords
Field
DocType
mutation,hydrolysis,phosphorylation,up regulation
Phosphorylation,Plasma protein binding,Multiprotein complex,Biology,Ubiquitin,Protein phosphorylation,Kinase,Beta-catenin,Bioinformatics,Genetics,Mutation
Journal
Volume
Issue
ISSN
9
9
1553-7358
Citations 
PageRank 
References 
0
0.34
10
Authors
2
Name
Order
Citations
PageRank
Dipak Barua1293.16
William S. Hlavacek227724.15