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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 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 kinases CK1α and GSK–3β, which are recruited by Axin, mediate phosphorylation of β—catenin, which initiates its ubiquitination and proteosomal degradation. The mechanism of regulation of β—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 β—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. In this paper, 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—catenin away from Axin and the Axin-recruited kinases CK1α and GSK–3β. Full-length APC also competes with Axin for binding to β—catenin; however, full-lengthmore » APC is able, through its SAMP repeats, which bind Axin and which are missing in truncated oncogenic forms of APC, to bring β—catenin into indirect association with Axin and Axin-recruited kinases. Because our model indicates that the positive effects of truncated APC on β—catenin levels depend on phosphorylation of APC, at the first 20-amino acid repeat, and because phosphorylation of this site is mediated by CK1ϵ, we suggest that CK1ϵ is a potential target for therapeutic intervention in colorectal cancer. Finally, specific inhibition of CK1ϵ is predicted to limit binding of β—catenin to truncated APC and thereby to reverse the effect of APC truncation.« less

Authors:
 [1];  [2]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics Group. Theoretical Division. Center for Nonlinear Studies
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics Group. Theoretical Division. Center for Nonlinear Studies; Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Biology; Translational Genomics Research Inst., Phoenix, AZ (United States). Clinical Translational Research Division
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1321723
Report Number(s):
LA-UR-13-20383
Journal ID: ISSN 1553-7358
Grant/Contract Number:  
AC52-06NA25396; R01GM076570; P50GM085273
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 9; Journal Issue: 9; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; biological science; antigen-presenting cells; phosphorylation; SW480 cells; protein interactions; cell binding; chemical dissociation; transfection; colorectal cancer

Citation Formats

Barua, Dipak, and Hlavacek, William S. Modeling the Effect of APC Truncation on Destruction Complex Function in Colorectal Cancer Cells. United States: N. p., 2013. Web. doi:10.1371/journal.pcbi.1003217.
Barua, Dipak, & Hlavacek, William S. Modeling the Effect of APC Truncation on Destruction Complex Function in Colorectal Cancer Cells. United States. doi:10.1371/journal.pcbi.1003217.
Barua, Dipak, and Hlavacek, William S. Thu . "Modeling the Effect of APC Truncation on Destruction Complex Function in Colorectal Cancer Cells". United States. doi:10.1371/journal.pcbi.1003217. https://www.osti.gov/servlets/purl/1321723.
@article{osti_1321723,
title = {Modeling the Effect of APC Truncation on Destruction Complex Function in Colorectal Cancer Cells},
author = {Barua, Dipak and Hlavacek, William S.},
abstractNote = {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 kinases CK1α and GSK–3β, which are recruited by Axin, mediate phosphorylation of β—catenin, which initiates its ubiquitination and proteosomal degradation. The mechanism of regulation of β—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 β—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. In this paper, 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—catenin away from Axin and the Axin-recruited kinases CK1α and GSK–3β. 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—catenin into indirect association with Axin and Axin-recruited kinases. Because our model indicates that the positive effects of truncated APC on β—catenin levels depend on phosphorylation of APC, at the first 20-amino acid repeat, and because phosphorylation of this site is mediated by CK1ϵ, we suggest that CK1ϵ is a potential target for therapeutic intervention in colorectal cancer. Finally, specific inhibition of CK1ϵ is predicted to limit binding of β—catenin to truncated APC and thereby to reverse the effect of APC truncation.},
doi = {10.1371/journal.pcbi.1003217},
journal = {PLoS Computational Biology (Online)},
number = 9,
volume = 9,
place = {United States},
year = {2013},
month = {9}
}

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