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 »
- Authors:
-
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics Group. Theoretical Division. Center for Nonlinear Studies
- 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 Laboratory (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. https://doi.org/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. https://doi.org/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 = {Thu Sep 26 00:00:00 EDT 2013},
month = {Thu Sep 26 00:00:00 EDT 2013}
}
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