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Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells
Dipak Barua1, William S Hlavacek
1Theoretical Biology and Biophysics Group, Theoretical Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
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. 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. Specific inhibition of CK1ε is predicted to limit binding of β-catenin to truncated APC and thereby to reverse the effect of APC truncation.
Insights
Truncated APC in colorectal cancer sequesters beta-catenin, preventing its degradation. Inhibiting CK1ε kinase may reverse this effect by disrupting beta-catenin binding to truncated APC.
Area of Science:
- Molecular Biology
- Computational Biology
- Cancer Research
Background:
- Truncated Adenomatous Polyposis Coli (APC) protein is common in colorectal cancer, disrupting beta-catenin degradation.
- Beta-catenin degradation is regulated by the destruction complex, involving APC, Axin, and kinases CK1α and GSK-3β.
- The precise role of APC truncation in colorectal cancer and beta-catenin regulation remains unclear.
Purpose of the Study:
- To investigate beta-catenin phosphorylation and degradation regulation by APC.
- To analyze the impact of APC truncation on the destruction complex's function using a computational model.
Main Methods:
- Development and analysis of a rule-based computational model.
- Integration of mechanistic knowledge on destruction complex component interactions and phosphorylation.
- Validation of the model against published experimental data.
Main Results:
- Phosphorylated truncated APC can sequester beta-catenin from Axin and its associated kinases (CK1α, GSK-3β) when Axin is limiting.
- Full-length APC facilitates beta-catenin association with Axin and kinases via its SAMP repeats, unlike truncated APC.
- Truncated APC's pro-beta-catenin effects are dependent on phosphorylation at the first 20-amino acid repeat, mediated by CK1ε.
Conclusions:
- CK1ε-mediated phosphorylation of APC is crucial for truncated APC's oncogenic function in colorectal cancer.
- CK1ε inhibition is a potential therapeutic strategy to disrupt beta-catenin binding to truncated APC.
- Targeting CK1ε could reverse the destabilizing effects of APC truncation on beta-catenin levels in colorectal cancer.
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