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...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS Computational Biology |
| Online Access: | http://europepmc.org/articles/PMC3784502?pdf=render |
| _version_ | 1811268597690925056 |
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| author | Dipak Barua William S Hlavacek |
| author_facet | Dipak Barua William S Hlavacek |
| author_sort | Dipak Barua |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T21:25:48Z |
| format | Article |
| id | doaj.art-71e8f886ac91401da0246ea4e49746fd |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-12T21:25:48Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-71e8f886ac91401da0246ea4e49746fd2022-12-22T03:16:11ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582013-01-0199e100321710.1371/journal.pcbi.1003217Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells.Dipak BaruaWilliam S HlavacekIn 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.http://europepmc.org/articles/PMC3784502?pdf=render |
| spellingShingle | Dipak Barua William S Hlavacek Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells. PLoS Computational Biology |
| title | Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells. |
| title_full | Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells. |
| title_fullStr | Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells. |
| title_full_unstemmed | Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells. |
| title_short | Modeling the effect of APC truncation on destruction complex function in colorectal cancer cells. |
| title_sort | modeling the effect of apc truncation on destruction complex function in colorectal cancer cells |
| url | http://europepmc.org/articles/PMC3784502?pdf=render |
| work_keys_str_mv | AT dipakbarua modelingtheeffectofapctruncationondestructioncomplexfunctionincolorectalcancercells AT williamshlavacek modelingtheeffectofapctruncationondestructioncomplexfunctionincolorectalcancercells |