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Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly
B Rubinfeld1, I Albert, E Porfiri
1Onyx Pharmaceuticals, Richmond, CA 94806, USA.
Abstract:
The adenomatous polyposis coli gene (APC) is mutated in most colon cancers. The APC protein binds to the cellular adhesion molecule beta-catenin, which is a mammalian homolog of ARMADILLO, a component of the WINGLESS signaling pathway in Drosophila development. Here it is shown that when beta-catenin is present in excess, APC binds to another component of the WINGLESS pathway, glycogen synthase kinase 3beta (GSK3beta), a mammalian homolog of Drosophila ZESTE WHITE 3. APC was a good substrate for GSK3 beta in vitro, and the phosphorylation sites were mapped to the central region of APC. Binding of beta-catenin to this region was dependent on phosphorylation by GSK3 beta.
Insights
The adenomatous polyposis coli (APC) protein interacts with beta-catenin, a key molecule in colon cancer. Phosphorylation by glycogen synthase kinase 3beta (GSK3beta) regulates this interaction, impacting cellular adhesion and signaling pathways.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Signaling
Background:
- The adenomatous polyposis coli (APC) gene is frequently mutated in colon cancers.
- APC protein interacts with beta-catenin, a homolog of Drosophila ARMADILLO.
- Beta-catenin is a component of the WINGLESS signaling pathway.
Purpose of the Study:
- To investigate the interaction between APC and beta-catenin.
- To elucidate the role of glycogen synthase kinase 3beta (GSK3beta) in regulating APC-beta-catenin binding.
- To map the phosphorylation sites on APC.
Main Methods:
- In vitro kinase assays to assess APC phosphorylation by GSK3beta.
- Mapping of phosphorylation sites on the APC protein.
- Analysis of beta-catenin binding to phosphorylated APC.
Main Results:
- APC is a substrate for GSK3beta in vitro.
- Phosphorylation sites were mapped to the central region of APC.
- Beta-catenin binding to APC is dependent on GSK3beta-mediated phosphorylation.
Conclusions:
- GSK3beta-mediated phosphorylation regulates the interaction between APC and beta-catenin.
- This phosphorylation-dependent binding is crucial for the WINGLESS signaling pathway.
- Findings provide insights into the molecular mechanisms underlying colon cancer development.