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Tumor-Associated NH₂-Terminal Fragments Are the Most Stable Part of the Adenomatous Polyposis Coli Protein and Can Be Regulated by Interactions with COOH-Terminal Domains

Division of Cell and Developmental Biology, School of Life Sciences, WTB/MSI Complex, University of Dundee, Dundee, United Kingdom

Requests for reprints: Inke S. Näthke, Division of Cell and Developmental Biology, School of Life Sciences, WTB/MSI Complex, University of Dundee, Dundee, DD1 5EH, United Kingdom. Phone: 01382-345821; Fax: 01382-345386; E-mail: inke{at}lifesci.dundee.ac.uk.

Truncation mutations in the adenomatous polyposis coli (APC) gene are responsible for familial and sporadic colorectal cancer. APC is a large, multifunctional protein involved in cell migration, proliferation, and differentiation. Dominant effects that have been attributed to the NH₂-terminal fragments of APC expressed in tumors may result from loss of functions due to lack of COOH-terminal regions or gain of functions due to fewer regulatory interactions. Resolving this issue and determining how structural changes contribute to the multiple functions of the APC protein requires knowledge about the structural organization of the APC molecule. To this end, we used limited proteolysis to distinguish regions of the molecule with limited structure from those that form well-folded domains. We discovered that the NH₂-terminal region of APC was most resistant to proteolytic degradation, whereas middle and COOH-terminal regions were significantly more sensitive. Binding of APC to microtubules protected COOH-terminal regions of APC against proteolysis, consistent with the idea that this region of the molecule becomes ordered when bound to microtubules. Furthermore, interactions between the NH₂- and COOH-terminal domains of APC were identified in vitro and in vivo, suggesting that NH₂-terminal fragments of APC may be regulated by interactions with COOH-terminal domains. Indeed, expressing COOH-terminal APC fragments in tumor cells resulted in changes in the protein interactions of endogenous NH₂-terminal fragments in these cells. Thus, the dominant function of NH₂-terminal APC fragments found in tumor cells could be explained by loss of this regulation in tumors where COOH-terminal domains are missing.

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