Epithelial tissues are affected in many cancers. Cancer results from alterations in normal cell behavior, often due to changes in cell-cell communication. Cell-cell signals and their signal transduction pathways play fundamental roles in normal embryonic development and adult physiology, influencing many processes including gene expression and the cytoskeleton. To understand the disease process, we must first understand the normal role of the proteins affected. We focus on the tumor suppressor APC. Mutations in APC occur in >70% of all colon cancers. A key breakthrough in understanding APC function came from the discovery that it binds to the protein B-catenin. B-catenin and its Drosophila homolog Armadillo (Arm) are key effectors in the Wnt signal transduction pathway. This allowed scientists studying APC to take advantage of the knowledge gained from studying Wnt signaling in model organisms, and rapidly led to a model suggesting that APC negatively regulates Wnt signaling by heaping target Bi-catenin/Arm for phosphorylation and ultimate proteolytic destruction. We established a model system to explore Pac's functions. We utilize the fruit fly Drosophila, combining classical and molecular genetics with cell biology and biochemistry, and thus capitalizing on the speed of this model system and its synergy with vertebrate cell biology. We found that Drosophila APC2 is a negative regulator of Wnt signaling in the embryonic epidermis. We also found an unexpected role for APC2 in regulating the link between the actin and microtubule cytoskeletons during mitosis. We hypothesize that APC family proteins are multi-functional components of several different protein complexes that link signal transduction and the cytoskeleton. We will test this hypothesis, exploring the functions of fly APC2 as a model for human APC.
Our specific aims are to: 1. Define the null phenotype of APC2 and assess redundancy between APC and APC2, 2. Define the contribution of individual protein domains to APC function, and use this information to test models for APC2 function in the destruction complex, 3. Determine APC2's role in cytoskeletal regulation, and 4. Use genetic and biochemical approaches to define new partners for APC2.
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