Cellular Functions of the Tumor Suppressor APC

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DESCRIPTION (provided by applicant): The colon cancer tumor suppressor Adenomatous polyposis coli (APC) acts as an essential negative regulator of the Wnt signal transduction pathway and also has fundamental roles in the regulation of the actin and microtubule cytoskeletons. The precise mechanisms by which APC proteins influence the cytoskeleton have not been defined and may contribute to the development of colon cancer. We have developed an in vivo system in which to study the cytoskeletal functions of Drosophila APC2 using the Drosophila syncytial embryo as a model for cytoskeletal organization. Here, dynamic rearrangements of cortical actin during the cell cycle are orchestrated by a number of known actin regulatory proteins and by interactions with centrosomes and microtubules. We have previously shown that Drosophila APC2 plays a role in organization of the syncytial cytoskeleton in a complex including the Drosophila B-catenin homolog, Armadillo, and a-catenin. Our continued study of APC2 in this system revealed that APC2 functions to organize actin structures in the syncytial embryo and that this function is carried out in part with a Drosophila formin homology domain protein Diaphanous. The overall goals of this project include defining the molecular interactions of APC2 within the Armadillo-a-catenin complex and the Diaphanous complex and to understand in detail how these complexes are functioning to organize the actin cytoskeleton using biochemical assays, live imaging techniques, analysis of actin and microtubule organization and behavior, and identification of other proteins partners and regulators. These findings will contribute not only to our appreciation of normal cell processes, but also to our understanding of cellular dysfunction and cancer.