Cell Adhesion, Signal Transduction, & Cancer: The Armadillo Connection
Epithelial tissues are affected in many cancers. To explore underlying causes of epithelial tumors, we focus on the Armadillo/_-catenin protein, which plays roles in human colon cancer and melanoma. Cancer results from alterations in normal cell behaviors. Drosophila Armadillo and its vertebrate homolog _-catenin play key roles both in cell-cell adherens junctions, initiating epithelial assembly, and as transducers of Wingless/Wnt family cell-cell signals. We study these processes in 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 demonstrated that Armadillo is a key component of cell-cell adherens junctions, where it joins transmembrane cadherins to a-catenin and the actin cytoskeleton. Armadillo and adherens junctions are essential for maintaining epithelial organization, cell polarity, and normal embryonic development. Armadillo plays a separate role in transducing Wingless/Wnt cell-cell signals. In this role, it forms a heterodimer with dTCF, creating a bipartite transcription factor that regulates Wingless target genes. We are currently focusing in more detail on Armadillo's roles in adherens junctions and in transduction of Wingless cell-cell signal, and are identifying and examining the function of other components of adherens junctions and the Wingless signal transduction pathway. We are also analyzing the function of the tumor suppressor APC. Our goal is to understand at the biochemical level the roles of Armadillo/_-catenin. They and their interactors are potential drug targets, via small molecule inhibitors of _-catenin action in carcinogenesis.