Biomedical science has twin goals, to understand the mechanisms underlying fundamental biological events and to apply this knowledge to understand human disease. Tremendous progress has been made on both fronts. One event which greatly hastened progress was the realization that all eukaryotic cells share similar cell biological machinery, and that all multicellular animals deploy this machinery in remarkably similar ways to direct normal development. This realization produced a revolutionary change, allowing us to study fundamental biological questions in tractable model systems and apply the resulting insights almost directly to the human system. We took this approach to develop an understanding of the relationship between cell adhesion and signal transduction, using Drosophila as our model. We approach these problems through the entrypoint of the Drosophila protein Armadillo (Arm). Arm and its mammalian homolog beta-catenin are 1) key components of cell-cell adherens junctions, and 2) transduce Wingless/Wnt family cell-cell signals. They thus influence both cell fate choices and assembly of cells into tissues. From this entrypoint, we broadened our perspective, and now seek to understand cell adhesion, transduction of Wg/Wnt signals, and possible connections between them. In addition to providing insights into fundamental biological problems, this research will also help us better understand the development of human disease. The recognition that all eukaryotic cells use similar cellular machinery has allowed scientists to adopt a functional genomics approach to understanding the function of key proteins involved in human diseases. Function of these proteins is rapidly examined in simple model systems like yeast or Drosophila, where one can combine molecular genetics with cell biology and biochemistry and thus capitalize on the speed of model systems and their synergy with vertebrate cell biology. Results of these analyses can then be applied to human cells. When inappropriately activated, beta-catenin contributes to colon carcinoma and melanoma. In contrast, loss-of-function mutations in beta-catenin or other components of the cadherin-catenin adhesion system contribute to metastasis. We study Arm function in the fruit fly Drosophila, taking advantage of its merits as a model system. Our goals are to understand at a biochemical level Arm/beta-catenin's roles, and in a broader sense, to use them as entrypoints in which to explore the function of cell-cell adhesive junctions, the Wg/Wnt signal transduction pathway, and connections between signal transduction and cell adhesion. We outline below a series of molecular, genetic, and biochemical approaches to these problems.
Our specific aims are to:
Aim I. Extend our in vivo study of Arm protein structure and function.
Aim II. Analyze the function of Drosophila p120 in cell adhesion in vivo.
Aim III. Analyze the role of Abl, Ena, and Dab in epithelial cell-cell junctions.
Aim I V. Complete the genetic screen for genes which interact with arm in cell adhesion, signaling or other functions, and characterize the interactors.
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