Role of Vinculin in Epithelial Cell Junctions

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DESCRIPTION (provided by applicant): The long-term goal of this research is to investigate the cytoskeletal regulation of cell-cell and cell-matrix adhesion-mediated events and the mechanism by which this regulation is subverted in neoplastic disease. The adhesion of cells to one another Is essential for the establishment and maintenance of normal tissue architecture. As such cell-cell contacts not only have an essential function in normal cell growth and motility but are also involved in cases of dysregulation that occur during carcinogenesis and metastasis. Cells have several mechanisms for linking to their neighbors. These so-called "cell junctions" consist of proteins that assemble into a variety of structures such as gap junctions, tight junctions, adherens junctions, desmosomes and hemidesmosomes, each with a different function. Despite their apparent stability, epithelial cell-cell junctions are highly dynamic regions of a cell that respond to cue from the extracellular environment. The morphological changes accompanying the response to these cues are mediated by the underlying actin cytoskeleton and their characteristics and integrity is controlled by kinases, phosphatases and small GTPases. A prominent phosphorylated protein that is reported to link cell-cell junctions to the actin cytoskeleton is vinculin. The role of vinculin at sites of adhesion to the matrix has been widely studied for many years, but the function of vinculin at sites of cell-cell contact remains largely unexplored. This proposal is directed towards answering this question. The hypothesis is that vinculin is an important regulator of epithelial cell junctions. This hypothesis will be tested and the role of vinculin dynamics and its phosphorylation in adherens and tight junction function will be examined.