Cells of epithelial tissues display tight intercellular interactions which are mediated by a variety of cellular structures including adherens junctions, desmosomes, gap junctions and tight junctions. These cell-cell associations are not only important in the formation of a tissue but are equally important in maintaining its integrity throughout the life of the organism. A family of proteins, termed cadherins has been shown to mediate calcium- dependent cell adhesion. Cadherin expression is developmentally regulated and correlates with morphogenetic events suggesting that these adhesion molecules are essential to normal development. In addition, it has been suggested that down-regulation of cadherin or cadherin function may contribute to the metastatic spread of carcinomas. Cadherins have highly conserved cytoplasmic domains that interact indirectly with the cytoskeleton. This interaction is essential for the cadherin to mediate adhesion. Several proteins, termed catenins, have been identified that are associated with the cadherins. The catenins are thought to 1) mediate cytoskeletal interactions with the cadherins, thus linking the cytoskeleton to the plasma membrane and 2) regulate adhesive activity of the cadherins. The goals of this project are to further our understanding of the roles of cadherins and the catenins in the interaction of cells with one another and to determine how the cadherin/catenin complex relates to the structure we know as an adherens junction.
The specific aims of this project are 1) to determine which domains of the catenins are necessary for association with the complex, 2) to characterize cadherin-mediated adhesion in cells that express more than one cadherin; 3) to look at cadherin/catenin complexes in cells that do not form typical complexes such as fibroblasts; and 4) to determine if beta- and gamma-catenin can substitute for one another in a cadherin complex. We will accomplish these aims by the use of molecular biological techniques to produce truncated versions of the various proteins; by using antibodies to inhibit function of the various proteins; and with ultrastructural analysis of junctional complexes.
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