Several mechanochemical processes coordinated at the cell surface are essential for normal tissue formation and integrity. A guiding theme for our work continues to be the idea that the primary processes of cell migration, cell proliferation and cell adhesion regulate and are regulated by the cross-linkage of cell surface glycoproteins and their interactions with the cytoskeleton (global modulation), and are influenced by changes in the amount, distribution and properties of specific cell surface receptors (local modulation). To corroborate this hypothesis and to examine the role of proteins involved in tissue formation in the control of primary processes, we have isolated and characterized three cell adhesion molecules (N-CAM, L-CAM, and Ng-CAM) and have recently discovered a novel extracellular matrix (ECM) protein (cytotacin) that is involved in both cell-matrix adhesion and cell migration. The distributions of each of these molecules show dynamic alterations during development that are consistent with their identified functions. Furthermore, expression of the CAMs and cytotactin is altered in transformed cells, raising the possibility that alterations in the expression of these molecules is a crucial correlate of the transformed phenotype. We now propose to extend and deepen our study of the dynamics of cell surface modulation. Specifically, we will: 1) determine the structural features of cytotactin at both the protein and nucleic acid levels, with particular regard to known features of CAMs and extracellular matrix proteins; 2) carry out functional assays to describe the role of cytotactin in cell movement and search for its cellular receptors; 3) use monoclonal antibodies to a carbohydrate antigen (NC-1/HNK-1) present on cytotactin, N-CAM, and Ng-CAM to identify other cell surface and ECM proteins that might be involved in adhesion; 4) relate local cell surface modulation to global modulation in nerve-muscle and hepatocyte interactions and determine whether ECM proteins can induce global modulation; and 5) determine whether the effects of viral transformation consistently correlate with modulation of molecules that mediate cell-cell and cell-substrate interactions in neural and epithelial cells. The results of these studies should provide valuable clues to the regulation of fundamental cellular processes, and may be of significant value to our understanding of a variety of disease states including birth defects, tissue disorders, cancer and metastasis.
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