The eucaryotic cell surface has been implicated in the control of cell adhesion, growth, motility, morphology and differentiation. Presumably, this is accomplished via specific cell surface receptors which """"""""sense"""""""" the cell's molecular and cellular environment and allow the cell to respond accordingly. These control mechanisms are central in the process of orderly morphogenesis and in neoplastic transformation and metastasis. The molecular mechanisms for cell-cell interactions are unknown, and their elucidation remains a major challenge. This proposal investigates the role of a major class of cell surface molecules--complex carbohydrates--in the control of cell surface interactions through the use of """"""""cell surface analogs"""""""": synthetic or natural cell surface glycoconjugates covalently immobilized on otherwise inert plastic surfaces. Primary hepatocytes and macrophages as well as normal and transformed fibroblast cell lines in culture will be used in our studies. Two complementary experimental approaches are proposed: 1. Cell Responses to Carbohydrate-derivatized Surfaces. Hepatocytes and macrophages adhere to carbohydrate-derivatized surfaces in a sugar-specific manner. Carbohydrate-directed adhesion is followed, as in cell-cell adhesion, by distinct responses which alter the nature of the adhesive bonds. Thus, hepatocytes appear to covalently modify extracellular carbohydrates subsequent to initial adhesion, perhaps via phosphorylation. This proposal details experiments which will identify the biochemistry of the extracellular carbohydrate modification(s) and their relationship to cell adhesion. These studies may reveal new information on the biochemical mechanisms underlying the control of cell behavior by intercellular interactions. 2. Cell Surface Components in Growth Regulation. The control of cellular growth is important to orderly morphogenesis and is lost upon neoplastic transformation. Evidence suggests that cell-cell contact regulates the rate of cell division via cell surface molecules which bind to complementary receptors on apposing cells. We will use fibroblasts in cell culture to test the ability of partially purified membrane glycoproteins, immobilized on """"""""cell surface analogs"""""""", to control cell division. This approach may help identify the active cell surface component(s).
