STRUCTURE AND BIOSYNTHESIS OF SELECTIN LIGANDS

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Project I- Structure and Biosynthesis of Selectin Ligands (Minoru Fukuda, Ph.D.) In the previous funding period, we have made critical progress in this field. First, we discovered that 6-sulfo sialyl Lewis x in high endothelial venules (HEV) can be formed in core2 branch and extended core1 O- glycans. Expression of novel sulfotransferase (LSST) and core1 extension enzyme (core1-beta3GlcNAcT) demonstrated that the expression of these structures in biantennary O-glycans leads to highly active L-selectin ligands. Second, that excessive expression of sialyl Lewis x on tumor cells results in cytolysis of those tumor cells by nature killer (NK) cells, while moderate expression of sialyl Lewis x facilitates tumor metastasis. Based on these findings, two major areas of study are proposed: I. Elucidation of structure and function of L-selectin ligands in HEV at peripheral lymph nodes and Peyer's patches. In collaboration with Drs. John Lowe, Michiko Fukuda, and Ole Hindsgaul, we will determine the complete structure of L-selectin ligands at HEV in peripheral and mucosal lymph nodes, and determine the roles of 6-sulfo sialyl Lewis x is an L-selectin ligand by generating a mutant mouse. II. Roles of carbohydrates in tumor metastasis. In collaboration with Drs. Michiko Fukuda and John Lowe, we will determine if the amount of sialyl Lewis x plays a major role in facilitating tumor metastasis or NK cell-mediated cytolysis. We will also determine if cell surface carbohydrates isolated from tumor cells inhibit tumor metastasis or NK cell-mediated cytolysis. These studies will allow us to understand the structure and biosynthesis of selectin ligands and the roles of cell surface carbohydrates of tumor cells in tumor metastasis and immune cell recognition.