SHEDDING, SECRETION, & TRANSFER OF GLYCOSPHINGOLIPIDS

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Glycosphingolipids are important constituents of cell membranes. The tremendous diversity of oligosaccharide structure and the number of glycosyltransferases necessary for synthesizing these structures suggest that they may have significant functions. As examples, they do function as human blood group allo- and autoantigens, as receptors for viruses and toxins, as tumor markers, and are involved in cell-cell interactions. Some of these functions, such as toxin binding and antigenicity, have been passively transferred to cells incubating the cells with the appropriate glycosphingolipid. Many tumor-associated glycosphingolipids have been described and some of these are shed by the tumor cells. Since some glycosphingolipids suppress immune responsiveness in vitro, glycosphingolipids shed from tumors may contribute to the immunosuppression found with some forms of human cancer. Glycosphingolipids form micelles in water since the monomers are virtually insoluble. Significant concentrations of glycosphingolipids are found in plasma and they are exclusively associated with lipoproteins. Little is known about the mechanisms by which glycosphingolipids enter plasma, whether by secretion, shedding from membranes, or absorption from cell membranes by lipoproteins. The ultimate goal of this proposal is to understand the mechanisms by which glycosphingolipids are secreted or shed from normal and malignant cells, interact with plasma lipoproteins, transfer between lipoproteins, and transfer from lipoproteins onto or into other cells. Human tumor cell lines will be used as models to study the secretion or shedding of glycosphingolipids and the role of lipoproteins in this process. Blood from various individuals with differing glycosphingolipid blood group antigens will be used to study the kinetics and mechanisms of transfer of glycosphingolipids between plasma lipoproteins and between lipoproteins and human erythrocytes, lymphocytes, and platelets. This work will lead to a better understanding of the way exogenous glycosphingolipids affect cell function and cell surface topography. It will also provide deeper insight into how lipoproteins interact with each other and with cells.