INTRACELLULAR TRAFFICKING AND RECYCLING OF GLYCOLIPIDS

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Glycosphingolipids (GLs) play important roles in the functioning of mammalian Cells through their involvement in cell-cell and cell-protein interactions and as modulators of receptor function. They also serve as receptors for many microorganisms responsible for human disease and can serve as tumor antigens in malignant cells. Although the structures and tissue distribution of GLs is quite well understood, the control of GL synthesis and metabolism and factors that govern their expression at the cell surface are poorly understood. It is known that the cell surface expression of GLs is quite dynamic and subject to internal and external influences. This project explores some aspects of the metabolism, intracellular processing and cell surface expression of GLs and the mechanisms involved.Specifically emphasized is a novel recycling pathway of exogenous and endogenous GLs from the plasma membrane, through the biosynthetic mechanisms of the cell, back to the cell surface. The initial emphasis will be on malignant melanoma cells, on which preliminary information has been developed. The project will study the fate of exogenous GLs added to melanoma and other cell types, the influence of GL structure on internalization and processing and factors (such as the glycosyltransferase profiles) that govern the nature of the processed products. Experimentally, the project involves the synthesis of suitable GL analogs (mainly of GM3 ganglioside) and their radioactive analogs and the use of these compounds to analyze the kinetic, stoichimetric and structural aspects of their processing by cells. The hypothesis that GLs bind to cells through specific cell surface receptors will also be examined. Furthermore, the question as to whether endogenous plasma membrane GLs also undergo similar recycling will be studied. Taken together these experiments will provide information on the extent and nature of GL recycling in cells and some aspects of the mechanisms involved. They will aid in a better understanding of GL metabolism in mammalian cells and factors that influence their cell surface expression and function.