Recently, we have shown that in contrast to GM3 isolated from bovine brain which inhibits cellular proliferation, GM3-NeuGc from equine erythrocytes enhances cell growth.This project will examine the function of ganglioside GM3 in regulation of cell proliferation, with emphasis on the possible role of ceramide composition of GM3. The hypothesis is that the chain length of the fatty acid residues attached to the long chain sphingoid base influences the bimodal growth response to GM3. As a first approach, the effects of GM3 with different fatty acid composition on the growth of Swiss 3T3 fibroblasts, a convenient system for the study of cell activation and growth will be examined. This approach will provide clues to structure-function relationships between fatty acid composition and the bimodal response to ganglioside GM3 in growth control. To investigate the interaction of GM3 with growth factor receptors, photoreactive derivatives of GM3 will be synthesized. Direct interactions of these GM3 derivatives will be studied by measurements of labeled proteins after SDS-PAGE. After establishing that ganglioside GM3 directly interacts with the growth factor receptor, it will be of interest to examine the subsequent events that occur after the binding of the growth factor to its receptor. Considerable progress has been made recently in the elucidation of the signaling events that occur downstream of receptor binding. The phosphorylated receptor recognizes and binds The possibility that interaction of GM3 with the growth factor receptor modulates important signal transduction proteins containing src homology 2 domains (SH2 proteins) that are recruited by the tyrosine kinase receptor will also be evaluated.
