The major important developments in our recent glycolipid studies supported by this grant are: (1) increasing evidence has been provided that gangliosides, particularly GM?3? and GM?1?, are involved in regulating cell proliferation through interaction with membrane receptors for fibroblast growth factors (FGF), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). Defective synthesis of GM?3? or GM?1? as has been found in many transformed cells may be related to the loss of cell growth regulation through dysfunction of growth factor receptors; (2) some gangliosides, such as GM?3?, GD?1a?, and GM?1?, have been found in the detergent-insoluble cell adhesion matrix, although the chemical quantity of total cellular gangliosides is decreased significantly. Therefore, a specific functional role of gangliosides in defining cell adhesion and changes in such a ganglioside function in the adhesion matrix of transformed cells are expected; and (3) a close correlation between ceramide composition, carbohydrate structure, and glycolipid antigenicity has been demonstrated. In view of these developments, we plan to study the following: (1) the mechanism for functional control of growth factor receptors via gangliosides, particularly a specific role of gangliosides in inducing conformational change of receptors through gangliosides; (2) the association of gangliosides in cell adhesion sites by comparison of increasing numbers of normal and transformed cells. Organization of glycolipids in the adhesion substratum will be studied by cross-linking reagents and with antibodies directed to gangliosides, adhesive proteins, and cytoskeletal components; and (3) the correlation between ceramide and the activity and organization of glycosyltransferases as well as the antigenicity of glycolipids. A comparative study of the possible role of ceramide in the antigenicity of glycolipids in normal and transformed cells is also planned. (A)
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