Regulation of growth factor receptors by gangliosides

Since their discovery in the 1940s, gangliosides have been associated with a number of biological processes, such as growth, differentiation, and toxin uptake. Hypotheses about regulation of these processes by gangliosides are based on indirect observations and lack a clear definition of their mechanisms within the cell. The first insights were provided when a reduction in cell proliferation in the presence of gangliosides was attributed to inhibition of the epidermal growth factor receptor (EGFR). Since that initial finding, most, if not all, growth factor receptors have been described as regulated by gangliosides. In this review, we describe the effects of gangliosides on growth factor receptors, beginning with a list of known effects of gangliosides on growth factor receptors; we then present three models based on fibroblast growth factor (FGFR), platelet-derived growth factor receptor (PDGFR), and EGFR. We focus first on ganglioside modulation of ligand binding; second, we discuss ganglioside regulation of receptor dimerization; and third, we describe a model that implicates gangliosides with receptor activation state and subcellular localization. The methodology used to develop the three models may be extended to all growth factor receptors, bearing in mind that the three models may not be mutually exclusive. We believe that gangliosides do not act independently of many well-established mechanisms of receptor regulation, such as clathrin-coated pit internalization and ubiquitination, but that gangliosides contribute to these functions and to signal transduction pathways. We hypothesize a role for the diverse structures of gangliosides in biology through the organization of the plasma membrane into lipid raft microdomains of unique ganglioside composition, which directly affect the signal duration and membrane localization of the growth factor receptor.