Cellular gangliosides promote growth factor-induced proliferation of fibroblasts

Cell surface gangliosides have been proposed as modulators of transmembrane signaling. In this study, we used two complementary approaches to investigate the function of cellular gangliosides in the response of mammalian fibroblasts to growth factors. First, inhibition of glucosyl ceramide synthase by a new specific inhibitor of d-l-threo-1-phenyl-2-hexadecanoylamino-3 -pyrrolidino-1-propanol-HC l (glucosylceramide synthase), which depletes cellular gangliosides at a concentration of 1 microm without causing an increase in ceramide levels, blocked epidermal growth factor-stimulated proliferation of fibroblasts. Similarly, responses to several other growth factors that activate receptor tyrosine kinases, including fibroblast growth factor, insulin-like growth factor-I, and platelet-derived growth factor, were inhibited by 50-100%. Conversely, enrichment of cellular gangliosides by preincubation of the mouse and human fibroblasts with exogenously added gangliosides enhanced growth factor-elicited cell proliferation. Novel findings of this study, distinguishing it from previous similar studies, include differential effects of preincubation versus continuous incubation of cells with gangliosides on growth factor-dependent cell proliferation and the growth factor-like action of NeuNAc alpha 2-3Gal beta 1-3GalNAc beta 1-4(NeuNAc alpha 2-3)Gal beta 1-4Glc beta 1-1Cer when cells are pretreated with the ganglioside.