The study of the intracellular signal transduction pathway for cell proliferation and differentiation - Modulation by gangliosides.

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[Objective]To elucidate the role of endogenous gangliosides (Gg) on the process of cell differentiation and proliferation, we analyzed the effect of Gg on the activity of intracellular signal transduction pathways for cell differentiation and proliferation.[Method]As for cell proliferation, we examined the activity of intracellular signal transduction pathway of epidermal growth factor (EGF) in skin fibroblasts from patients with GM1 gangliosidosis and normal controls. We previously reported that GM1 ganglioside is accumulated in fibroblasts from GM1 gangliosidosis when compared with that of normal controls. As for cell differentiation, we examined the effect of B subunit cholera toxin (CTB)-pretreatment, which specifically binds to GM1 and causes the re-distribution of GM1 on the plane of the plasma membrances, on NGF-signaling pathway in PC12 cells.[Results and Discussion]GM1 was found to be the negative regulator of EGF receptor function by reducing EGF-binding and by inhibiting EGF receptor associated tyrosine kinase (TK) activity. On the other hand, CTB augmented the intracellular NGF-signaling pathway. Moreover, in Trk A-immune complex kinase assay, GM1 was found to be a potent activator of Trk A-associated TK activity that is senseitve to NGF.Thus, GM1 seems to be an endogenous stimulator for cell differentiation.