FAS-INDUCED APOPTOSIS IS MEDIATED VIA A CERAMIDE-INITIATED RAS SIGNALING PATHWAY

Fas receptor-induced apoptosis plays critical roles in immune homeosta sis. However, most of the signal transduction events distal to Fas lig ation have not been elucidated. Here, we show that Res is activated fo llowing ligation of Fas on lymphoid lines. The activation of Ras is a critical component of this apoptotic pathway, since inhibition of Res by neutralizing antibody or a dominant-negative Res mutant interfered with Fas-induced apoptosis. Furthermore, ligation of Fas also resulted in stimulation of the sphingomyelin signaling pathway to produce cera mides, which, in turn, are capable of inducing both Res activation and apoptosis. This suggests that ceramides acts as second messengers in Fas signaling via Ras. Thus, ligation of the Fas molecule on lymphocyt e lines induces activation of Ras via the action of ceramide, and this activation is necessary, but not sufficient, for subsequent apoptosis .