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FAS-induced apoptosis is mediated via a ceramide-initiated RAS signaling pathway
E Gulbins1, R Bissonnette, A Mahboubi
1La Jolla Institute for Allergy and Immunology, California 92037, USA.
Abstract:
Fas receptor-induced apoptosis plays critical roles in immune homeostasis. However, most of the signal transduction events distal to Fas ligation have not been elucidated. Here, we show that Ras is activated following ligation of Fas on lymphoid lines. The activation of Ras is a critical component of this apoptotic pathway, since inhibition of Ras by neutralizing antibody or a dominant-negative Ras mutant interfered with Fas-induced apoptosis. Furthermore, ligation of Fas also resulted in stimulation of the sphingomyelin signalling pathway to produce ceramides, which, in turn, are capable of inducing both Ras activation and apoptosis. This suggests that ceramides acts as second messengers in Fas signaling via Ras. Thus, ligation of the Fas molecule on lymphocyte lines induces activation of Ras via the action of ceramide, and this activation is necessary, but not sufficient, for subsequent apoptosis.
Insights
Fas receptor ligation activates Ras, a key protein in apoptosis signaling. Ceramides mediate this process, acting as crucial second messengers in immune cells.
Area of Science:
- Immunology
- Cell Biology
- Molecular Signaling
Background:
- Fas receptor-induced apoptosis is vital for immune homeostasis.
- Signal transduction pathways downstream of Fas ligation remain largely uncharacterized.
Purpose of the Study:
- To elucidate the signal transduction events following Fas ligation.
- To investigate the role of Ras and ceramide in Fas-mediated apoptosis.
Main Methods:
- Ligation of Fas receptor on lymphoid cell lines.
- Inhibition of Ras using neutralizing antibodies and dominant-negative mutants.
- Analysis of sphingomyelin signaling pathway and ceramide production.
Main Results:
- Fas ligation activates Ras in lymphoid cells.
- Ras activation is essential for Fas-induced apoptosis.
- Fas ligation stimulates ceramide production via the sphingomyelin pathway.
- Ceramides activate Ras and induce apoptosis, acting as second messengers.
Conclusions:
- Fas signaling in lymphocytes involves ceramide-mediated activation of Ras.
- Ras activation is a necessary, though not sufficient, step for Fas-induced apoptosis.