Fas-induced apoptosis is mediated by activation of a Ras and Rac protein-regulated signaling pathway.
Fas induces apoptosis in lymphocytes via a poorly defined intracellular signaling mechanism. We and others have previously demonstrated the involvement and significance of a signaling cascade from the Fas receptor via sphingomyelinases and ceramide to Ras in apoptosis (Gulbins, E., Bissonette, R., Mahboubi, A., Nishioka, W., Brunner, T., Baier G., Baier-Bitterlich, G., Byrd, C., Lang, F., Kolesnick, R., Altman, A., and Green, D. (1995) Immunity 2, 341; Cifone, M. G., DeMaria, R., Roncali, P., Rippo, M. R., Azuma, M., Lanier, L. L., Santoni, A., and Testi, R. (1994) J. Exp. Med. 180, 1547-1552; Gill, B. M., Nishikata, H., Chan, G., Delovitch, T. L., and Ochi, A. (1994) Immunol. Rev. 142, 113-126). Here, we demonstrate an activation of the small G-proteins Rac 1 and Rac 2 after Fas receptor triggering. Expression of a transdominant inhibitory Ras mutant (N17Ras) prevents Rac 1 and Rac 2 stimulation, suggesting a signaling cascade from the Fas receptor via Ras to Rac 1 and Rac 2. Genetic and pharmacological inhibition of Ras or Rac 1 and Rac 2 stimulation blocks Fas-induced apoptosis, pointing to an important function of a Ras and Rac protein-regulated signaling pathway in Fas-mediated programmed cell death.
Gulbins
E
E
Department of Physiology, University of Tuebingen, Gmelinstrasse 5, 72076 Tuebingen, Germany.
Coggeshall
K M
KM
Brenner
B
B
Schlottmann
K
K
Linderkamp
O
O
Lang
F
F
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D053200:Fas-Associated Death Domain Protein; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008954:Models, Biological; D017830:Octoxynol; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D012995:Solubility; D013347:Subcellular Fractions / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*; D020744:rac GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D019014:fas Receptor; D017830:Octoxynol; D019204:GTP-Binding Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020744:rac GTP-Binding Proteins