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 intracellula r signaling mechanism. We and others have previously demonstrated the involvement and significance of a signaling cascade from the Fas recep tor 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., a nd Green, D. (1995) Immunity 2, 341; Cifone, M. G., DeMaria, R., Ronca li, 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., C han, 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 transdominan t 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 import ant function of a Ras and Rac protein-regulated signaling pathway in F as-mediated programmed cell death.