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| The EMBO Journal
(1997) 16, 2794–2804, doi:10.1093/emboj/16.10.2794 |
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| FLICE is activated by association with the CD95 death-inducing signaling complex (DISC) |
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| Jan Paul Medema1, 3, Carsten Scaffidi1, 3, Frank C. Kischkel1, Andrej Shevchenko2, Matthias Mann2, Peter H. Krammer1 and Marcus E. Peter1 |
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1 Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany 2 Protein and Peptide Group, EMBL, Meyerhofstrasse 1, D-69012 Heidelberg, Germany 3 J.P.Medema and C.Scaffidi contributed equally to this work To whom correspondence should be addressed Marcus E. Peter, M.Peter@dkfz-heidelberg.de Received 13 November 1996; Revised 30 December 1996. |
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| Abstract |
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| Upon activation, the apoptosis-inducing cell membrane receptor CD95 (APO-1/Fas) recruits a set of intracellular signaling proteins (CAP1-4) into a death-inducing signaling complex (DISC). In the DISC, CAP1 and CAP2 represent FADD/MORT1. CAP4 was identified recently as an ICE-like protease, FLICE, with two death effector domains (DED). Here we show that FLICE binds to FADD through its N-terminal DED. This is an obligatory step in CD95 signaling detected in the DISC of all CD95-sensitive cells tested. Upon prolonged triggering of CD95 with agonistic antibodies all cytosolic FLICE gets proteolytically activated. Physiological FLICE cleavage requires association with the DISC and occurs by a two-step mechanism. Initial cleavage generates a p43 and a p12 fragment further processed to a p10 fragment. Subsequent cleavage of the receptor-bound p43 results in formation of the prodomain p26 and the release of the active site-containing fragment p18. Activation of FLICE is blocked by the peptide inhibitors zVAD-fmk, zDEVD-fmk and zIETD-fmk, but not by crmA or Ac-YVAD-CHO. Taken together, our data indicate that FLICE is the first in a cascade of ICE-like proteases activated by CD95 and that this activation requires a functional CD95 DISC. |
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| Keywords: apoptosis, CAP1-4, CD95(APO-1/Fas), DISC, ICE-proteases |
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