EMBO J 1997,
PMID: 9184224
Medema, J P; Scaffidi, C; Kischkel, F C; Shevchenko, A; Mann, M; Krammer, P H; Peter, M E
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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Text Mining Data
FLICE → DISC: "
FLICE is
activated by association with the CD95 death inducing signaling complex (
DISC )
"
p18 ⊣ p43: "
Subsequent cleavage of the receptor bound p43 results in formation of the prodomain p26 and the release of the active site containing fragment p18
"
FLICE → DISC: "
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
"
Manually curated Databases
-
NCI Pathway Database FAS (CD95) signaling pathway:
cIAP1-2 (BIRC2/BIRC3)
→
Caspase 8 (CASP8)
(modification, inhibits)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
cIAP1-2 (BIRC2/BIRC3)
→
FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8)
(modification, inhibits)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
cIAP1-2 (BIRC2/BIRC3)
→
c-FLIP (CFLAR)
(modification, inhibits)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
cIAP1-2 (BIRC2/BIRC3)
→
Caspase 8 p10 (CASP8)
(modification, inhibits)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
cIAP1-2 (BIRC2/BIRC3)
→
FASLG/FAS (trimer)/FADD/FADD complex (FAS-FASLG-FADD)
(modification, inhibits)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
cIAP1-2 (BIRC2/BIRC3)
→
FASLG/FAS (trimer)/FADD/FADD/CFLIP complex (FAS-FASLG-FADD-CFLAR)
(modification, inhibits)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
cIAP1-2 (BIRC2/BIRC3)
→
FASLG/FAS (trimer)/FADD/FADD/CASP8 p43/c-FLIP p43 complex (FAS-FASLG-FADD-CASP8-CFLAR)
(modification, inhibits)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
cIAP1-2 (BIRC2/BIRC3)
→
c-FLIP p12 (CFLAR)
(modification, inhibits)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 (CASP8)
→
FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 (CASP8)
→
c-FLIP (CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 (CASP8)
→
Caspase 8 p10 (CASP8)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 (CASP8)
→
FASLG/FAS (trimer)/FADD/FADD complex (FAS-FASLG-FADD)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 (CASP8)
→
FASLG/FAS (trimer)/FADD/FADD/CFLIP complex (FAS-FASLG-FADD-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 (CASP8)
→
FASLG/FAS (trimer)/FADD/FADD/CASP8 p43/c-FLIP p43 complex (FAS-FASLG-FADD-CASP8-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 (CASP8)
→
c-FLIP p12 (CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8)
→
c-FLIP (CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8)
→
Caspase 8 p10 (CASP8)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8)
→
FASLG/FAS (trimer)/FADD/FADD complex (FAS-FASLG-FADD)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8)
→
FASLG/FAS (trimer)/FADD/FADD/CFLIP complex (FAS-FASLG-FADD-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8)
→
FASLG/FAS (trimer)/FADD/FADD/CASP8 p43/c-FLIP p43 complex (FAS-FASLG-FADD-CASP8-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8)
→
c-FLIP p12 (CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
c-FLIP (CFLAR)
→
Caspase 8 p10 (CASP8)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
c-FLIP (CFLAR)
→
FASLG/FAS (trimer)/FADD/FADD complex (FAS-FASLG-FADD)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
c-FLIP (CFLAR)
→
FASLG/FAS (trimer)/FADD/FADD/CFLIP complex (FAS-FASLG-FADD-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
c-FLIP (CFLAR)
→
FASLG/FAS (trimer)/FADD/FADD/CASP8 p43/c-FLIP p43 complex (FAS-FASLG-FADD-CASP8-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
c-FLIP (CFLAR)
→
c-FLIP p12 (CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 p10 (CASP8)
→
FASLG/FAS (trimer)/FADD/FADD complex (FAS-FASLG-FADD)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 p10 (CASP8)
→
FASLG/FAS (trimer)/FADD/FADD/CFLIP complex (FAS-FASLG-FADD-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 p10 (CASP8)
→
FASLG/FAS (trimer)/FADD/FADD/CASP8 p43/c-FLIP p43 complex (FAS-FASLG-FADD-CASP8-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 p10 (CASP8)
→
c-FLIP p12 (CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD complex (FAS-FASLG-FADD)
→
FASLG/FAS (trimer)/FADD/FADD/CFLIP complex (FAS-FASLG-FADD-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD complex (FAS-FASLG-FADD)
→
FASLG/FAS (trimer)/FADD/FADD/CASP8 p43/c-FLIP p43 complex (FAS-FASLG-FADD-CASP8-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD complex (FAS-FASLG-FADD)
→
c-FLIP p12 (CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CFLIP complex (FAS-FASLG-FADD-CFLAR)
→
FASLG/FAS (trimer)/FADD/FADD/CASP8 p43/c-FLIP p43 complex (FAS-FASLG-FADD-CASP8-CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CFLIP complex (FAS-FASLG-FADD-CFLAR)
→
c-FLIP p12 (CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CASP8 p43/c-FLIP p43 complex (FAS-FASLG-FADD-CASP8-CFLAR)
→
c-FLIP p12 (CFLAR)
(modification, collaborate)
Evidence: mutant phenotype, assay, physical interaction
-
NCI Pathway Database HIV-1 Nef: Negative effector of Fas and TNF-alpha:
c-FLIP (CFLAR)
→
FAS/FADD/DAXX/Ask1/Caspase 8/Caspase 8/FASLG complex (FASLG-CASP8-MAP3K5-FAS-DAXX-FADD)
(modification, inhibits)
-
NCI Pathway Database HIV-1 Nef: Negative effector of Fas and TNF-alpha:
c-FLIP (CFLAR)
→
Caspase 8 (4 units) complex (CASP8)
(modification, inhibits)
-
NCI Pathway Database HIV-1 Nef: Negative effector of Fas and TNF-alpha:
FAS/FADD/DAXX/Ask1/Caspase 8/Caspase 8/FASLG complex (FASLG-CASP8-MAP3K5-FAS-DAXX-FADD)
→
Caspase 8 (4 units) complex (CASP8)
(modification, activates)
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8)
→
Caspase 8 (tetramer)/FADD/FADD complex (CASP8-FADD)
(modification, inhibits)
Evidence: mutant phenotype, assay
-
NCI Pathway Database FAS (CD95) signaling pathway:
FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8)
→
FADD/FADD/CASP8/CASP8 complex (FADD-CASP8)
(modification, inhibits)
Evidence: mutant phenotype, assay
-
NCI Pathway Database FAS (CD95) signaling pathway:
Caspase 8 (tetramer)/FADD/FADD complex (CASP8-FADD)
→
FADD/FADD/CASP8/CASP8 complex (FADD-CASP8)
(modification, collaborate)
Evidence: mutant phenotype, assay
In total, 36 gene pairs are associated to this article in curated databases