Gene interactions and pathways from curated databases and text-mining
J Cell Biol 2004, PMID: 15289496

NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP.

Kreuz, Sebastian; Siegmund, Daniela; Rumpf, Jost-Julian; Samel, Dierk; Leverkus, Martin; Janssen, Ottmar; Häcker, Georg; Dittrich-Breiholz, Oliver; Kracht, Michael; Scheurich, Peter; Wajant, Harald

Fas (APO-1/CD95) is the prototypic death receptor, and the molecular mechanisms of Fas-induced apoptosis are comparably well understood. Here, we show that Fas activates NFkappaB via a pathway involving RIP, FADD, and caspase-8. Remarkably, the enzymatic activity of the latter was dispensable for Fas-induced NFkappaB signaling pointing to a scaffolding-related function of caspase-8 in nonapoptotic Fas signaling. NFkappaB was activated by overexpressed FLIPL and FLIPS in a cell type-specific manner. However, in the context of Fas signaling both isoforms blocked FasL-induced NFkappaB activation. Moreover, down-regulation of both endogenous FLIP isoforms or of endogenous FLIPL alone was sufficient to enhance FasL-induced expression of the NFkappaB target gene IL8. As NFkappaB signaling is inhibited during apoptosis, FasL-induced NFkappaB activation was most prominent in cells that were protected by Bcl2 expression or caspase inhibitors and expressed no or minute amounts of FLIP. Thus, protection against Fas-induced apoptosis in a FLIP-independent manner converted a proapoptotic Fas signal into an inflammatory NFkappaB-related response.

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Text Mining Data

NFkappaB → Fas: " NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP "

NFkappaB → Fas: " Remarkably, the enzymatic activity of the latter was dispensable for Fas induced NFkappaB signaling pointing to a scaffolding related function of caspase-8 in nonapoptotic Fas signaling "

NFkappaB → FasL: " However, in the context of Fas signaling both isoforms blocked FasL induced NFkappaB activation "

IL8 → FasL: " Moreover, down-regulation of both endogenous FLIP isoforms or of endogenous FLIPL alone was sufficient to enhance FasL induced expression of the NFkappaB target gene IL8 "

NFkappaB → FasL: " As NFkappaB signaling is inhibited during apoptosis, FasL induced NFkappaB activation was most prominent in cells that were protected by Bcl2 expression or caspase inhibitors and expressed no or minute amounts of FLIP "

Manually curated Databases

  • NCI Pathway Database FAS (CD95) signaling pathway: FASLG/FAS (trimer)/FADD/FADD/RIP complex (FAS-FASLG-FADD-RIPK1) → IKK complex complex (CHUK-IKBKB-IKBKG) (modification, activates)
    Evidence: mutant phenotype, assay
  • NCI Pathway Database FAS (CD95) signaling pathway: FASLG/FAS (trimer)/FADD/FADD/CASP8/CASP8 complex (FAS-FASLG-FADD-CASP8) → IKK complex complex (CHUK-IKBKB-IKBKG) (modification, activates)
    Evidence: mutant phenotype, assay
  • Reactome Reaction: FAS → CFLAR (indirect_complex)
  • Reactome Reaction: CASP8 → CFLAR (reaction)
  • Reactome Reaction: CASP8 → CFLAR (direct_complex)
  • Reactome Reaction: FADD → CASP8 (indirect_complex)
  • Reactome Reaction: FASLG → CFLAR (reaction)
  • Reactome Reaction: CASP8 → FASLG (indirect_complex)
  • Reactome Reaction: FADD → CFLAR (reaction)
  • Reactome Reaction: FADD → CFLAR (indirect_complex)
  • Reactome Reaction: FASLG → CFLAR (indirect_complex)
  • Reactome Reaction: FAS → CFLAR (reaction)
  • Reactome Reaction: CASP8 → FAS (indirect_complex)
In total, 31 gene pairs are associated to this article in curated databases