The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways

Curr Biol. 2000 Jun 1;10(11):640-8. doi: 10.1016/s0960-9822(00)00512-1.

Abstract

Background: Activation of Fas (CD95) by its ligand (FasL) rapidly induces cell death through recruitment and activation of caspase-8 via the adaptor protein Fas-associated death domain protein (FADD). However, Fas signals do not always result in apoptosis but can also trigger a pathway that leads to proliferation. We investigated the level at which the two conflicting Fas signals diverge and the protein(s) that are implicated in switching the response.

Results: Under conditions in which proliferation of CD3-activated human T lymphocytes is increased by recombinant FasL, there was activation of the transcription factors NF-kappaB and AP-1 and recruitment of the caspase-8 inhibitor and FADD-interacting protein FLIP (FLICE-like inhibitory protein). Fas-recruited FLIP interacts with TNF-receptor associated factors 1 and 2, as well as with the kinases RIP and Raf-1, resulting in the activation of the NF-kappaB and extracellular signal regulated kinase (Erk) signaling pathways. In T cells these two signal pathways are critical for interleukin-2 production. Increased expression of FLIP in T cells resulted in increased production of interleukin-2.

Conclusions: We provide evidence that FLIP is not simply an inhibitor of death-receptor-induced apoptosis but that it also mediates the activation of NF-kappaB and Erk by virtue of its capacity to recruit adaptor proteins involved in these signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CD3 Complex / physiology
  • Carrier Proteins / metabolism*
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors*
  • Cells, Cultured
  • Fas Ligand Protein
  • Humans
  • Interleukin-2 / biosynthesis
  • Intracellular Signaling Peptides and Proteins*
  • Membrane Glycoproteins / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / metabolism*
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-raf
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Receptors, Tumor Necrosis Factor / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / physiology*
  • TNF Receptor-Associated Factor 1
  • TNF Receptor-Associated Factor 2
  • Transcription Factor AP-1 / metabolism
  • fas Receptor / physiology

Substances

  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CD3 Complex
  • CFLAR protein, human
  • Carrier Proteins
  • Caspase Inhibitors
  • FASLG protein, human
  • Fas Ligand Protein
  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • TNF Receptor-Associated Factor 1
  • TNF Receptor-Associated Factor 2
  • Transcription Factor AP-1
  • fas Receptor
  • Proto-Oncogene Proteins c-raf
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinases
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9