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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CD3 Complex / physiology
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Carrier Proteins / metabolism*
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Caspase 8
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Caspase 9
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Caspase Inhibitors*
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Cells, Cultured
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Fas Ligand Protein
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Humans
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Interleukin-2 / biosynthesis
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Intracellular Signaling Peptides and Proteins*
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Membrane Glycoproteins / pharmacology
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Mitogen-Activated Protein Kinases / metabolism*
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NF-kappa B / metabolism*
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Proteins / metabolism
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Proto-Oncogene Proteins c-raf
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Receptor-Interacting Protein Serine-Threonine Kinases
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Receptors, Tumor Necrosis Factor / physiology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / physiology*
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 2
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Transcription Factor AP-1 / metabolism
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fas Receptor / physiology
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CD3 Complex
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CFLAR protein, human
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Carrier Proteins
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Caspase Inhibitors
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FASLG protein, human
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Fas Ligand Protein
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Interleukin-2
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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NF-kappa B
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Proteins
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Receptors, Tumor Necrosis Factor
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TNF Receptor-Associated Factor 1
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TNF Receptor-Associated Factor 2
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Transcription Factor AP-1
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fas Receptor
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Proto-Oncogene Proteins c-raf
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RIPK1 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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CASP8 protein, human
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CASP9 protein, human
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Caspase 8
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Caspase 9