Article: article from journal or magazin.
The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways.
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.
Antigens, CD3/physiology, Antigens, CD95/physiology, Apoptosis, CASP8 and FADD-Like Apoptosis Regulating Protein, Carrier Proteins/metabolism, Caspase 8, Caspase 9, Caspases/antagonists &, 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, TNF Receptor-Associated Factor 1, TNF Receptor-Associated Factor 2, Transcription Factor AP-1/metabolism
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