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.
Kataoka
T
T
Institute of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Epalinges, CH-1066, Switzerland.
Budd
R C
RC
Holler
N
N
Thome
M
M
Martinon
F
F
Irmler
M
M
Burns
K
K
Hahne
M
M
Kennedy
N
N
Kovacsovics
M
M
Tschopp
J
J
D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017252:CD3 Complex / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D018808:Transcription Factor AP-1 / Q000378:metabolism; D019014:fas Receptor / Q000502:physiology
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017252:CD3 Complex; C506386:CFLAR protein, human; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D018808:Transcription Factor AP-1; D019014:fas Receptor; D019908:Proto-Oncogene Proteins c-raf; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9