The Fas-associated death domain protein/caspase-8/c-FLIP signaling pathway is involved in TNF-induced activation of ERK.
The cytokine TNF activates multiple signaling pathways leading to cellular responses ranging from proliferation and survival to apoptosis. While most of these pathways have been elucidated in detail over the past few years, the molecular mechanism leading to the activation of the MAP kinases ERK remains ill defined and is controversially discussed. Therefore, we have analyzed TNF-induced ERK activation in various human and murine cell lines and show that it occurs in a cell-type-specific manner. In addition, we provide evidence for the involvement of the signaling components Fas-associated death domain protein (FADD), caspase-8, and c-FLIP in the pathway activating ERK in response to TNF. This conclusion is based on the following observations: (I) Overexpression of FADD, caspase-8, or a c-FLIP protein containing the death effector domains only leads to enhanced and prolonged ERK activation after TNF treatment. (II) TNF-induced ERK activation is strongly diminished in the absence of FADD. Interestingly, the enzymatic function of caspase-8 is not required for TNF-induced ERK activation. Additional evidence suggests a role for this pathway in the proliferative response of murine fibroblasts to TNF.
Lüschen
Silke
S
Institut für Immunologie, Universitätsklinikum Schleswig-Holstein Campus Kiel, Michaelisstrasse 5, 24105 Kiel, Germany.
Falk
Markus
M
Scherer
Gudrun
G
Ussat
Sandra
S
Paulsen
Maren
M
Adam-Klages
Sabine
S
D048868:Adaptor Proteins, Signal Transducing; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000502:physiology*; D053181:Caspase 8; D020169:Caspases / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056970:Co-Repressor Proteins; D015536:Down-Regulation; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000502:physiology*; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
D048868:Adaptor Proteins, Signal Transducing; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D048069:Tumor Necrosis Factors; D048049:Extracellular Signal-Regulated MAP Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases