title: Fas ligand-induced c-Jun kinase activation in lymphoid cells requires extensive receptor aggregation but is independent of DAXX, and Fas-mediated cell death does not involve DAXX, RIP, or RAIDD.
abstract: Jun kinase signaling can be elicited by death receptor activation, but the mechanism and significance of this event are still unclear. It has been reported that cross-linking Abs to Fas trigger c-Jun N-terminal kinase (JNK) signaling via caspase-mediated activation of MEKK1 (JNK kinase kinase), elevation of ceramide levels or by recruitment of death domain associated protein (DAXX) to Fas. The effect of physiological ligand for Fas on JNK signaling was never investigated, although evidence is accumulating that Fas ligand is able to induce cellular responses distinct from those evoked by Ab-mediated cross-linking of Fas. Therefore, we investigated the effect of Fas ligand on JNK signaling. Like its ability to induce cell death, Fas ligand reliably activated JNK only upon extensive aggregation of the receptor. Although this was partially dependent on caspase activation, DAXX was not required. DAXX and other death receptor-associated proteins, which have been reported to bind directly or indirectly to Fas, such as receptor interacting protein (RIP) and RIP-associated ICH-1/CED-3-homologous protein with a death domain (RAIDD), were shown to be dispensable for Fas ligand-induced apoptosis.
authors.affiliation: The Walter and Eliza Hall Institute, Melbourne, Australia; and Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Villunger
authors.forename: D C
authors.initials: DC
authors.lastname: Huang
authors.forename: N
authors.initials: N
authors.lastname: Holler
authors.forename: J
authors.initials: J
authors.lastname: Tschopp
authors.forename: A
authors.initials: A
authors.lastname: Strasser
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D002461:Cell Line, Transformed; D056970:Co-Repressor Proteins; D004789:Enzyme Activation / Q000276:immunology; D053222:Fas Ligand Protein; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008024:Ligands; D008214:Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011940:Receptor Aggregation / Q000276:immunology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C491473:Daxx protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011506:Proteins; D019014:fas Receptor; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases