title: A novel cytoplasmic domain of the p55 tumor necrosis factor receptor initiates the neutral sphingomyelinase pathway.
abstract: The human p55 tumor necrosis factor (TNF) receptor (TR55) initiates at least two independent signaling cascades. The acidic sphingomyelinase (A-SMase) pathway involves a phosphatidylcholine-specific phospholipase C, an endosomal A-SMase, and controls expression of multiple TNF-responsive genes through induction of transcription factors such as NF-kappaB. The neutral sphingomyelinase (N-SMase) pathway comprises a membrane-bound N-SMase, proline-directed protein kinases, as well as phospholipase A2 and appears critical for the inflammatory responses induced by TNF. While the domain of TR55 that induces A-SMase is probably identical to the death domain, the exact location and extent of a putative N-SMase activation domain are still unknown. Structure-function analysis of TR55 deletion mutants revealed a novel region of 11 amino acids at position 309-319 that is both necessary and sufficient for activation of N-SMase. The N-SMase activation domain is distinct from the death domain and incapable of induction of A-SMase, NF-kappaB, and cytotoxicity. Taken together, our results suggest that a functionally independent region of TR55 is responsible for selectively initiating the N-SMase pathway that couples to an important inflammatory signaling cascade.
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität Kiel, 24105 Kiel, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Adam
authors.forename: K
authors.initials: K
authors.lastname: Wiegmann
authors.forename: S
authors.initials: S
authors.lastname: Adam-Klages
authors.forename: A
authors.initials: A
authors.lastname: Ruff
authors.forename: M
authors.initials: M
authors.lastname: Krönke
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D003062:Codon; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D011869:Radioligand Assay; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D003062:Codon; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013108:Sphingomyelin Phosphodiesterase