Tumor necrosis factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system.
The mechanism of tumor necrosis factor (TNF)-alpha signaling is unknown. TNF-alpha signaling may involve sphingomyelin hydrolysis to ceramide by a sphingomyelinase and stimulation of a ceramide-activated protein kinase. In a cell-free system, TNF-alpha induced a rapid reduction in membrane sphingomyelin content and a quantitative elevation in ceramide concentrations. Ceramide-activated protein kinase activity also increased. Kinase activation was mimicked by addition of sphingomyelinase but not by phospholipases A2, C, or D. Reconstitution of this cascade in a cell-free system demonstrates tight coupling to the receptor, suggesting this is a signal transduction pathway for TNF-alpha.
Dressler
K A
KA
Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Mathias
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S
Kolesnick
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RN
D002474:Cell-Free System; D002518:Ceramides / Q000502:physiology*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000187:drug effects*; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology*; D013109:Sphingomyelins / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002518:Ceramides; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D066246:ErbB Receptors; D013108:Sphingomyelin Phosphodiesterase