Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase. |
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| Authors: | A Huwiler J Brunner R Hummel M Vervoordeldonk S Stabel H van den Bosch J Pfeilschifter |
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| Affiliation: | Department of Pharmacology, Biozentrum, University of Basel, Switzerland. |
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| Abstract: | Interleukin 1 is the prototype of an inflammatory cytokine, and evidence suggests that it uses the sphingomyelin pathway and ceramide production to trigger mitogen-activated protein kinase (MAPK) activation and subsequent gene expression required for acute inflammatory processes. To identify downstream signaling targets of ceramide, a radioiodinated photoaffinity labeling analog of ceramide ([125I] 3-trifluoromethyl-3-(m-iodophenyl)diazirine-ceramide) was employed. It is observed that ceramide specifically binds to and activates protein kinase c-Raf, leading to a subsequent activation of the MAPK cascade. Ceramide does not bind to any other member of the MAPK module nor does it bind to protein kinase C-zeta. These data identify protein kinase c-Raf as a specific molecular target for interleukin 1 beta-stimulated ceramide formation and demonstrate that ceramide is a lipid cofactor participating in regulation of c-Raf activity. |
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