Involvement of sphingomyelinases in TNF signaling pathways.

Sphingomyelin (N-acylsphingosin-1-phosphorylcholine) is a phospholipid preferentially found in the plasma membrane of mammalian cells. Signaling through the sphingomyelin pathway is associated with generation of ceramide, which acts as a second messenger in activating a variety of cellular functions. Ceramide belongs to the group of sphingosine-based lipid second messenger molecules that are critically involved in the regulation of signal transduction of diverse cell surface membrane receptors. The emerging picture suggests that coupling of ceramide to specific signaling cascades is both stimulus- and cell type-specific and depends on the subcellular topology of its production. Following membrane receptor triggering, neutral and acid isoforms of sphingomyelinases are rapidly activated generating ceramide through sphingomyelin hydrolysis. Here the molecular mechanisms of TNF-induced activation of sphingomyelinases and the functional consequences of ceramide generation will be discussed.