Involvement of sphingomyelinases in TNF signaling pathways

Sphingomyelin (N-acylsphingosin-1-phosphorylcholine) is a phospholipid pref erentially found in the plasma membrane of mammalian cells. Signaling throu gh the sphingomyelin pathway is associated with generation of ceramide, whi ch 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 transdu ction of diverse cell surface membrane receptors. The emerging picture sugg ests that coupling of ceramide to specific signaling cascades is both stimu lus- and cell type-specific and depends on the subcellular topology of its production. Following membrane receptor triggering, neutral and acid isofor ms of sphingomyelinases are rapidly activated generating ceramide through s phingomyelin hydrolysis. Here the molecular mechanisms of TNF-induced activ ation of sphingomyelinases and the functional consequences of ceramide gene ration will be discussed. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.