Ceramide and cell death receptor clustering.

Acid sphingomyelinase (ASM) has been shown to be activated by a variety of receptor molecules and stimuli including CD95, the tumor necrosis factor receptor (TNF-R), CD40, CD28, LFA-1, CD5, during development, irradiation, heat shock, UV light or bacterial and viral infections. The central role of ASM-released ceramide in the response to those stimuli is confirmed by several genetic studies. ASM and ceramide might mediate their biological effects by the activation of several intracellular signaling molecules including cathepsin D, phospholipase A(2) or the kinase suppressor of Ras. In addition, recent fluorescence microscopy studies indicate that distinct, small membrane domains, termed rafts, are modified by ceramide to form larger domains, which serve to cluster receptor molecules. The generation of a high receptor density might be required for initiation of receptor-specific signaling and explain the function of the ASM and ceramide in multiple signaling pathways.