STRESS-INDUCED APOPTOSIS AND THE SPHINGOMYELIN PATHWAY

The sphingomyelin pathway is a ubiquitous, evolutionarily conserved si gnaling system initiated by hydrolysis of the plasma membrane phosphol ipid sphingomyelin to generate the second messenger ceramide. Sphingom yelin degradation is catalyzed by acid and neutral sphingomyelinase (S Mase) isoforms. Most, if not ail mammalian cells, appear capable of si gnaling though the sphingomyelin pathway. Diverse receptor types and e nvironmental stresses utilize the sphingomyelin pathway as a downstrea m effector system. In some cellular systems, ceramide initiates differ entiation or cell proliferation, while in other systems, ceramide sign als apoptosis. Recent investigations link the activation of neutral SM ase to the extracellular signal regulated kinase (ERK) cascade and pro -inflammatory responses, and acid SMase to the stress-activated protei n kinase/c-jun kinase (SAPK/JNK) cascade and apoptotic responses. Envi ronmental stresses act directly on membrane to activate acid pH-depend ent sphingomyelinase (ASMase), whereas cytokine receptors signal ASMas e activation through motifs termed death domains. The present review f ocuses on mechanisms of activation of ASMase and on ceramide signaling of the apoptotic response. (C) 1997 Elsevier Science Inc.