The physiological role of ceramide formation in response to cell stimulation remains controversial. Here, we emphasize that ceramide is not a priori an apoptotic signalling molecule. Recent work points out that the conversion of sphingomyelin into ceramide can play a membrane structural (physical) role, with consequences for membrane microdomain function, membrane vesiculation, fusion/fission and vesicular trafficking. These processes contribute to cellular signalling. At the Golgi, ceramide takes part in a metabolic flux towards sphingomyelin, diacylglycerol and glycosphingolipids, which drives lipid raft formation and vesicular transport towards the plasma membrane. At the cell surface, receptor clustering in lipid rafts and the formation of endosomes can be facilitated by transient ceramide formation. Also, signalling towards mitochondria may involve glycosphingolipid-containing vesicles. Ceramide may affect the permeability of the mitochondrial outer membrane and the release of cytochrome c. In the effector phase of apoptosis, the breakdown of plasma membrane sphingomyelin to ceramide is a consequence of lipid scrambling, and may regulate apoptotic body formation. Thus ceramide formation serves many different functions at distinct locations in the cell. Given the limited capacity for spontaneous intracellular diffusion or membrane flip-flop of natural ceramide species, the topology and membrane sidedness of ceramide generation are crucial determinants of its impact on cell biology.

Abbreviations used: aSMase, acid sphingomyelinase; Cer, ceramide; C2-Cer, N-acetylsphingosine; C6-Cer, N-hexanoylsphingosine; DAG, diacylglycerol; ERK, extracellular-signal-regulated kinase; GCS, glucosylceramide synthase; JNK, c-Jun N-terminal kinase; KSR, kinase suppressor of Ras; MAPK, mitogen-activated protein kinase; nSMase, neutral sphingomyelinase; PC, phosphatidylcholine; PI 3-kinase, phosphoinositide 3-kinase; PKB, protein kinase B; PKC, protein kinase C; SAPK, stress-activated protein kinase; SM, sphingomyelin; TGN, trans-Golgi network; TNF, tumour necrosis factor.

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