Sphingosine kinase ADP

Sphingosine 1-phosphate decrease in sphingomyelin levels as ceramide is formed followed by a return to normal levels, in some instances (particularly in apoptosis) there is a net loss of sphingomyelin and a net increase in ceramide. Several sphingolipid derivatives are formed which can have regulatory properties -lactosylceramide, glycosylceramide, ceramide, cer-amide phosphate, sphingosine and sphingosine phosphate.

One of the first clues that sphingolipid catabolites could be important in cellular regulation was the observation by Hannun, Bell and colleagues that ceramide was released from sphingomyelin when HL-60 cells were stimulated by dihydroxyvitamin D3, to make them differentiate. The sphingomyelinase enzyme responsible has now been found in eight different forms differing in pH optimum and subcellular localization. The best known is the acidic lysosomal sphingomyelinase, which is needed for turnover of membrane sphingomyelin and whose deficiency is responsible for Niemann-Pick disease (Section 7.8). There are also neutral (often Mg2+-dependent) sphingomyelinases that are located in plasma membrane, endoplasmic reticu-lum or nuclear membranes. An alkaline sphingo-myelinase also occurs in the gastrointestinal mucosa and in bile.

Ceramide is the best-studied of the sphingoid signalling molecules. Its production, by activation of sphingomyelinase, can be increased by a wide variety of different agents (Table 7.13). Ceramide will activate a number of important protein kinases, which in turn will affect important cellular activities (Fig. 7.30) such as growth arrest, apoptosis and inflammatory responses. It can also inhibit phos-pholipase D (Section 7.11) and affect phosphatidyl-inositol-3-kinase (Section 7.10), thus providing 'cross-talk' to these signalling pathways. Moreover, protein kinase C (the activity of which is altered by the diacylglycerol generated by both the phospho-lipase C and phospholipase D pathways; Sections 7.9 and 7.11) has been suggested, in at least some instances, to modify sphingomyelinase activity.

Ceramide is hydrolysed by ceramidase to yield sphingosine (or its equivalent base). Thus this enzyme has the intriguing property of converting one lipid messenger into another. Sphingosine

Table 7.13 Examples of stimuli known to increase ceramide production

Inducers of apoptosis

Tumour necrosis factor-a

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