Sphingosine-1-Phosphate - A New Lipid Signaling Molecule

Sphingolipid metabolites have been suggested to play an important role in cellular signaling. Branching pathways of sphingolipid metabolism may regulate either apoptosis or mitogenic effects depending on the cell type and the nature of the stimulus. Ceramide produced by sphingomyelinase activation has been shown to induce apoptosis and cell growth arrest, whereas further metabolites of ceramide, sphingosine and sphingosine-1-phosphate (SPP), induce mitogenesis in many cell types and have been implicated as second messengers in cellular proliferation induced by PDGF and serum. Mitogens such as PDGF and serum, but not EGF, increase levels of sphingosine and SPP and also activate cytosolic sphingosine kinase activity. Dihydrosphingosine, an inhibitor of sphingosine kinase, reduces DNA synthesis induced by PDGF and serum but not by EGF. Thus elevation of sphingosine and SPP levels and activation of sphingosine kinase may have important biological roles in signal transduction pathways activated by specific growth factors. SPP mobilizes calcium from internal stores in an inositol trisphosphate-independent manner, increases phosphatidic acid levels by activation of PLD, and also activates extracellular signal regulated kinases (ERK), which are all prominent events in the control of cellular proliferation. SPP-induced activation of the transcription factor AP-1, one of the transcription factors activated by the ERK pathway, is the first link between the effects of sphingolipids metabolites on cellular proliferation and gene expression. Recently, we found that SPP prevents the appearance of the hallmarks of apoptosis, such as intranucleosomal DNA fragmentation and morphological changes, that result from elevations of ceramide. Our results suggest that the balance between intracellular levels of ceramide and SPP determines the fate of the cell.