Sphingosine-1-phosphate: an enigmatic signalling lipid

Sphingosine-1-phosphate (S1P) levels in cells are regulated by the balance between its synthesis, which is catalysed by sphingosine kinases (SphKs), and degradation, which is catalysed by specific S1P phosphatases (SPPs) and an S1P lyase (Spl). The genes encoding all of these enzymes have now been cloned and their regulation is an important area of investigation. Sphingolipid metabolites have important roles in regulating stress responses. Some clues about this come from studies in yeast. The relative cellular balance between ceramide and sphingosine, which are both associated with growth arrest and apoptosis, versus S1P, which is proliferative and anti-apoptotic, can be considered as a kind of rheostat that determines whether cells live or die. Regulation of cellular calcium levels is crucial to almost all physiological processes. This regulation is an important function of S1P, which seems to be conserved throughout evolution. There are five specific S1P receptors that couple to different G proteins and regulate many downstream signalling pathways. The biological functions of S1P are now known to depend on the relative expression of these receptors. Crosstalk back and forth between G-protein-coupled receptors, such as those that S1P functions as the ligand for, and other types of cell-surface receptors is an important mechanism that allows cells to integrate many external signals to specifically regulate physiological responses. It is not known exactly how external stimuli increase SphK1 activity but some recent studies indicate that it might be phosphorylated or translocated to membranes where its substrate, sphingosine, resides. The list of growth factors, cytokines, agonists, and so on, that are reported to stimulate SphK1 and increase the formation of S1P is lengthy and growing rapidly. New molecular approaches should help sort out those responses that are really crucial for normal and pathophysiology.