Sphingosine kinases (SPHKs) catalyze the phosphorylation of sphingosine to form sphingosine-1-phosphate (S1P), a lipid mediator with both intra- and extracellular functions. Together with other sphingolipid metabolizing enzymes, SPHKs regulate the balance of the lipid mediators, ceramide, sphingosine, and S1P (1-4). Two distinct SPHK isoforms, SPHK1 and SPHK2, have been cloned and characterized (5,6). SPHK1 and SPHK2 are highly conserved and diversely expressed (7,8). The SPHKs are activated by G protein-coupled receptors, receptor tyrosine kinases, immunoglobulin receptors, cytokines, and other stimuli (9-12). The molecular mechanisms by which SPHK1 and SPHK2 are specifically regulated are complex and only partially understood.