is consistent with its function as a second messenger. It was found that immediate hydrolysis of only 3 to 10% of newly generated ceramide may double the levels of Sph. Treatment of HL60 cells (a type of leukemia cell line) by a plant-derived organic compound called phorbol ester increased Sph levels threefold, whereby the cells differentiated into white blood cells called macrophages. Treatment of the same cells by exogenous Sph caused apoptosis. A specific protein kinase phosphorylates 14-3-3, otherwise known as sphingosine-dependent protein kinase 1 (SDK1), only in the presence of Sph. Sph is also known to interact with protein targets such as the protein kinase H homologue (PKH) and the yeast protein kinase (YPK). These targets in turn mediate the effects of Sph and its related sphingoid bases, with known roles in regulating the actin cytoskeleton, endocytosis, the cell cycle and apoptosis. It is important to note however that the second messenger function of Sph is not yet established unambiguously. Sphingosine-1-Phosphate Sphingosine-1-phosphate (S1P), like Sph, is composed of a single hydrophobic chain and has sufficient solubility to move between membranes. S1P is formed by phosphorylation of sphingosine by sphingosine kinase (SK). The phosphate group of the product can be detached (dephosphorylated) to regenerate sphingosine via S1P phosphatase enzymes or S1P can be broken down by S1P lyase enzymes to ethanolamine phosphate and hexadecenal. Similar to Sph, its second messenger function is not yet clear. However, there is substantial evidence that implicates S1P to cell survival, cell migration, and inflammation. Certain growth-inducing proteins such as platelet-derived growth factor (PDGF), insulin-like growth factor (IGF) and vascular endothelial growth factor (VEGF) promote the formation of SK enzymes, leading to increased levels of S1P. Other factors that induce SK include cellular communication molecules called cytokines, such as tumor necrosis factor α (TNFα) and interleukin-1 (IL-1), hypoxia or lack of oxygen supply in cells, oxidized low-density lipoproteins (oxLDL) and several immune complexes. S1P is probably formed at the inner leaflet of the plasma membrane in response to TNFα and other receptor activity-altering compounds called agonists. S1P, being present in low nanomolar concentrations in the cell, has to interact with high-affinity receptors that are capable of sensing their low levels. So far, the only identified receptors for S1P are the high-affinity G protein-coupled receptors (GPCRs), also known as S1P receptors (S1PRs). S1P is required to reach the extracellular side (outer leaflet) of the plasma membrane