text: 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 to interact with S1PRs and launch typical GPCR signaling pathways.  However, the zwitterionic headgroup of S1P makes it unlikely to flip-flop spontaneously. To overcome this difficulty, the ATP-binding cassette (ABC) transporter C1 (ABCC1) serves as the "exit door" for S1P.  On the other hand, the cystic fibrosis transmembrane regulator (CFTR) serves as the means of entry for S1P into the cell.  In contrast to its low intracellular concentration, S1P is found in high nanomolar concentrations in serum where it is bound to albumin and lipoproteins.  Inside the cell, S1P can induce calcium release independent of the S1PRs—the mechanism of which remains unknown.  To date, the intracellular molecular targets for S1P are still unidentified.
  The SK1-S1P pathway has been extensively studied in relation to cytokine action, with multiple functions connected to effects of TNFα and IL-1 favoring inflammation.  Studies show that knockdown of key enzymes such as S1P lyase and S1P phosphatase increased prostaglandin production, parallel to increase of S1P levels. This strongly suggests that S1P is the mediator of SK1 action and not subsequent compounds.  Research done on endothelial and smooth muscle cells is consistent to the hypothesis that S1P has a crucial role in regulating endothelial cell growth, and movement.  Recent work on a sphingosine analogue, FTY270, demonstrates its ability to act as a potent compound that alters the activity of S1P receptors (agonist).  FTY270 was further verified in clinical tests to have roles in immune modulation, such as that on multiple sclerosis.  This highlights the importance of S1P in the regulation of lymphocyte function and immunity.  Most of the studies on S1P are used to further understand diseases such as cancer, arthritis and inflammation, diabetes, immune function and neurodegenerative disorders.