The Outs and the Ins of the Pleiotropic Lipid Mediator Sphingosine‐1‐Phosphate

Abstract

Sphingosine‐1‐phosphate (S1P) is now widely recognized as a bioactive sphingolipid metabolite that plays a key role in regulation of many fundamental cellular processes important for human health and diseases. Sphingosine kinases, which catalyze the phosphorylation of sphingosine to S1P, are central regulators of the cell fate determining sphingolipid rheostat. Activation of sphingosine kinases by a variety of agonists increases intracellular S1P, which in turn can function intracellularly, and importantly, be secreted out of the cell and act extracellularly by binding to and signaling through a family of specific S1P receptors in autocrine and/or paracrine manners. Recent studies suggest that this "inside‐out" signaling by S1P may play a role in cancer, atherosclerosis, inflammation, and autoimmune disorders such as multiple sclerosis. In this lecture, I will summarize progress made in understanding metabolism of S1P, mechanisms of sphingosine kinase activation, potential new intracellular targets of S1P, how S1P is exported out of cells to activate its receptors and their downstream signaling pathways, and examine relationships to multiple disease processes. I will also describe some recent preclinical and clinical trials of therapies targeting S1P signaling. Supported by NIH grants, R37GM043880, R01CA61774, R01AI50094, and 1U19AI077435.