Export and functions of sphingosine-1-phosphate

Abstract

The sphingolipid metabolite, sphingosine-1-phosphate (S1P), has emerged as a critical player in a number of fundamental biological processes and is important in cancer, angiogenesis, wound healing, cardiovascular function, atherosclerosis, immunity and asthma, among others. Activation of sphingosine kinases, enzymes that catalyze the phosphorylation of sphingosine to S1P, by a variety of agonists, including growth factors, cytokines, hormones, and antigen, increases intracellular S1P. Many of the biological effects of S1P are mediated by its binding to five specific G protein-coupled receptors located on the cell surface in an autocrine and/or paracrine manner. Therefore, understanding the mechanism by which intracellularly generated S1P is released out of cells is both interesting and important. In this review, we will discuss how S1P is formed and released. We will focus particularly on the current knowledge of how the S1P gradient between tissues and blood is maintained, and the role of ABC transporters in S1P release.

Fig. 1

Formation, secretion, and actions of S1P. Many growth factors, including EGF, bind to a tyrosine kinase receptor, to stimulate and translocate SphK1 to the plasma membrane where its substrate sphingosine (sph) resides. This leads to spatially restricted formation of S1P that can be exported out of cells by ABC transporter family members. S1P can then bind to its receptors on the same or neighboring cells (S1PR) to stimulate G-protein regulated signaling pathways.