Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors

Sphingosine I-phosphate (S1P) is stored in and released from platelets in r esponse to cell activation. However, recent studies show that it is also re leased from a number of cell types, where it can function as a paracrine/au tocrine signal to regulate cell proliferation, differentiation, survival, a nd motility. This review discusses the role of SIP in cellular regulation, both at the molecular level and in terms of health and disease. The main bi ochemical routes for SIP synthesis (sphingosine kinase) and degradation (S1 P lyase and SIP phosphatase) are described. The major focus is on the abili ty of S1P to bind to a novel family of G-protein-coupled receptors (endothe lial differentiation gene [EDG]-1, -3, -5, -6, and -8) to elicit signal tra nsduction (via G(q)- G(i)-, G(12)- G(13)-, and Rho-dependent routes). Effec tor pathways regulated by S1P are divergent, such as extracellular signal-r egulated kinase, p38 mitogen-activated protein kinase, phospholipases C and D, adenylyl cyclase, and focal adhesion kinase, and occur in multiple cell types, such as immune cells, neurones, smooth muscle, etc. This provides a molecular basis for the ability of S1P to act as a pleiotropic bioactive l ipid with an important role in cellular regulation. We also give an account of the expanding role for SIP in health and disease; in particular, with r egard to its role in atherosclerosis, angiogenesis, cancer, and inflammatio n. Finally, we describe future directions for SIP research and novel approa ches whereby S1P signalling can be manipulated for therapeutic intervention in disease. (C) 2000 Elsevier Science Inc. All rights reserved.