Sphingosine 1-phosphate signalling and termination at lipid phosphate receptors

Sphingosine 1-phosphate (S1P) is a polar lysophospholipid metabolite that is stored in platelets and released upon their activation. However, diverse stimuli such as growth factors, cytokines, G-protein coupled receptor (GPCR) agonists and antigens have been shown to increase sphingosine kinase activity and S1P formation in other cell types, such as smooth muscle. Indeed, S1P has been implicated in the regulation of several important cellular processes, such as proliferation, differentiation, apoptosis and migration in these cells. Over the past few years, there has been a major advance in our understanding of how S1P can act as an intercellular mediator by binding to a new class of G-protein coupled receptors to regulate cell function. This review focuses on the enzymatic regulation of S1P formation and degradation and its interaction with a novel tethered receptor complex containing the S1P receptor (S1P(1)) and the platelet-derived growth factor (PDGF) beta receptor. This tethered receptor complex enables coincident integrative signalling to p42/p44 MAPK. This is compared with a sequential model in which PDGF promotes S1P release, which in turn acts on S1P(1) to promote Rac signalling.