Trends in Cell Biology
ReviewSphingosine-1-phosphate signaling and its role in disease
Section snippets
S1P: a signaling molecule
Like glycerophospholipids, sphingolipids are ubiquitous components of mammalian membranes that are metabolized to form signaling molecules. It is now recognized that sphingolipid metabolites play important roles in regulation of many cellular processes important for health and disease. One of the most important of these metabolites is sphingosine-1-phosphate (S1P, Figure 1). It has been 20 years since the discovery that S1P is a signaling molecule that regulates cell growth [1] and suppresses
Localized production of S1P
S1P is formed by the phosphorylation of sphingosine, the backbone of sphingolipids, by two kinases, sphingosine kinase 1 and 2 (SphK1 and SphK2). S1P levels are tightly controlled both by the enzymes that produce its substrate sphingosine, by the SphKs themselves and by the enzymes that degrade S1P, which include S1P lyase (SPL), two S1P-specific phosphatases and three lipid phosphate phosphatases.
Numerous agonists activate SphK1, including growth factors, hormones, proinflammatory cytokines,
S1P acts extracellularly though cell surface receptors
There are five specific cell surface G-protein-coupled receptors for S1P, termed S1PR1–5, all with low nM Kd values. Differential signaling induced by binding of S1P to these receptors is due to distinct, though sometimes overlapping, coupling to diverse heterotrimeric G proteins (Figure 1). These receptors have been implicated in a variety of developmental and disease-related processes. For example, S1PR1 activation plays a crucial role in the trafficking of immune cells [14]. The pro-drug
S1P is an intracellular messenger
Many lines of evidence point to an intracellular role for S1P, which counteracts apoptosis mediated by its pro-apoptotic precursor ceramide and SphK1 is suggested to play a crucial role in this ‘sphingolipid rheostat’ (Figure 1) (reviewed in [33]). Moreover, early studies demonstrated that S1P could induce calcium release from the ER 34, 35, 36, although no target has been conclusively identified. For nearly two decades, no bona fide intracellular targets of S1P had been identified. Recently,
S1P in disease
As summarized above, the SphKs/S1P/S1PRs axis is implicated in regulation of many physiological processes, drawing attention to their potential functions in pathophysiology and diseases (Figure 2). The important and rapidly emerging area of targeting S1PRs in inflammation and multiple sclerosis, has been extensively reviewed recently 3, 15, 42. Therefore, we will focus on selected recent advances in understanding the role of S1P in cancer, atherosclerosis, diabetes and osteoporosis.
Concluding remarks
The sum of a plethora of in vitro and in vivo studies in the decades since S1P was first discovered to be a second messenger has taught us much about its mechanisms of action. We now understand why S1P is so important for regulation of many normal and pathophysiological processes. The successful development of the sphingosine analog FTY720, a pro-S1P mimetic, as a useful drug for treatment of multiple sclerosis has proven that it is possible and beneficial to specifically target S1P signaling
Acknowledgements
We apologize to authors whose work has not been cited here owing to space limitations. This work was supported by US National Institutes of Health grants R01CA61774, R37GM043880, R01AI50094 and 1U19AI077435 (to S.S.).
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