Trends in Cell Biology
Volume 22, Issue 1, January 2012, Pages 50-60
Journal home page for Trends in Cell Biology

Review
Sphingosine-1-phosphate signaling and its role in disease

https://doi.org/10.1016/j.tcb.2011.09.003Get rights and content

The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) is now recognized as a critical regulator of many physiological and pathophysiological processes, including cancer, atherosclerosis, diabetes and osteoporosis. S1P is produced in cells by two sphingosine kinase isoenzymes, SphK1 and SphK2. Many cells secrete S1P, which can then act in an autocrine or paracrine manner. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. More recently, it was shown that S1P also has important intracellular targets involved in inflammation, cancer and Alzheimer's disease. This suggests that S1P actions are much more complex than previously thought, with important ramifications for development of therapeutics. This review highlights recent advances in our understanding of the mechanisms of action of S1P and its roles 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.).

References (103)

  • T.K. Ghosh

    Sphingosine 1-phosphate generated in the endoplasmic reticulum membrane activates release of stored calcium

    J. Biol. Chem.

    (1994)
  • M. Mattie

    Sphingosine-1-phosphate, a putative second messenger, mobilizes calcium from internal stores via an inositol trisphosphate-independent pathway

    J. Biol. Chem.

    (1994)
  • P. Xia

    Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-alpha signaling

    J. Biol. Chem.

    (2002)
  • M. Artal-Sanz et al.

    Prohibitin and mitochondrial biology

    Trends Endocrinol. Metab.

    (2009)
  • H. Chi

    Sphingosine-1-phosphate and immune regulation: trafficking and beyond

    Trends Pharmacol. Sci.

    (2011)
  • A. Salas

    Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A

    Blood

    (2011)
  • S.W. Paugh

    A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia

    Blood

    (2008)
  • C. Loveridge

    The sphingosine kinase 1 inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole induces proteasomal degradation of sphingosine kinase 1 in mammalian cells

    J. Biol. Chem.

    (2010)
  • G.M. Deevska et al.

    The twists and turns of sphingolipid pathway in glucose regulation

    Biochimie

    (2011)
  • T.E. Fox

    Circulating sphingolipid biomarkers in models of type 1 diabetes

    J. Lipid Res.

    (2011)
  • T. Imasawa

    Blockade of sphingosine 1-phosphate receptor 2 signaling attenuates streptozotocin-induced apoptosis of pancreatic beta-cells

    Biochem. Biophys. Res. Commun.

    (2010)
  • I. Reines

    Topical application of sphingosine-1-phosphate and FTY720 attenuate allergic contact dermatitis reaction through inhibition of dendritic cell migration

    J. Invest. Dermatol.

    (2009)
  • S. Tsunemi

    Effects of the novel immunosuppressant FTY720 in a murine rheumatoid arthritis model

    Clin. Immunol.

    (2010)
  • Y. Chiba

    SKI-II, an inhibitor of sphingosine kinase, ameliorates antigen-induced bronchial smooth muscle hyperresponsiveness, but not airway inflammation, in mice

    J. Pharmacol. Sci.

    (2010)
  • A.S. Awad

    Chronic sphingosine 1-phosphate 1 receptor activation attenuates early-stage diabetic nephropathy independent of lymphocytes

    Kidney Int.

    (2011)
  • H.J. Kim

    Fingolimod and related compounds in a spontaneous autoimmune polyneuropathy

    J. Neuroimmunol.

    (2009)
  • F. Niessen

    Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality

    Blood

    (2009)
  • A. Olivera et al.

    Sphingosine-1-phosphate as a second messenger in cell proliferation induced by PDGF and FCS mitogens

    Nature

    (1993)
  • O. Cuvillier

    Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate

    Nature

    (1996)
  • S. Spiegel et al.

    The outs and the ins of sphingosine-1-phosphate in immunity

    Nat. Rev. Immunol.

    (2011)
  • S.M. Pitson

    Regulation of sphingosine kinase and sphingolipid signaling

    Trends Biochem. Sci.

    (2010)
  • T.M. Leclercq

    Guanine nucleotides regulate sphingosine kinase 1 activation by eukaryotic elongation factor 1A and provide a mechanism for eEF1A-associated oncogenesis

    Oncogene

    (2011)
  • N.C. Hait

    Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate

    Science

    (2009)
  • G.M. Strub

    Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration

    FASEB J.

    (2011)
  • S.E. Schnitzer

    Hypoxia enhances sphingosine kinase 2 activity and provokes sphingosine-1-phosphate-mediated chemoresistance in A549 lung cancer cells

    Mol. Cancer Res.

    (2009)
  • B.K. Wacker

    Hypoxic preconditioning-induced cerebral ischemic tolerance: role of microvascular sphingosine kinase 2

    Stroke

    (2009)
  • S.R. Schwab et al.

    Finding a way out: lymphocyte egress from lymphoid organs

    Nat. Immunol.

    (2007)
  • V. Brinkmann

    Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis

    Nat. Rev. Drug Discov.

    (2010)
  • J.G. Cyster

    B cell follicles and antigen encounters of the third kind

    Nat. Immunol.

    (2010)
  • C.N. Jenne

    T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow

    J. Exp. Med.

    (2009)
  • S.M. Pitson et al.

    Regulation of stem cell pluripotency and neural differentiation by lysophospholipids

    Neurosignals

    (2009)
  • E. Camerer

    Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice

    J. Clin. Invest.

    (2009)
  • E.Q. Scherer

    Tumor necrosis factor-alpha enhances microvascular tone and reduces blood flow in the cochlea via enhanced sphingosine-1-phosphate signaling

    Stroke

    (2010)
  • K. Sato

    Critical role of ABCA1 transporter in sphingosine 1-phosphate release from astrocytes

    J. Neurochem.

    (2007)
  • P. Mitra

    Role of ABCC1 in export of sphingosine-1-phosphate from mast cells

    Proc. Natl. Acad. Sci. U.S.A.

    (2006)
  • A. Kawahara

    The sphingolipid transporter spns2 functions in migration of zebrafish myocardial precursors

    Science

    (2009)
  • S.R. Schwab

    Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients

    Science

    (2005)
  • E.V. Berdyshev

    Intracellular S1P generation is essential for S1P-induced motility of human lung endothelial cells: role of sphingosine kinase 1 and S1P lyase

    PLoS ONE

    (2011)
  • J.T. Bagdanoff

    Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932)

    J. Med. Chem.

    (2010)
  • S. Spiegel et al.

    Sphingosine-1-phosphate: an enigmatic signalling lipid

    Nat. Rev. Mol. Cell Biol.

    (2003)
  • Cited by (0)

    View full text