Sphingosine 1‐Phosphate Signalling


Studies of the last two decades have clearly established that sphingosine 1‐phosphate (S1P), considered for many years a mere by‐product of the membrane phospholipid sphingomyelin catabolism, serves indeed as powerful signalling molecule. Intensive research in the field have clarified the complexity of S1P metabolism as well as the multifaceted mechanism of action of this potent lysophospholipid, which acts both as intracellular mediator, capable of regulating the properties of different proteins, and high‐affinity ligand of five specific G‐protein coupled receptors, termed S1P1‐S1P5. In parallel, it has been progressively disclosed the versatile biological activity endowed by S1P, which appears to be crucially implicated in the control of many key parameters, ranging from cell proliferation to cell motility and survival. Besides to act as ubiquitous cellular mediator, notably, circulating S1P plays a significant physiological role. S1P concentrations are high in blood and lymph but low in tissues. S1P chemotactic gradients are indeed essential for lymphocyte egress and physiological cell trafficking.

Key Concepts

  • S1P is generated via phosphorylation of the amino alcohol sphingosine catalysed by sphingosine kinase (SphK), which exists in two isoforms: SphK1 and SphK2.
  • Ceramide, either synthesised de novo or formed by sphingomyelin catabolism, is the precursor of sphingosine, released by ceramidase‐dependent deacylation.
  • Intracellular production of S1P in under the control of a wide array of hormones, neurotransmitters, cytokines and growth factors.
  • S1P is a powerful bioactive sphingolipid, which acts both as intracellular mediator and ligand of specific G‐protein coupled receptors, named S1P receptors (S1PR).
  • There are five specific S1PR that couple to different G proteins and regulate many downstream signalling pathways. The biological functions of S1P depend on the relative expression of these receptors.
  • In many instances, S1P acts via inside‐out signalling, intracellularly generated in response to extracellular cues, is exported outside the cell and binds S1PR in paracrine or autocrine fashion.
  • S1P1 is crucial for the regulation of lymphocyte trafficking, its downregulation causes redistribution of the immune cells to secondary lymphoid tissues, resulting in the depletion from the circulation.
  • S1P concentrations are elevated in plasma and lymph compared to the interstitial fluid of tissues. This S1P gradient is essential for many of the physiologic functions provided by extracellular S1P.

Keywords: sphingosine 1‐phosphate; S1P receptors; G‐protein coupled receptors; sphingosine kinases; ceramide; HDL ; ApoM ; S1P transporters

Figure 1. Sphingolipid metabolism. Ceramide produced by de novo synthesis in the endoplasmic reticulum is transported to the Golgi complex to produce glycosphingolipids. In addition, ceramide is generated by the hydrolysis of sphingomyelin. Enzymes involved in sphingolipid metabolism are abbreviated in blue. CDase: ceramidase; CERS: ceramide synthase; DES: dihydroceramide desaturase; GBA: glucosylceramidase; KDSR: 3‐keto dihydrosphingosine reductase; SMase: sphingomyelinase; SMS: sphingomyelin synthase; SphK: sphingosine kinase; SPP: sphingosine 1‐phosphate phosphatase; SPT: serine‐palmitoyltransferase; UGCG: UDP‐glucose ceramide glucosyltransferase.
Figure 2. Chemical structures of principal bioactive sphingolipids. In the figure, R represents a fatty acid residue.
Figure 3. Metabolism of S1P. S1P synthesis and degradation are depicted. Enzymes and transporters involved in S1P metabolism are shown in blue.
Figure 4. S1P signalling. Extracellular and intracellular mechanism of actions of S1P are shown: S1P can act as ligand of a family of G protein‐coupled receptors (S1PR), and, in addition, can function inside the cell interacting with intracellular targets.
Figure 5. S1P receptors. S1P receptors (S1P1 –5) are coupled to different G‐proteins. Multiple downstream signalling pathways are depicted. AC: adenylate cyclase; Akt: protein kinase B; ERK: extracellular signal‐regulated kinases, PI3K: phosphatidylinositide 3‐kinase; PLC: phospholipase C.


Alvarez SE , Harikumar KB , Hait NC , et al. (2010) Sphingosine‐1‐phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2. Nature 465 (7301): 1084–1088.

An S , Zheng Y and Bleu T (2000) Sphingosine 1‐phosphate‐induced cell proliferation, survival, and related signaling events mediated by G protein‐coupled receptors Edg3 and Edg5. Journal of Biological Chemistry 275 (1): 288–296.

Bektas M , Allende ML , Lee BG , et al. (2010) Sphingosine 1‐phosphate lyase deficiency disrupts lipid homeostasis in liver. Journal of Biological Chemistry 285 (14): 10880–10889.

Bernacchioni C , Turano P and Donati C (2017) Targeting sphingosine kinase 1 localization as novel target for ovarian cancer therapy. Translational Cancer Research 6 (Suppl 7): S1277–S1280.

Blaho VA , Galvani S , Engelbrecht E , et al. (2015) HDL‐bound sphingosine‐1‐phosphate restrains lymphopoiesis and neuroinflammation. Nature 523 (7560): 342–346.

Blaho VA and Hla T (2014) An update on the biology of sphingosine 1‐phosphate receptors. Journal of Lipid Research 55 (8): 1596–1608.

Brinkmann V , Billich A , Baumruker T , et al. (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nature Reviews. Drug Discovery 9 (11): 883–897.

Cencetti F , Bernacchioni C , Nincheri P , Donati C and Bruni P (2010) Transforming growth factor‐beta1 induces transdifferentiation of myoblasts into myofibroblasts via up‐regulation of sphingosine kinase‐1/S1P3 axis. Molecular Biology of the Cell 21 (6): 1111–1124.

Cencetti F , Bernacchioni C , Tonelli F , et al. (2013) TGFbeta1 evokes myoblast apoptotic response via a novel signaling pathway involving S1P4 transactivation upstream of Rho‐kinase‐2 activation. The FASEB Journal 27 (11): 4532–4546.

Christoffersen C , Obinata H , Kumaraswamy SB , et al. (2011) Endothelium‐protective sphingosine‐1‐phosphate provided by HDL‐associated apolipoprotein M. Proceedings of the National Academy of Sciences of the United States of America 108 (23): 9613–9618.

Cuvillier O , Pirianov G , Kleuser B , et al. (1996) Suppression of ceramide‐mediated programmed cell death by sphingosine‐1‐phosphate. Nature 381 (6585): 800–803.

Ding G , Sonoda H , Yu H , Kajimoto T , et al. (2007) Protein kinase D‐mediated phosphorylation and nuclear export of sphingosine kinase 2. Journal of Biological Chemistry 282 (37): 27493–27502.

Donati C , Cencetti F and Bruni P (2013) New insights into the role of sphingosine 1‐phosphate and lysophosphatidic acid in the regulation of skeletal muscle cell biology. Biochimica et Biophysica Acta 1831 (1): 176–184.

Dusaban SS , Chun J , Rosen H , Purcell NH and Brown JH (2017) Sphingosine 1‐phosphate receptor 3 and RhoA signaling mediate inflammatory gene expression in astrocytes. Journal of Neuroinflammation 14 (1): 111.

Golfier S , Kondo S , Schulze T , Takeuchi T , et al. (2010) Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine‐1‐phosphate receptor S1P4. The FASEB Journal 24 (12): 4701–4710.

Gräler MH , Grosse R , Kusch A , et al. (2003) The sphingosine 1‐phosphate receptor S1P4 regulates cell shape and motility via coupling to Gi and G12/13. Journal of Cellular Biochemistry 89 (3): 507–519.

Hait NC , Allegood J , Maceyka M , et al. (2009) Regulation of histone acetylation in the nucleus by sphingosine‐1‐phosphate. Science 325 (5945): 1254–1257.

Hannun YA and Obeid LM (2018) Sphingolipids and their metabolism in physiology and disease. Nature Reviews. Molecular Cell Biology 19 (3): 175–191.

Hanson MA , Roth CB , Jo E , et al. (2012) Crystal structure of a lipid G protein‐coupled receptor. Science 335 (6070): 851–855.

Himmel HM , Meyer Zu Heringdorf D , Graf E , et al. (2000) Evidence for Edg‐3 receptor‐mediated activation of I(K.ACh) by sphingosine‐1‐phosphate in human atrial cardiomyocytes. Molecular Pharmacology 58 (2): 449–454.

Hou J , Chen Q , Wu X , et al. (2017) S1PR3 signaling drives bacterial killing and is required for survival in bacterial sepsis. American Journal of Respiratory and Critical Care Medicine 196 (12): 1559–1570.

Ishii I , Fukushima N , Ye X and Chun J (2004) Lysophospholipid receptors: signaling and biology. Annual Review of Biochemistry 73: 321–354.

Jaillard C , Harrison S , Stankoff B , et al. (2005) Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. Journal of Neuroscience 25 (6): 1459–1469.

Kono M , Mi Y , Liu Y , et al. (2004) The sphingosine‐1‐phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. The Journal of Biological Chemistry 279 (28): 29367–29373.

Kono M , Belyantseva IA , Skoura A , et al. (2007) Deafness and stria vascularis defects in S1P2 receptor‐null mice. The Journal of Biological Chemistry 282 (14): 10690–10696.

Książek M , Chacinska M , Chabowski A and Baranowski M (2015) Sources, metabolism, and regulation of circulating sphingosine‐1‐phosphate. The Journal of Lipid Research 56 (7): 1271–1281.

Lee MJ , Van Brocklyn JR , Thangada S , et al. (1998) Sphingosine‐1‐phosphate as a ligand for the G protein‐coupled receptor EDG‐1. Science 279 (5356): 1552–1555.

Levkau B (2015) HDL‐S1P: cardiovascular functions, disease‐associated alterations, and therapeutic applications. Frontiers in Pharmacology 6: 243.

Maceyka M , Milstien S and Spiegel S (2009) Sphingosine‐1‐phosphate: the Swiss army knife of sphingolipid signaling. The Journal of Lipid Research 50 (Suppl): S272–S276.

Malek RL , Toman RE , Edsall LC , et al. (2001) Nrg‐1 belongs to the endothelial differentiation gene family of G protein‐coupled sphingosine‐1‐phosphate receptors. The Journal of Biological Chemistry 276 (8): 5692–5699.

Meacci E , Cencetti F , Donati C , et al. (2003) Down‐regulation of EDG5/S1P2 during myogenic differentiation results in the specific uncoupling of sphingosine 1‐phosphate signalling to phospholipase D. Biochimica et Biophysica Acta 1633 (3): 133–142.

Nishi T , Kobayashi N , Hisano Y , Kawahara A and Yamaguchi A (2014) Molecular and physiological functions of sphingosine 1‐phosphate transporters. Biochimica et Biophysica Acta 1841 (5): 759–765.

Nofer JR , van der Giet M , Tolle M , et al. (2004) HDL induces NO‐dependent vasorelaxation via the lysophospholipid receptor S1P3. Journal of Clinical Investigation 113 (4): 569–581.

Novgorodov AS , El‐Alwani M , Bielawski J , Obeid LM and Gudz TI (2007) Activation of sphingosine‐1‐phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. The FASEB Journal 21 (7): 1503–1514.

Obeid LM , Linardic CM , Karolak LA and Hannun YA (1993) Programmed cell death induced by ceramide. Science 259 (5102): 1769–1771.

Olivera A and Spiegel S (1993) Sphingosine‐1‐phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 365 (6446): 557–560.

Panneer Selvam S , De Palma RM , Oaks JJ , et al. (2015) Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation. Science Signaling 8 (381): ra58.

Patmanathan SN , Wang W , Yap LF , Herr DR and Paterson IC (2017) Mechanisms of sphingosine 1‐phosphate receptor signalling in cancer. Cellular Signalling 34: 66–75.

Pitson SM (2011) Regulation of sphingosine kinase and sphingolipid signaling. Trends in Biochemical Sciences 36 (2): 97–107.

Romero‐Guevara R , Cencetti F , Donati C and Bruni P (2015) Sphingosine 1‐phosphate signaling pathway in inner ear biology. New therapeutic strategies for hearing loss? Frontiers in Aging Neuroscience 7: 60.

Rosen H , Gonzalez‐Cabrera PJ , Sanna MG and Brown S (2009) Sphingosine 1‐phosphate receptor signaling. Annual Review of Biochemistry 78: 743–768.

Schwab SR and Cyster JG (2007) Finding a way out: lymphocyte egress from lymphoid organs. Nature Immunology 8 (12): 1295–1301.

Strub GM , Paillard M , Liang J , et al. (2011) Sphingosine‐1‐phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. The FASEB Journal 25 (2): 600–612.

Takabe K , Paugh SW , Milstien S and Spiegel S (2008) “Inside‐out” signaling of sphingosine‐1‐phosphate: therapeutic targets. Pharmacological Reviews 60 (2): 181–195.

Terai K , Soga T , Takahashi M , et al. (2003) Edg‐8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS. Neuroscience 116 (4): 1053–1062.

Tidhar R and Futerman AH (2013) The complexity of sphingolipid biosynthesis in the endoplasmic reticulum. Biochimica et Biophysica Acta 1833 (11): 2511–2518.

Vu TM , Ishizu AN , Foo JC , et al. (2017) Mfsd2b is essential for the sphingosine‐1‐phosphate export in erythrocytes and platelets. Nature 550 (7677): 524–528.

Walzer T , Chiossone L , Chaix J , et al. (2007) Natural killer cell trafficking in vivo requires a dedicated sphingosine 1‐phosphate receptor. Nature Immunology 8 (12): 1337–1344.

Wang W , Graeler MH and Goetzl EJ (2005) Type 4 sphingosine 1‐phosphate G protein‐coupled receptor (S1P4) transduces S1P effects on T cell proliferation and cytokine secretion without signaling migration. The FASEB Journal 19 (12): 1731–1733.

Yang AH , Ishii I and Chun J (2002) In vivo roles of lysophospholipid receptors revealed by gene targeting studies in mice. Biochimica et Biophysica Acta 1582 (1–3): 197–203.

Zheng W , Kollmeyer J , Symolon H , et al. (2006) Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochimica et Biophysica Acta 1758 (12): 1864–1884.

Further Reading

Bruni P and Donati C (2013) Role of sphingosine 1‐phosphate in skeletal muscle cell biology. Handbook of Experimental Pharmacology 216: 457–467.

Donati C and Bruni P (2006) Sphingosine 1‐phosphate regulates cytoskeleton dynamics: implications in its biological response. Biochimica et Biophysica Acta 1758 (12): 2037–2048.

Kihara A (2014) Sphingosine 1‐phosphate is a key metabolite linking sphingolipids to glycerophospholipids. Biochimica et Biophysica Acta 1841 (5): 766–772.

Maceyka M , Harikumar KB , Milstien S and Spiegel S (2012) Sphingosine‐1‐phosphate signalling and its role in disease. Trends in Cell Biology 22 (1): 50–60.

Pulkoski‐Gross MJ , Donaldson JC and Obeid LM (2015) Sphingosine‐1‐phosphate metabolism: a structural perspective. Critical Reviews in Biochemistry and Molecular Biology 50 (4): 298–313.

Pyne S and Pyne NJ (2000) Sphingosine 1‐phosphate signalling in mammalian cells. The Biochemical Journal 349 (Pt 2): 385–402.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Bernacchioni, Caterina, Cencetti, Francesca, Donati, Chiara, and Bruni, Paola(Feb 2019) Sphingosine 1‐Phosphate Signalling. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028300]