Sphingosine 1‐Phosphate Signalling

Abstract

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.
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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.

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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]