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Sphingosine-1-phosphate: an enigmatic signalling lipid

Key Points

  • Sphingosine-1-phosphate (S1P) levels in cells are regulated by the balance between its synthesis, which is catalysed by sphingosine kinases (SphKs), and degradation, which is catalysed by specific S1P phosphatases (SPPs) and an S1P lyase (Spl). The genes encoding all of these enzymes have now been cloned and their regulation is an important area of investigation.

  • Sphingolipid metabolites have important roles in regulating stress responses. Some clues about this come from studies in yeast.

  • The relative cellular balance between ceramide and sphingosine, which are both associated with growth arrest and apoptosis, versus S1P, which is proliferative and anti-apoptotic, can be considered as a kind of rheostat that determines whether cells live or die.

  • Regulation of cellular calcium levels is crucial to almost all physiological processes. This regulation is an important function of S1P, which seems to be conserved throughout evolution.

  • There are five specific S1P receptors that couple to different G proteins and regulate many downstream signalling pathways. The biological functions of S1P are now known to depend on the relative expression of these receptors.

  • Crosstalk back and forth between G-protein-coupled receptors, such as those that S1P functions as the ligand for, and other types of cell-surface receptors is an important mechanism that allows cells to integrate many external signals to specifically regulate physiological responses.

  • It is not known exactly how external stimuli increase SphK1 activity but some recent studies indicate that it might be phosphorylated or translocated to membranes where its substrate, sphingosine, resides.

  • The list of growth factors, cytokines, agonists, and so on, that are reported to stimulate SphK1 and increase the formation of S1P is lengthy and growing rapidly. New molecular approaches should help sort out those responses that are really crucial for normal and pathophysiology.

Abstract

The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions. In higher eukaryotes, S1P is the ligand for a family of five G-protein-coupled receptors. These S1P receptors are differentially expressed, coupled to various G proteins, and regulate angiogenesis, vascular maturation, cardiac development and immunity, and are important for directed cell movement.

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Figure 1: Formation and degradation of S1P.
Figure 2: The sphingolipid rheostat: a conserved stress regulator.
Figure 3: S1P regulates calcium homeostasis in plants, yeast and mammals.
Figure 4: S1P is a ligand for five G-protein-coupled receptors.
Figure 5: S1P, through S1P receptors, regulates important physiological processes.
Figure 6: Crosstalk of VEGF and S1P signalling.
Figure 7: Transactivation of EDG1/S1P1 and PDGF-directed cell movement.

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Acknowledgements

We apologize that out of more than 650 citations in PubMed to S1P, we cited only 91. The authors also gratefully acknowledge the generous support of the National Institutes of Health and the Department of the Army.

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Correspondence to Sarah Spiegel.

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DATABASES

<i>Saccharomyces</i> Genome Database

BST1

Dpl1

Lbp1

Lcb3

Lcb4

Lcb5

SwissProt

EDG1

EDG3

EDG5

EDG6

EDG8

RPK118

Slp

SphK1

SphK2

SPP1

SPP2

TRAF-2

VEGFR-2

FURTHER INFORMATION

Sarah Spiegel's laboratory

Glossary

MITOCHONDRIAL OR INTRINSIC DEATH PATHWAY

The pathway that leads to death through the release, by stress-induced signals, of cytochrome c and other apoptogenic factors from the mitochondrial intermembrane space.

SPHINGOMYELINASE

An enzyme that catalyses the hydrolysis of sphingomyelin to ceramide (N-acylsphingosine) and choline phosphate.

CASPASES

A family of intracellular cysteine endopeptidases that have a crucial role in inflammation and mammalian apoptosis. They cleave proteins at specific aspartic acid residues.

PHOSPHOLIPASE C

A phosphoric diester hydrolase that splits the bond between the phosphorus atom and the oxygen atom at C1 of the glycerol moiety of a glycerophospholipid.

STOMATA

The pores in the epidermis of plants, in particular in the leaves, through which gaseous exchange occurs.

GUARD CELLS

Cells that are found on the underside of plant leaves, which pair up to form stomata, or leaf pores. Guard cells control the size of the stomata, and so, in turn, regulate gas exchange in the leaf.

G-PROTEIN-COUPLED RECEPTOR

A seven-helix transmembrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.

HETEROTRIMERIC G PROTEIN

A component of receptor-mediated activation or inhibition of adenylyl cyclase and other second messenger systems.

PARAXIAL CELLS

Cells of a region of the mesoderm, which is known as the paraxial mesoderm, that is adjacent to the notochord. The paraxial mesoderm becomes segmented rostrocaudally to give rise to the somites early in development.

PERICYTE

A support cell of the capillaries. Pericytes are known as smooth muscle cells in larger vessels.

IMMUNOMODULATOR

Any agent that alters the extent of the immune response to an antigen.

LYMPHOPENIA

A decrease in the number of lymphocytes in the blood, which might occur in various diseases.

DOMINANT-NEGATIVE

A defective protein that retains interaction abilities and so distorts or competes with normal proteins.

SMALL INTERFERING RNA

(siRNA). Short (21–23mers) sequences of double-stranded RNA that are used in RNA interference, a process by which the expression of homologous genes is silenced through degradation of their cognate mRNA.

PERTUSSIS TOXIN

A mixture of proteins that is produced by Bordetella pertussis. It causes the persistent activation of Gi proteins by catalysing the ADP-ribosylation of the α-subunit.

PHORBOL ESTERS

Polycyclic esters that are isolated from croton oil. The most common is phorbol myristoyl acetate (PMA, also known as 12,13-tetradecanoyl phorbol acetate or TPA). They are potent co-carcinogens or tumour promoters because they mimic diacylglycerol, thereby irreversibly activating protein kinase C.

PHOX HOMOLOGY DOMAIN

A domain that is similar in function to pleckstrin homology domains. It has an affinity for certain phosphorylated phospholipids.

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Spiegel, S., Milstien, S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4, 397–407 (2003). https://doi.org/10.1038/nrm1103

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