Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewSphingosine kinase, sphingosine-1-phosphate, and apoptosis
Section snippets
Sphingolipid metabolism
Sphingolipids are ubiquitous constituents of eukaryotic membranes characterized by the presence of an acylated sphingoid base, ceramide (Cer). Cer is deacylated by ceramidases, yielding a sphingoid base, the most common of these in mammals is sphingosine (Sph). In order for the sphingoid base to be catabolized, it must be phosphorylated on the 1-OH by Sph kinases (SphK). The product of this reaction, Sph-1-phosphate (S1P), is irreversibly degraded in the endoplasmic reticulum by S1P lyase to
SphK, the enzymes
The first mammalian SphK, murine or mSphK1, was cloned [29] based on tryptic peptides derived from highly purified rat SphK [30]. Two isoforms were cloned, termed mSphK1a and mSphK1b, that likely arose from alternative mRNA splicing and that differ by only a few amino acids at their amino-termini. Subsequently, human SphK1 was also cloned [31], [32], [33]. mSphK1 and hSphK1 have similar and broad adult tissue distributions, with mRNA being more highly expressed in brain, heart, lung, and
Activation of SphK
There is a rapidly growing list of agonists, especially growth and survival factors, that have been reported to increase SphK activity. These include ligands for G-protein coupled receptors (GPCR), including acetylcholine [41], [42], prosaposin [43], lysophosphatidic acid [44], formylmethionine peptide [45], and others [46], [47], [48]. Even S1P itself has been shown to activate SphK through a specific GPCR [49]. Agonists of growth factor receptor tyrosine kinases also mediate activation of
SphK and apoptosis
A number of studies demonstrate the pro-growth and anti-apoptotic effects of SphK. Perhaps the clearest of these involve the enforced expression of SphK1. Expression of SphK1 in NIH3T3, HEK293, and Jurkat T cells results in four- to eightfold increases in S1P levels but, somewhat paradoxically, almost 1000-fold increase in SphK activity measured in vitro [63]. The SphK1 overexpressing cells had decreased levels of Cer and Sph. Surprisingly, these cells still responded to PDGF like the vector
S1P and apoptosis
S1P was originally proposed to be an intracellular second messenger [83]. However, the demonstration that the endothelial differentiation gene-1 (EDG-1) family of GPCRs bind S1P has injected a note of caution into the interpretation of findings with exogenous S1P treatment of cells. Moreover, direct intracellular targets for S1P have yet to be identified. Complicating matters still further is the fact that S1P can be released from cells as an autocrine or paracrine signal [4]. Nonetheless,
S1P as an extracellular inhibitor of apoptosis
Although many studies support an intracellular site of action for the anti-apoptotic effects of S1P, there are some contradictory reports that propose an extracellular mechanism for S1P-induced cell survival and proliferation mediated by S1PRs. For example, nanomolar concentrations of S1P protected the T lymphoblastoma cell line Tsup-1 from Cer- and Fas-induced apoptosis as well as reduced levels of the pro-apoptotic protein Bax [104]. Transfection with antisense plasmids for S1P3/EDG-3 and S1P2
Acknowledgements
We thank the members of the Spiegel lab for their contributions to the studies that were quoted in this review. This work was supported by research grants from the National Institutes of Health (GM43880 and CA61774 to SS) and the Department of Defense (DAMD 17-02-1-0060 to SS) and postdoctoral fellowship (DAMD 7-02-1-0240 to MM). We apologize to those authors whose work could not be cited owing to space limitations.
References (107)
- et al.
Curr. Biol.
(2000) - et al.
Cell
(1999) - et al.
Trends Cell Biol.
(2000) - et al.
Trends Biochem. Sci.
(1999) - et al.
Biochim. Biophys. Acta
(1999) - et al.
J. Biol. Chem.
(2001) - et al.
Cell
(1995) - et al.
J. Biol. Chem.
(2001) - et al.
J. Biol. Chem.
(1986) - et al.
J. Biol. Chem.
(1986)
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
FEBS Lett.
Gene
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Biochim. Biophys. Acta
Life Sci.
J. Biol. Chem.
J. Biol. Chem.
Cell. Immunol.
Eur. J. Pharmacol.
FEBS Lett.
J. Biol. Chem.
Biochem. Biophys. Res. Commun.
Biochim. Biophys. Acta
J. Biol. Chem.
FEBS Lett.
J. Biol. Chem.
FEBS Lett.
Semin. Cell Dev. Biol.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Exp. Cell Res.
Curr. Opin. Cell Biol.
J. Biol. Chem.
Cited by (515)
Comprehensive metabolic profiling of dioxin-like compounds exposure in laying hens: Implications for toxicity assessment
2024, Journal of Environmental Sciences (China)The two-way immunotoxicity in native fish induced by exudates of Microcystis aeruginosa: Immunostimulation and immunosuppression
2024, Journal of Hazardous MaterialsSphingolipids and impaired hypoxic stress responses in Huntington disease
2023, Progress in Lipid ResearchProteomics analysis reveals three potential cacao target that interacts with Moniliophthora perniciosa NEP during witches broom disease
2023, Physiological and Molecular Plant Pathology