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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.R800065-JLR200 on November 5, 2008

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Journal of Lipid Research, Vol. 50, S272-S276, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Signaling

Sphingosine-1-phosphate: the Swiss army knife of sphingolipid signaling

Michael Maceyka*, Sheldon Milstien{dagger} and Sarah Spiegel1,*

* Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298
{dagger} National Institute of Mental Health, Bethesda, MD 20892

Supported by National Institutes of Health Grants R37GM043880, RO1CA61774, RO1AI050094, and U19AI077435-018690 (SS) and the NIMH Intramural Research Program (SM).

Published, JLR Papers in Press, November 5, 2008.

1 To whom correspondence should be addressed. e-mail: sspiegel{at}vcu.edu


ABSTRACT

The sphingolipid metabolite sphingosine-1-phosphate (S1P) and the kinases that produce it have emerged as critical regulators of numerous fundamental biological processes important for health and disease. Activation of sphingosine kinases (SphKs) by a variety of agonists increases intracellular S1P, which in turn can be secreted out of the cell and bind to and signal through S1P receptors (S1PRs) in an autocrine and/or paracrine manner. Recent studies suggest that this "inside-out" signaling by S1P may play a role in many human diseases. As the roles of the S1PRs in cell and organismal physiology are discussed elsewhere in this volume, we focus this review mainly on recent reports showing how SphKs are activated and S1P reaches its receptors, the role of SphKs and S1P in regulating sphingolipid homeostasis, and the potential importance of the SphK/S1P axis as a therapeutic target in human diseases.

Supplementary key words ceramide • ceramide synthase • sphingosine kinase • sphingosine-1-phosphate phosphohydrolase • sphingosine-1-phosphate receptor

Abbreviations: S1P, sphingosine-1-phosphate; S1PR, S1P receptor; SphK, sphingosine kinase


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