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© The Rockefeller University Press, 0021-9525/1998//229 $5.00
The Journal of Cell Biology, Volume 142, Number 1, , 1998 229-240

Articles

Dual Actions of Sphingosine-1-Phosphate: Extracellular through the Gi-coupled Receptor Edg-1 and Intracellular to Regulate Proliferation and Survival



James R. Van Brocklyn*, Menq-Jer Lee||, Ramil Menzeleev*, Ana Olivera*, Lisa Edsall*, Olivier Cuvillier*, Dianne M. Thomas*,{ddagger}, Peter J.P. Coopman§, Shobha Thangada||, Catherine H. Liu||, Timothy Hla||, and Sarah Spiegel*

* Department of Biochemistry and Molecular Biology, {ddagger} Tumor Biology Training Program, § Department of Cell Biology, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007; and || Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut 06030

Sphingosine-1-phosphate (SPP), a bioactive lipid, acts both intracellularly and extracellularly to cause pleiotropic biological responses. Recently, we identified SPP as a ligand for the G protein–coupled receptor Edg-1 (Lee, M.-J., J.R. Van Brocklyn, S. Thangada, C.H. Liu, A.R. Hand, R. Menzeleev, S. Spiegel, and T. Hla. 1998. Science. 279:1552–1555). Edg-1 binds SPP with remarkable specificity as only sphinganine-1-phosphate displaced radiolabeled SPP, while other sphingolipids did not. Binding of SPP to Edg-1 resulted in inhibition of forskolin-stimulated cAMP accumulation, in a pertussis toxin–sensitive manner. In contrast, two well-characterized biological responses of SPP, mitogenesis and prevention of apoptosis, were clearly unrelated to binding to Edg-1 and correlated with intracellular uptake. SPP also stimulated signal transduction pathways, including calcium mobilization, activation of phospholipase D, and tyrosine phosphorylation of p125FAK, independently of edg-1 expression. Moreover, DNA synthesis in Swiss 3T3 fibroblasts was significantly and specifically increased by microinjection of SPP. Finally, SPP suppresses apoptosis of HL-60 and pheochromocytoma PC12 cells, which do not have specific SPP binding or expression of Edg-1 mRNA. Conversely, sphinganine-1-phosphate, which binds to and signals via Edg-1, does not have any significant cytoprotective effect. Thus, SPP is a prototype for a novel class of lipid mediators that act both extracellularly as ligands for cell surface receptors and intracellularly as second messengers.

Key Words: sphingolipids • mitogenesis • G proteins • apoptosis • signal transduction

Abbreviations used in this paper: BrdU, bromodeoxyuridine; C2-ceramide, N-acetyl sphingosine; C8-cer-1-P, N-octanoyl ceramide-1-phosphate; fura-2/AM, fura-2/acetoxy-methyl ester; IBMX, 3-isobutyl-1-methylxanthine; LPA, lysophosphatidic acid; MAP, mitogen-activating protein; RIgG, rabbit IgG; p125FAK, p125 focal adhesion kinase; SPC, sphingosylphosphorylcholine; SPP, sphingosine-1-phosphate.

J.R. Van Brocklyn, M.-J. Lee, T. Hla, and S. Spiegel contributed equally to this study.

Address all correspondence to Dr. Sarah Spiegel, Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, 357 Basic Science Building, 3900 Reservoir Road NW, Washington, DC 20007. Tel.: (202) 687-1432; Fax: (202) 687-7186. E-mail: spiegel{at}biochem1.basic-sci.georgetown.edu


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