J. Cell Biol., Volume 142, Number 1, July 13, 1998 229-240

Dual Actions of Sphingosine-1-Phosphate: Extracellular through the G_i-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,^* Peter J.P. Coopman,^§ Shobha Thangada, Catherine H. Liu, Timothy Hla, and Sarah Spiegel^*

^* Department of Biochemistry and Molecular Biology,  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 p125^FAK, 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.

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