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





* Department of Biochemistry and Molecular Biology, 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.
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
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