Lysophosphatidic acid stimulates the G-protein-coupled receptor EDG-1 as a low affinity agonist

EDG-1, an inducible G-protein-coupled receptor from vascular endothelial cells, is a high affinity receptor for sphingosine I-phosphate (SPP) (Lee, M-J., van Brocklyn, J. R., Thangada, S., Liu, C. H., Hand, A. R., Menzeleev, R., Spiegel, S., and Hla, T. (1998) Science 279, 1552-1555). In this study, we show that lysophosphatidic acid (LPA), a platelet-derived bioactive lipid structurally related to SPP, is an agonist for EDG-1. LPA binds to EDG-1 receptor with an apparent K-d of 2.3 mu M. In addition, LPA binding to EDG-1 induces receptor phosphorylation, mitogen-activated protein kinase activation, as well as Rho-dependent morphogenesis and P-cadherin expression. These data suggest that LPA is a low-affinity agonist for EDG-1. Activation of the endothelial receptor EDG-1 by platelet-derived lipids LPA and SPP may be important in thrombosis and angiogenesis, conditions in which critical platelet-endothelial interactions occur.