Role of LPA 4 /p2y9/GPR23 in Negative Regulation of Cell Motility

Lysophosphatidic acid (LPA) is a ligand of multiple G protein–coupled receptors. The LPA 1–3 receptors are members of the endothelial cell differentiation gene (Edg) family. LPA 4 /p2y9/GPR23, a member of the purinergic receptor family, and recently identified LPA 5 /GPR92 and p2y5 are structurally distant from the canonical Edg LPA receptors. Here we report targeted disruption of lpa 4 in mice. Although LPA 4 -deficient mice displayed no apparent abnormalities, LPA 4 -deficient mouse embryonic fibroblasts (MEFs) were hypersensitive to LPA-induced cell migration. Consistent with negative modulation of the phosphatidylinositol 3 kinase pathway by LPA 4 , LPA 4 deficiency potentiated Akt and Rac but decreased Rho activation induced by LPA. Reconstitution of LPA 4 converted LPA 4 -negative cells into a less motile phenotype. In support of the biological relevance of these observations, ectopic expression of LPA 4 strongly inhibited migration and invasion of human cancer cells. When coexpressed with LPA 1 in B103 neuroblastoma cells devoid of endogenous LPA receptors, LPA 4 attenuated LPA 1 -driven migration and invasion, indicating functional antagonism between the two subtypes of LPA receptors. These results provide genetic and biochemical evidence that LPA 4 is a suppressor of LPA-dependent cell migration and invasion in contrast to the motility-stimulating Edg LPA receptors.