Role of LPA4/p2y9/GPR23 in Negative Regulation of Cell Motility.
Mol Biol Cell. 2008 Oct 8;
Authors: Lee Z, Cheng CT, Zhang H, Subler MA, Wu J, Mukherjee A, Windle JJ, Chen CK, Fang X
Monitoring Editor: Carl-Henrik Heldin Lysophosphatidic acid (LPA) is a ligand of multiple G protein-coupled receptors. The LPA1-3 receptors are members of the endothelial cell differentiation gene (Edg) family. LPA4/p2y9/GPR23, a member of the purinergic receptor family, and recently identified LPA5/GPR92 and LPA6/p2y5 are structurally distant from the canonical Edg LPA receptors. Here we report targeted disruption of lpa4 in mice. Although LPA4-deficient mice displayed no apparent abnormalities, LPA4-deficient mouse embryonic fibroblasts (MEFs) were hypersensitive to LPA-induced cell migration. Consistent with negative modulation of the phosphatidylinositol 3 kinase pathway by LPA4, LPA4 deficiency potentiated Akt and Rac but decreased Rho activation induced by LPA. Reconstitution of LPA4 converted LPA4-negative cells into a less motile phenotype. In support of the biological relevance of these observations, ectopic expression of LPA4 strongly inhibited migration and invasion of human cancer cells. When coexpressed with LPA1 in B103 neuroblastoma cells devoid of endogenous LPA receptors, LPA4 attenuated LPA1-driven migration and invasion, indicating functional antagonism between the two subtypes of LPA receptors. These results provide genetic and biochemical evidence that LPA4 is a suppressor of LPA-dependent cell migration and invasion in contrast to the motility-stimulating Edg LPA receptors.
PMID: 18843048 [PubMed - as supplied by publisher]