Role of LPA4/p2y9/GPR23 in negative regulation of cell motility

Mol Biol Cell. 2008 Dec;19(12):5435-45. doi: 10.1091/mbc.e08-03-0316. Epub 2008 Oct 8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / physiology*
  • Cells, Cultured
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Enzyme Activation
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Humans
  • Lysophospholipids / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Invasiveness
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Lysophosphatidic Acid / genetics
  • Receptors, Lysophosphatidic Acid / metabolism
  • Receptors, Purinergic / genetics
  • Receptors, Purinergic / metabolism*
  • Signal Transduction / physiology
  • Tissue Distribution
  • rac GTP-Binding Proteins / metabolism

Substances

  • Lpar4 protein, mouse
  • Lysophospholipids
  • Protein Isoforms
  • Receptors, Lysophosphatidic Acid
  • Receptors, Purinergic
  • Proto-Oncogene Proteins c-akt
  • rac GTP-Binding Proteins
  • lysophosphatidic acid