Role of LPA4/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.
Lee
Zendra
Z
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Cheng
Ching-Ting
CT
Zhang
Helen
H
Subler
Mark A
MA
Wu
Jinhua
J
Mukherjee
Abir
A
Windle
Jolene J
JJ
Chen
Ching-Kang
CK
Fang
Xianjun
X
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism; D011983:Receptors, Purinergic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014018:Tissue Distribution; D020744:rac GTP-Binding Proteins / Q000378:metabolism
C523574:Lpar4 protein, mouse; D008246:Lysophospholipids; D020033:Protein Isoforms; D049368:Receptors, Lysophosphatidic Acid; D011983:Receptors, Purinergic; D051057:Proto-Oncogene Proteins c-akt; D020744:rac GTP-Binding Proteins; C032881:lysophosphatidic acid