A lysophosphatidic acid receptor lacking the PDZ-binding domain is constitutively active and stimulates cell proliferation

Biochim Biophys Acta. 2008 May;1783(5):748-59. doi: 10.1016/j.bbamcr.2007.11.013. Epub 2007 Dec 5.


Lysophosphatidic acid (LPA) is an extracellular signaling lipid that regulates cell proliferation, survival, and motility of normal and cancer cells. These effects are produced through G protein-coupled LPA receptors, LPA(1) to LPA(5). We generated an LPA(1) mutant lacking the SerValVal sequence of the C-terminal PDZ-binding domain to examine the role of this domain in intracellular signaling and other cellular functions. B103 neuroblastoma cells expressing the mutant LPA(1) showed rapid cell proliferation and tended to form colonies under serum-free conditions. The enhanced cell proliferation of the mutant cells was inhibited by exogenous expression of the plasmids inhibiting G proteins including G(betagamma), G(alphai) and G(alphaq) or G(alpha12/13), or treatment with pertussis toxin, phosphoinositide 3-kinase (PI3K) inhibitors or a Rho inhibitor. We confirmed that the PI3K-Akt and Rho pathways were intrinsically activated in mutant cells by detecting increases in phosphorylated Akt in western blot analyses or by directly measuring Rho activity. Interestingly, expression of the mutant LPA(1) in non-tumor mouse fibroblasts induced colony formation in a clonogenic soft agar assay, indicating that oncogenic pathways were activated. Taken together, these observations suggest that the mutant LPA(1) constitutively activates the G protein signaling leading to PI3K-Akt and Rho pathways, resulting in enhanced cell proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation*
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Mice
  • PDZ Domains*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Receptors, Lysophosphatidic Acid / antagonists & inhibitors
  • Receptors, Lysophosphatidic Acid / chemistry*
  • Receptors, Lysophosphatidic Acid / genetics
  • Sequence Deletion
  • rho GTP-Binding Proteins / metabolism


  • Receptors, Lysophosphatidic Acid
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • GTP-Binding Protein alpha Subunits, G12-G13
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • rho GTP-Binding Proteins