QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 12, 5435-5445, December 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E08-03-0316v1 19/12/5435    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, Z. Articles by Fang, X. Search for Related Content PubMed PubMed Citation Articles by Lee, Z. Articles by Fang, X.

Role of LPA₄/p2y9/GPR23 in Negative Regulation of Cell Motility

Zendra Lee^*, Ching-Ting Cheng^*, Helen Zhang, Mark A. Subler, Jinhua Wu^*, Abir Mukherjee^*, Jolene J. Windle, Ching-Kang Chen^*, and Xianjun Fang^*

Departments of *Biochemistry and Molecular Biology and Human Genetics, and Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298

Submitted March 26, 2008; Revised August 20, 2008; Accepted September 25, 2008
Monitoring Editor: Carl-Henrik Heldin

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. LPA₄/p2y9/GPR23, a member of the purinergic receptor family, and recently identified LPA₅/GPR92 and 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.

Address correspondence to: Xianjun Fang (xfang{at}vcu.edu).

Abbreviations used: LPA, lysophosphatidic acid; GPCR, G protein–coupled receptor; KO, knockout; MEF, mouse embryonic fibroblast.

This article has been cited by other articles:

				Z. Pamuklar, L. Federico, S. Liu, M. Umezu-Goto, A. Dong, M. Panchatcharam, Z. Fulerson, E. Berdyshev, V. Natarajan, X. Fang, et al. Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis J. Biol. Chem., March 13, 2009; 284(11): 7385 - 7394. [Abstract] [Full Text] [PDF]