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Gene Review

LPAR2  -  lysophosphatidic acid receptor 2

Homo sapiens

Synonyms: EDG-4, EDG4, LPA receptor 2, LPA-2, LPA2, ...
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Disease relevance of EDG4

  • EDG4 receptor mRNA expression was increased 3-fold in differentiated thyroid cancer (p < 0.01), both papillary (p < 0.01) and follicular (p < 0.05), compared to normal thyroid or goiter [1].
  • Our results suggest that LPA acts as a potent stimulator of colon cancer progression, although the binding to LPA1 and LPA2 induces slightly different responses [2].
  • Both Edg2 and Edg4 were detected in ovarian cancer cells; however, only Edg2 was present in normal ovarian surface epithelial cells and IOSE-29 cells [3].
  • The Ca2+ mobilization by Edg2 and Edg4 was further characterized in stable transfectants of rat HTC4 hepatoma cells [4].
  • In comparison, colorectal cancers expressed LPA1 mRNA at a significantly lower level (0.3-fold; P<0.05), and LPA2 mRNA at a significantly higher level (three-fold; P<0.05), as compared with normal tissues [5].

High impact information on EDG4

  • NHERF2 specifically interacts with LPA2 receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta3 activation [6].
  • We show that immature and mature DCs express the mRNA for different LPA receptors such as endothelial differentiation gene (EDG)-2, EDG-4, and EDG-7 [7].
  • Lysophosphatidic acid-induced Ca2+ mobilization requires intracellular sphingosine 1-phosphate production. Potential involvement of endogenous EDG-4 receptors [8].
  • The amino acid sequence of the EDG7 protein is 53.7 and 48.8% identical to those of the human functional LPA receptors EDG2 and EDG4, respectively, previously identified [9].
  • In PC12 cells, EDG4 but not EDG2 or EDG7 mediated the activation of MAP kinase by LPA [9].

Chemical compound and disease context of EDG4


Biological context of EDG4


Anatomical context of EDG4


Associations of EDG4 with chemical compounds

  • Other LPA receptors, EDG4 but not EDG2, transduced the Ca(2+) response by LPA when expressed in Sf9 cells [9].
  • Induction of protein growth factor systems in the ovaries of transgenic mice overexpressing human type 2 lysophosphatidic acid G protein-coupled receptor (LPA2) [17].
  • The coincident production of inositol phosphates and the inhibition of Ca2+ mobilization by the phospholipase C inhibitor U73122 strongly suggested that Edg2 and Edg4 mobilize Ca2+ through inositol trisphosphate generated by phospholipase C activation [4].
  • N-Palmitoyl-L-serine-phosphoric acid and N-palmitoyl-L-tyrosine-phosphoric acid, which had been previously shown to be antagonists for Xenopus laevis LPA receptors, did not antagonize the Ca2+-mobilizing effects of Edg2 and Edg4 [4].
  • The oleoyloxy-substituted cyclic phosphonate 4 had unique receptor-selective properties as a ligand, showing partial activation of the LPA2 GPCR and weak antagonism of the LPA1 GPCR [18].

Physical interactions of EDG4

  • LPA-2 binds specifically and with high affinity (Ki ~ 0.6 x 10-10 M) to leptin receptor and is a potent inhibitor of its functions in rabbit endometrial cells [16].

Regulatory relationships of EDG4


Other interactions of EDG4

  • We further assessed mRNA expression of high-affinity receptors EDG2 and EDG4 in 14 normal thyroids, 29 papillary thyroid cancers, 7 follicular thyroid cancers and 13 goiters by quantitative RT-PCR [1].
  • A human cDNA encoding a G protein-coupled receptor, designated Edg4, was identified by searching the GenBankTM for homologs of the human Edg2 LPA receptor [11].
  • We also found that LPA2 interacts with Na+/H+ exchanger regulatory factor 2 (NHERF2) [10].
  • We found that the normal retina has a baseline expression of the LPA receptors, EDG-2 and EDG-4, which are significantly upregulated in the inner layers in response to ischemia [19].

Analytical, diagnostic and therapeutic context of EDG4

  • Northern blots revealed that two edg4 mRNA transcripts of 1.8 and 8 kilobases are distributed very differently from edg2 mRNAs in adult human tissues and several cancer cell lines [11].
  • The molecular cloning of three high-affinity lysophosphatidic acid receptors, LPA1, LPA2, and LPA3, provides a platform for developing receptor type-selective ligands [20].
  • In 48 (57%) out of 84 cases, enhanced expression of LPA2 protein was confirmed in carcinoma cells as compared with normal mammary epithelium by immunohistochemistry [21].
  • Southern-blot analysis, cloning, and sequencing of the ZmIpk gene from lpa2 revealed that the lpa2-1 allele is caused by the genomic sequence rearrangement in the ZmIpk locus and the lpa2-2 allele has a nucleotide mutation that generated a stop codon in the N-terminal region of the ZmIpk open reading frame [22].


  1. Lysophosphatidic acid, a novel lipid growth factor for human thyroid cells: over-expression of the high-affinity receptor edg4 in differentiated thyroid cancer. Schulte, K.M., Beyer, A., Köhrer, K., Oberhäuser, S., Röher, H.D. Int. J. Cancer (2001) [Pubmed]
  2. Lysophosphatidic acid (LPA) enhances the metastatic potential of human colon carcinoma DLD1 cells through LPA1. Shida, D., Kitayama, J., Yamaguchi, H., Okaji, Y., Tsuno, N.H., Watanabe, T., Takuwa, Y., Nagawa, H. Cancer Res. (2003) [Pubmed]
  3. Lysophosphatidic acid induction of vascular endothelial growth factor expression in human ovarian cancer cells. Hu, Y.L., Tee, M.K., Goetzl, E.J., Auersperg, N., Mills, G.B., Ferrara, N., Jaffe, R.B. J. Natl. Cancer Inst. (2001) [Pubmed]
  4. Recombinant human G protein-coupled lysophosphatidic acid receptors mediate intracellular calcium mobilization. An, S., Bleu, T., Zheng, Y., Goetzl, E.J. Mol. Pharmacol. (1998) [Pubmed]
  5. Aberrant expression of lysophosphatidic acid (LPA) receptors in human colorectal cancer. Shida, D., Watanabe, T., Aoki, J., Hama, K., Kitayama, J., Sonoda, H., Kishi, Y., Yamaguchi, H., Sasaki, S., Sako, A., Konishi, T., Arai, H., Nagawa, H. Lab. Invest. (2004) [Pubmed]
  6. NHERF2 specifically interacts with LPA2 receptor and defines the specificity and efficiency of receptor-mediated phospholipase C-beta3 activation. Oh, Y.S., Jo, N.W., Choi, J.W., Kim, H.S., Seo, S.W., Kang, K.O., Hwang, J.I., Heo, K., Kim, S.H., Kim, Y.H., Kim, I.H., Kim, J.H., Banno, Y., Ryu, S.H., Suh, P.G. Mol. Cell. Biol. (2004) [Pubmed]
  7. The influence of lysophosphatidic acid on the functions of human dendritic cells. Panther, E., Idzko, M., Corinti, S., Ferrari, D., Herouy, Y., Mockenhaupt, M., Dichmann, S., Gebicke-Haerter, P., Di Virgilio, F., Girolomoni, G., Norgauer, J. J. Immunol. (2002) [Pubmed]
  8. Lysophosphatidic acid-induced Ca2+ mobilization requires intracellular sphingosine 1-phosphate production. Potential involvement of endogenous EDG-4 receptors. Young, K.W., Bootman, M.D., Channing, D.R., Lipp, P., Maycox, P.R., Meakin, J., Challiss, R.A., Nahorski, S.R. J. Biol. Chem. (2000) [Pubmed]
  9. Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid. Bandoh, K., Aoki, J., Hosono, H., Kobayashi, S., Kobayashi, T., Murakami-Murofushi, K., Tsujimoto, M., Arai, H., Inoue, K. J. Biol. Chem. (1999) [Pubmed]
  10. LPA2 receptor mediates mitogenic signals in human colon cancer cells. Yun, C.C., Sun, H., Wang, D., Rusovici, R., Castleberry, A., Hall, R.A., Shim, H. Am. J. Physiol., Cell Physiol. (2005) [Pubmed]
  11. Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid. An, S., Bleu, T., Hallmark, O.G., Goetzl, E.J. J. Biol. Chem. (1998) [Pubmed]
  12. Cell density-dependent expression of EDG family receptors and mesangial cell proliferation: role in lysophosphatidic acid-mediated cell growth. Xing, Y., Ganji, S.H., Noh, J.W., Kamanna, V.S. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  13. Dual mechanisms for lysophosphatidic acid stimulation of human ovarian carcinoma cells. Hu, Y.L., Albanese, C., Pestell, R.G., Jaffe, R.B. J. Natl. Cancer Inst. (2003) [Pubmed]
  14. Differential effects of sphingosine 1-phosphate and lysophosphatidic acid on endothelial cells. Panetti, T.S. Biochim. Biophys. Acta (2002) [Pubmed]
  15. Lysophospholipid mediators of immunity and neoplasia. Huang, M.C., Graeler, M., Shankar, G., Spencer, J., Goetzl, E.J. Biochim. Biophys. Acta (2002) [Pubmed]
  16. A peptide derived from the human leptin molecule is a potent inhibitor of the leptin receptor function in rabbit endometrial cells. Gonzalez, R.R., Leavis, P.C. Endocrine (2003) [Pubmed]
  17. Induction of protein growth factor systems in the ovaries of transgenic mice overexpressing human type 2 lysophosphatidic acid G protein-coupled receptor (LPA2). Huang, M.C., Lee, H.Y., Yeh, C.C., Kong, Y., Zaloudek, C.J., Goetzl, E.J. Oncogene (2004) [Pubmed]
  18. Synthesis of cyclic phosphonate analogues of (lyso)phosphatidic acid using a ring-closing metathesis reaction. Zhang, H., Tsukuhara, R., Tigyi, G., Prestwich, G.D. J. Org. Chem. (2006) [Pubmed]
  19. EDG receptors as a potential therapeutic target in retinal ischemia-reperfusion injury. Savitz, S.I., Dhallu, M.S., Malhotra, S., Mammis, A., Ocava, L.C., Rosenbaum, P.S., Rosenbaum, D.M. Brain Res. (2006) [Pubmed]
  20. Activity of 2-substituted lysophosphatidic acid (LPA) analogs at LPA receptors: discovery of a LPA1/LPA3 receptor antagonist. Heise, C.E., Santos, W.L., Schreihofer, A.M., Heasley, B.H., Mukhin, Y.V., Macdonald, T.L., Lynch, K.R. Mol. Pharmacol. (2001) [Pubmed]
  21. Over-expression of lysophosphatidic acid receptor-2 in human invasive ductal carcinoma. Kitayama, J., Shida, D., Sako, A., Ishikawa, M., Hama, K., Aoki, J., Arai, H., Nagawa, H. Breast Cancer Res. (2004) [Pubmed]
  22. The maize low-phytic acid mutant lpa2 is caused by mutation in an inositol phosphate kinase gene. Shi, J., Wang, H., Wu, Y., Hazebroek, J., Meeley, R.B., Ertl, D.S. Plant Physiol. (2003) [Pubmed]
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