Disease relevance of Edg2

• Blocking LPA1 receptors by pertussis toxin and the inhibition of epithelial growth factor receptor tyrosine kinase significantly attenuated the protective effect [1].
• Small interfering RNA against LPA1 receptors specifically inhibited the receptor mRNA expression and abolished the migration response to ascites [2].
• A significant level of LPA1 receptor mRNA is expressed in pancreatic cancer cells with high migration activity to ascites but not in cells with low migration activity [2].
• Here we report that silencing of the type 1 LPA receptor (LPA(1)) in cancer cells blocks the production of tumor-derived cytokines that are potent activators of osteoclast-mediated bone destruction and significantly reduces the progression of osteolytic bone metastases [3].
• Northern blot analysis showed that most ovarian cancer cell lines express Edg-2 [4].

High impact information on Edg2

• Reverse-transcription polymerase chain reaction (RT-PCR) was applied to examine the expression of LPA-receptor transcripts [1].
• Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex [5].
• To assess its function, vzg-1 was overexpressed in a cell line from which it was cloned, inducing serum-dependent "cell rounding." Lysophosphatidic acid (LPA), a bioactive lipid present in high concentrations in serum, reproduced the effect seen with serum alone [5].
• The first identified LPA receptor gene, lp(A1)/vzg-1/edg-2, was previously shown to have remarkably enriched embryonic expression in the cerebral cortex and dorsal olfactory bulb and postnatal expression in myelinating glia including Schwann cells [6].
• Characterization of lpa(2) (Edg4) and lpa(1)/lpa(2) (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa(2) [7].

Chemical compound and disease context of Edg2

• Lysophosphatidic acid (LPA) in malignant ascites stimulates motility of human pancreatic cancer cells through LPA1 [2].

Biological context of Edg2

• Unlike lpA1 and lpA2, which contain multiple coding exons, all lpB members contained a single coding exon [8].
• At all postnatal ages, vzg-1 expression was concentrated in and around developing white matter tracts, and its expansion, peak, and subsequent downregulation closely paralleled the progress of myelination [9].
• Consistent with this, vzg-1 mRNA expression was reduced by 40% in the brains of jimpy mice, which exhibit aberrant oligodendrocyte differentiation and cell death [9].
• A cDNA homologous to that encoding sheep Edg2 protein was cloned from a human lung cDNA library [10].
• HEK293 cells expressing the human Edg2 protein showed an elevated response to lysophosphatidic acid (LPA) in a serum response element reporter gene assay, which was LPA concentration-dependent and specific to LPA compared to other lysophospholipids [10].

Anatomical context of Edg2

• Together with our characterization of vzg-1 during cortical neurogenesis, these data suggest distinct pre- and postnatal roles for LPA in the development of neurons and oligodendrocytes and implicate lysophospholipid signaling as a potential regulator of myelination [9].
• Vzg-1 expression was undetectable by in situ hybridization at birth, but reappeared in the hindbrain during the 1st postnatal week [9].
• Over-expression of human Edg2 in CHO cells correlated with increases in specific binding of [3H]-LPA [10].
• Human blood unactivated CD4+ T cells express predominant ly Edg-4 LPA R over marginal levels of Edg-2 LPA R, as assessed by semiquantitative PCR and Western blots [11].
• We found highest expression levels of each of the three LPA receptor genes in adult mouse testes, relatively high expression levels of lp(A2) and lp(A3) in kidney, and moderate expression of lp(A2) and lp(A3) in lung [12].

Associations of Edg2 with chemical compounds

• Superfusion of hippocampal slices revealed that basal levels of tyrosine, aspartate and glutamate release were significantly increased while K+ -evoked release of glutamate and GABA were significantly decreased in lpa1(-/-) mice [13].
• Fast cyclic voltammetry measurements in the dorsal raphe nucleus demonstrated significant decreases in electrically evoked 5-HT efflux in lpa1(-/-) mice [13].
• These findings indicate that plasma exudation induced by LPA is mediated by histamine release from mast cells via LPA receptor(s), presumably LPA1 and/or LPA3, coupled to G(i/o) proteins [14].
• In addition, LPA and angiotensin II were also capable of inducing LPA1 receptor phosphorylation, showing that LPA1 receptor can be subjected to homologous and heterologous desensitization [15].
• Developmental expression patterns of its first cloned receptor gene, lpA1/vzg-1 (Hecht et al., 1996; Fukushima et al., 1998) in the VZ suggested that functional LPA receptors were synthesized at these early times, and thus, LPA could be an earlier stimulus to VZ cells than the neurotransmitters GABA and L-glutamate [16].

Physical interactions of Edg2

• Three cognate G protein-coupled receptors encoded by lpa(1)/lp(A1)/Edg-2/Gpcr26, lpa(2)/lp(A2)/Edg-4, and lpa(3)/lp(A3)/Edg-7 mediate the cellular effects of LPA [7].

Regulatory relationships of Edg2

• Interestingly, the LPA1 receptor was co-expressed in DDC-treated livers with the stem cell antigen SCA-1, suggesting that this receptor may be associated with bone marrow-derived progenitors [17].

Other interactions of Edg2

• Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are extracellular ligands for a family of G protein-coupled receptors (GPCRs), LPA1/2/3 and S1P1/2/3/4/5 [18].
• In contrast, a dual LPA1/LPA3-receptor antagonist, VPC-12249, reduced I/R injury, but this protective effect was lost when the antagonist was coadministered with OMPT [19].
• Significant reduction in the number of implantation sites and uterine horns with implanted embryos was found after intrauterine injection of LPA-1 (1 of 22) vs. LPA-1Sc (11 of 15) and LPA-2 (3 of 17) vs. LPA-2Sc (14 of 16) [20].
• A single cell assay system was used to examine the functional interaction of the LPA receptor with G proteins in intact mouse fibroblasts, by measuring LPA-stimulated induction of the immediate-early gene, c-fos, as read out by a stably expressed fos-lacZ reporter gene [21].
• These findings suggest that rho p21 works as a link between the LPA receptor signal and the subsequent tyrosine phosphorylation and PI 3-kinase activation in these cells [22].

Analytical, diagnostic and therapeutic context of Edg2

• Here, we have investigated the subsequent reappearance of vzg-1 expression in the postnatal murine brain, by using in situ hybridization and northern blot analyses [9].
• Molecular cloning of the human Edg2 protein and its identification as a functional cellular receptor for lysophosphatidic acid [10].
• The vzg-1 cDNA hybridized to a 3.8-kb mRNA transcript and encoded a protein with a predicted molecular mass of 41-42 kD, confirmed by Western blot analysis [5].
• Southern blot analysis revealed that clone 4.9 is encoded by a single copy gene containing at least two separate exons [23].

References