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Oncogene. 2004 Aug 19;23(37):6299-303.
G protein-coupled receptors GPR4 and TDAG8 are oncogenic and overexpressed in human cancers.
Sin WC1, Zhang Y, Zhong W, Adhikarakunnathu S, Powers S, Hoey T, An S, Yang J.
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Abstract
The GPR4 subfamily consists of four G protein-coupled receptors that share significant sequence homology. In addition to GPR4, this subfamily includes OGR1, TDAG8 and G2A. G2A has previously been shown to be a potent transforming oncogene for murine 3T3 cells. Here we show that GPR4 also malignantly transforms NIH3T3 cells and that TDAG8 malignantly transforms the normal mammary epithelial cell line NMuMG. Overexpression of GPR4 or TDAG8 in HEK293 cells led to transcriptional activation from SRE- and CRE-driven promoters, independent of exogenously added ligand. TDAG8 and GPR4 are also overexpressed in a range of human cancer tissues. Our results suggest that GPR4 and TDAG8 overexpression in human tumors plays a role in driving or maintaining tumor formation.
PMID: 15221007 [PubMed – indexed for MEDLINE]
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Differential proton sensitivity of related G protein [?]-coupled receptors T cell death-associated gene 8 [?] and G2Aexpressed in immune cells.

Radu CG, Nijagal A, McLaughlin J, Wang L, Witte ON
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.

G2A, T cell death-associated gene 8 [?] (TDAG8 [?]), ovarian cancer G protein-coupled receptor 1 (OGR1), and G protein-coupled receptor 4 (GPR4) form a group of structurally related G protein-coupled receptors (GPCRs) originally proposed to bind proinflammatory lipids. More recent studies have challenged the identification of lipid agonists for these GPCRs and have suggested that they function primarily as proton sensors. We compared the ability of these four receptors to modulate pH-dependent responses by using transiently transfected cell lines. In accordance with previously published reports, OGR1was found to evoke strong pH-dependent responses as measured by inositol phosphate accumulation. We also confirmed the pH-dependent cAMP production by GPR4 and TDAG8 [?]. However, we found the activity of the human G2A receptor and its mouse homolog to be significantly less sensitive to pH fluctuations as measured by inositol phosphate and cAMP accumulation. Sequence homology analysis indicated that, with one exception, the histidine residues that were previously shown to be important for pH sensing by OGR1, GPR4, and TDAG8 [?] were not conserved in the G2A receptor. We further addressed the pH-sensing properties of G2A and TDAG8 [?] in a cellular context where these receptors are coexpressed. In thymocytes and splenocytes explanted from receptor-deficient mice, TDAG8 [?] was found to be critical for pH-dependent cAMP production. In contrast, G2A was found to be dispensable for this process. We conclude that members of this GPCR [?] group exhibit differential sensitivity to extracellular protons, and that expression of TDAG8 [?] by immune cells may regulate responses in acidic microenvironments.

Proc. Natl. Acad. Sci. U.S.A. (2005)
PMID: 15665078 Fulltext – Related articles – Download citation

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