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Chemokine Eskine CCR10, a Specific Receptor for the Receptor G

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Chemokine Eskine CCR10, a Specific Receptor for the Receptor G ● Cutting Edge: Identification of the Orphan Receptor G-Protein-Coupled Receptor 2 as CCR10, a Specific Receptor for the Chemokine ESkine1,2 David I. Jarmin,* Miriam Rits,* Dalena Bota,* Norma P. Gerard,* Gerard J. Graham,† Ian Clark-Lewis,‡ and Craig Gerard3* (1, 2). Chemokines mediate their functions through their binding to A number of orphan G-protein coupled receptors (GPR) have specific cell-surface receptors, and these receptors are members of been reported as putative chemokine receptors. One previ- the seven transmembrane spanning G protein-coupled-receptor ously reported orphan receptor is an incomplete PCR clone, (GPR)4 superfamily. To date, this interaction appears subfamily called GPR2. Here we report the cloning of full-length human specific, and receptors have been identified for CC chemokines (h)GPR2 and mouse (m)GPR2 cDNAs, and the identification of (CCR1–9), CXC (CXCR1–5), C (XCR1), and CX3C (CX3CR1) GPR2 as a receptor for a novel CC chemokine called ESkine. (1–6). In addition to the known chemokine/receptor pairings, a hGPR2 is expressed at high levels in testis and small intestine, number of orphan GPRs have been reported (7–9). Several che- and at lower levels in other tissues. mGPR2 was expressed at mokines have also been identified, for which the specific recep- high levels in small intestine, colon, lymph nodes, and Peyer’s tor(s) is not yet known (10–12). patches and at lower levels in thymus and spleen. Stimulation One orphan receptor previously reported as having homology to of L1.2/hGPR2 transfectants with hESkine induced their mi- known chemokine receptors is GPR2 (13). The GPR2 gene cloned gration and resulted in intracellular calcium mobilization. previously from human genomic DNA lacked an initiating methi- These results provide evidence that GPR2 is a specific receptor onine, suggesting the existence of an intron in the 5Ј region. No for ESkine. We propose that GPR2 be renamed as CCR10. positive data on the expression of GPR2 has been reported to date. The expression pattern of mGPR2/CCR10 suggests that it may Here we report that GPR2 is a specific receptor for the novel CC by guest on October 1, 2021. Copyright 2000 Pageant Media Ltd. play a role in the homing/trafficking of leukocytes within in- chemokine known as ESkine/ALP/ILC/CTACK (14–17). ESkine testinal and lymphoid environments. The Journal of Immu- induced chemotaxis of the murine pre-B cell line L1.2, when trans- fected with human (h)GPR2. Moreover, calcium flux assays demon- nology, 2000, 164: 3460–3464. strated that hGPR2 and mouse (m)GPR2 transfectants responded to human or murine ESkine. Here we also report the low-level con- hemokines are believed to play a critical role in the traf- stitutive expression of GPR2 RNA in a variety of tissues and, in ficking, homing, and activation of leukocytes, as well as particular, higher levels of mGPR2 RNA expression in the intestine, C mediating a wide range of other functions (1). At present colon, lymph node, Peyer’s patches, spleen, and thymus. Previous reports have indicated that those chemokines and their receptors https://www.jimmunol.org they are classified into four separate subfamilies on the basis of the spacing of conserved cysteine residues within their N-terminal re- (namely EBI1-ligand chemokine (ELC)/secondary lymphoid tissue gions: these are known as the CC, CXC, C, and CX3C subfamilies chemokine (SLC)/CCR7, liver- and activation-regulated chemokine (LARC)/CCR6, and thymus-expressed chemokine (TECK)/CCR9), whose expression is relatively lymphoid restricted, appear to play crit- *Ina Sue Perlmutter Laboratory, Children’s Hospital, Harvard Medical School, Bos- ical roles in the homing and localization of leukocytes (18–20). ton, MA 02115; †The Beatson Institute for Cancer Research, Cancer Research Cam- Therefore, we speculate that GPR2 may also play a similar role. Using ‡ Downloaded from paign Laboratories, Glasgow, Scotland, United Kingdom; and Biomed Research Center, University of British Columbia, Vancouver, British Columbia, Canada the current nomenclature rules for chemokine receptors, we propose that GPR2 be designated as CCR10. Received for publication December 13, 1999. Accepted for publication February 2, 2000. The costs of publication of this article were defrayed in part by the payment of page Materials and Methods charges. This article must therefore be hereby marked advertisement in accordance Cloning and sequencing of human and mouse GPR2 cDNAs with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported in part by a grant from The Wellcome Trust, U.K. The full-length cDNA for hGPR2 was cloned from a CEMx 174 cell line (053125; to D.I.J.), National Institutes of Health Grant HL39579 (to C.G.), and by the (T cell/B cell hybrid) cDNA library, while the mGPR2 cDNA was cloned Rubenstein/Cable Fund at the Perlmutter Laboratory. from a Peyer’s patch cDNA library. The cDNA libraries were constructed 2 The sequences presented in this article have been submitted to GenBank under accession numbers AF215981 (hCCR10), AF215982, and AF215983 (mCCR10). 4 Abbreviations used in this paper: GPR, G-protein-coupled receptor, h, human; m, 3 Address correspondence and reprint requests to Dr. Craig Gerard, Ina Sue Perlmut- mouse; SLC, secondary lymphoid-tissue chemokine, ELC, EBI1-ligand chemokine; ter Laboratory, Enders Suite 144, Children’s Hospital, 320 Longwood Avenue, Bos- LARC, liver- and activation-regulated chemokine; TECK, thymus-expressed ton, MA 02115. E-mail address: [email protected] chemokine. Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 ● The Journal of Immunology 3461 FIGURE 1. A, Alignment of the predicted amino acid sequences of human and mouse GPR2. Transmembrane domains (TM) are outlined with lines above the corresponding amino acids. The eight additional N-terminal amino acids are indicated with a bold line. B, Schematic of mGPR2 cDNA clones. Two forms of mGPR2 are shown. Potential exons are indicated above boxes using the Superscript plasmid kit (Life Technologies, Grand Island, NY) twice with RPMI 1640/1% FBS and then used in mobilization studies. according to the manufacturer’s instructions. The cDNA libraries were Chemotaxis assays were also performed on untransfected L1.2 cells, screened with 32P-labeled PCR-derived probe fragments encoding the 5Ј hGPR2/L1.2 transfectants, or mGPR2 transfectants in Costar 5.0-␮m regions of hGPR2 and mGPR2 (human, 5Ј-GTTTCCTGGGCCATTAC-3Ј 24-well cluster transwells (Corning, Corning, NY) as described (21). The and 5Ј-ACAGCGTCGTTGGCCTTC-3Ј; mouse, 5Ј-GTCTCCTGGGGAC number of migrating cells was determined by comparison against a stan- by guest on October 1, 2021. Copyright 2000 Pageant Media Ltd. TTTAC-3Ј and 5[pime]-GCTGAAAGAAAGCGCAGG-3Ј). The murine dard curve derived from a dilution series of a known number of cells, and probe sequence was derived from an incomplete cDNA clone derived from the number of migrated cells was expressed as a percentage of the total a murine Th1 cDNA library (our unpublished data), whose sequence was number of input cells. homologous to the clone previously reported (13). Positive cDNA inserts were subcloned into the pcDNA 3 vector (Stratagene, La Jolla, CA) (hu- man, EcoRI and XbaI; mouse, NotI and XbaI) and sequenced fully. Results and Discussion Comparison of the hGPR2 sequence to known chemokine receptors Chemokines and cells suggests that this orphan receptor may be a putative chemokine re- Chemokines were purchased from PeproTech (Rocky Hill, NJ) or R&D ceptor. We examined the expression of mGPR2 RNA in various Systems (Minneapolis, MN). Mouse and human ESkine were chemically https://www.jimmunol.org mouse tissues and determined that it was expressed at low levels in the synthesized as previously described (14). hGPR2 and mGPR2 were trans- fected into the murine pre-B cell line L1.2 by electroporation, and stable thymus. This data prompted us to further characterize GPR2. transfectants were obtained after G418 selection, as described (21). Cloning of full-length hGPR2 and mGPR2 cDNAs Northern blot analysis Expression of mGPR2 RNA in the thymus suggested that hGPR2 Multiple tissue Northern blots (Clontech Laboratories, Palo Alto, CA) were would be expressed in human T cells. Therefore, we screened a probed with a 32P-labeled 5Ј hGPR2-specific DNA probe, according to the Downloaded from CEMx 174 cell cDNA library and identified several GPR2-like suppliers instructions. Total RNA from 4- to 8-wk-old BALB/c mouse tissues were stored in RNA Later (Ambion, Austin, TX) before their ex- clones. The nucleic sequence of one of these clones encoded an traction using the RNAqueous kit (Ambion). Next, 15 ␮g of each sample additional 8 aa at the amino terminus, compared with the previ- was electrophoresed on a denaturing formaldehyde-agarose gel and blotted ously published sequence of the hGPR2 gene (13) (Fig. 1A). In this onto Hybond N membranes (Amersham Pharmacia Biotech, Piscataway, report, it was speculated that there was an exon in the 5Ј terminal NJ). The membranes were prehybridized using an SDS/phosphate buffer before hybridization with a 32P-labeled 5Ј mGPR2-specific DNA probe, as region of hGPR2, and our data supports this conclusion. described (22). After washing, the blots were exposed to BioMax MR film Further analysis of mGPR2 RNA expression revealed a striking using BioMax MS intensifying screens (Eastman Kodak, Rochester, NJ). level of expression in Peyer’s patches (see below, and Fig. 2B). Therefore, we constructed a cDNA library from murine Peyer’s Chemotaxis and calcium mobilization patches. Two murine clones were identified and sequenced. Con- Calcium mobilization studies were performed on untransfected L1.2 cells, ceptual translation of one of the cDNA clones revealed that the hGPR2/L1.2 transfectants, or mGPR2 transfectants loaded with fura-2AM encoded protein was 8 aa longer than that previously reported in (Molecular Probes, Eugene, OR), as previously described (21).
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