| Written | 2008-04 | Makoto Mark Taketo, Kenji Kawada |
| Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan |
| Identity |
| Alias_names | GPR9 |
| G protein-coupled receptor 9 | |
| chemokine (C-X-C motif) receptor 3 | |
| Alias_symbol (synonym) | CKR-L2 |
| CMKAR3 | |
| IP10-R | |
| MigR | |
| CD183 | |
| Other alias | CD182 |
| CXC-R3 | |
| CXCR-3 | |
| IP10 | |
| Mig-R | |
| HGNC (Hugo) | CXCR3 |
| LocusID (NCBI) | 2833 |
| Atlas_Id | 40224 |
| Location | Xq13.1 [Link to chromosome band Xq13] |
| Location_base_pair | Starts at 71615916 and ends at 71618517 bp from pter ( according to hg19-Feb_2009) [Mapping CXCR3.png] |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| Note | CXCR3 is a G protein-coupled receptor with selectivity for three chemokines, termed IP10 (CXCL10), Mig (CXCL9) and I-TAC (CXCL11). IP10, Mig and I-TAC belong to the structural subfamily of CXC chemokines, in which a single amino acid residue separates the first two of four highly conserved Cys residues. Binding of chemokines to CXCR3 induces cellular responses that are involved in leukocyte traffic, most notably integrin activation, cytoskeletal changes and chemotactic migration. A hallmark of CXCR3 is its prominent expression in in vitro cultured effector/memory T cells, and in T cells present in many types of inflamed tissues. In addition, IP10, Mig and I-TAC are commonly produced by local cells in inflammatory lesions, suggesting that CXCR3 and its chemokines participate in the recruitment of inflammatory cells. |
| DNA/RNA |
| Note | CXCR3-A is a receptor for CXCL9, CXCL10 and CXCL11 and mediates the proliferation of human mesangial cells. CXCR3-B is a receptor for CXCL4 and also mediates the inhibitory activities of CXCL9, CXCL10 and CXCL11 on the growth of human microvascular endothelial cells. CXCR3-B may play a role in angiogenesis. |
 | |
| The CXCR3 gene generates two distinct mRNAs. | |
| Description | Alternative splicing of the CXCR3 gene generates two distinct chemokine receptors. The CXCR3 gene generates two distinct mRNAs, resulting from alternative splicing of three different exons. The already known CXCR3, renamed CXCR3-A,results from splicing of a single intron. The first exon encodes 4 amino acids and the second exon encodes the remaining 312 amino acids. The recently identified splicing variant, CXCR3-B,results from an alternative splicing between the same donor site used by the known CXCR3-A and a novel acceptor site localized 233 base pairs upstream of the CXCR3-A acceptor site. This novel exon (exon2) encodes 51 different amino acids, which are selectively expressed in CXCR3-B. |
| Transcription | CXCR3-A and CXCR3-B transcripts of 1.6 and 1.8 kb, respectively. |
| Protein |
| Description | Size: 368 amino acids; 40660 Da. |
| Expression | CXCR3-A and CXCR3-B are mainly expressed in the heart, kidney, liver and skeletal muscle. CXCR3-A is also expressed in the placenta. |
| Localisation | Cell membrane; Multi-pass membrane protein. |
| Function | Dijkstra et al. showed that human CCL21, in the absence of its primary receptor, CCR7, is a functional ligand for CXCR3, inducing chemotaxis in adult microglial cells, but not in kidney epithelial cells. CCL21 signaling through CXCR3 depends on the cellular background in which CXCR3 is expressed. Lasagni et al. found that both CXCR3-A and CXCR3-B bound CXCL9, CXCL10, and CXCL11, but only CXCR3-B bound CXCL4 (PF4), following expression in a microvascular endothelial cell line. Overexpression of CXCR3-A induced an increase in endothelial cell survival, whereas overexpression of CXCR3-B upregulated apoptotic pathways. CXCR3B-specific monoclonal antibodies reacted with neoplastic tissue endothelial cells, providing evidence that CXCR3-B is expressed in vivo and may account for the angiostatic effects of CXC chemokines. |
| Implicated in |
| Note | |
| Entity | Melanoma |
| Prognosis | Forty primary melanomas were analyzed. 57% of the tumors expressed CXCR3 and 35% expressed CXCR4 on the melanoma cells. Co-expression of both CXCR3 and CXCR4 conferred a significantly poorer outcome similar to the expression of CXCR4 alone. |
| Oncogenesis | Several human melanoma cell lines as well as melanoma cells on macroscopically infiltrated lymph nodes express the chemokine receptors CXCR3 and CXCR4. In a murine model with B16F10 melanoma cells, reduced CXCR3 expression by antisense RNA showed significantly reduced metastatic activities to lymph nodes. |
| Entity | Breast cancer |
| Oncogenesis | Activation of Ras in MDA-MB-435 and MCF-7 breast cancer cells promotes CXCL10 expression and down-regulates CXCR3-B expression to promote tumor cell proliferation. In a murine model of metastatic breast cancer, a small molecular weight antagonist of CXCR3 inhibits lung metastasis. |
| Entity | Colon cancer |
| Prognosis | In 92 colon cancer samples, 31 samples (33.7%) expressed CXCR3 on cancer epithelial cells. The patients with CXCR3-positive tumors had a significantly poorer prognosis than those with CXCR3-negative tumors. In addition, the patients with tumors dobly positive for CXCR3 and CXCR4 had a significantly poorer prognosis than those with tumors positive only for CXCR4 or doubly negative. |
| Oncogenesis | In a murine model of metastatic colon cancer, overexpression of CXCR3 significantly promotes lymph node metastasis, although metastasis to the liver or lung was unaffected. |
| Entity | Renal cell carcinoma |
| Oncogenesis | Real-time RT-PCR analysis showed that expression levels of I-TAC, Mig, and CXCR3 in RCC tissues were greater 14.9 times, 30.3 times, and 9.9 times, respectively, compared with the levels in the corresponding normal kidney tissues. |
| Entity | B-cell Lymphoma |
| Oncogenesis | CXCR3 expression was seen in 37 of 39 cases of chronic lymphocytic leukemia / small lymphocytic lymphoma, whereas mantle cell lymphoma (30 cases), follicular lymphoma (27 cases) and small noncleaved cell lymphoma (8 cases) were negative in all but 2 cases. |
| Bibliography |
| Ras-induced modulation of CXCL10 and its receptor splice variant CXCR3-B in MDA-MB-435 and MCF-7 cells: relevance for the development of human breast cancer. |
| Datta D, Flaxenburg JA, Laxmanan S, Geehan C, Grimm M, Waaga-Gasser AM, Briscoe DM, Pal S. |
| Cancer Res. 2006 Oct 1;66(19):9509-18. |
| PMID 17018607 |
| Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells. |
| Dwinell MB, Lugering N, Eckmann L, Kagnoff MF. |
| Gastroenterology. 2001 Jan;120(1):49-59. |
| PMID 11208713 |
| The expression of the chemokine receptor CXCR3 and its ligand, CXCL10, in human breast adenocarcinoma cell lines. |
| Goldberg-Bittman L, Neumark E, Sagi-Assif O, Azenshtein E, Meshel T, Witz IP, Ben-Baruch A. |
| Immunol Lett. 2004 Mar 29;92(1-2):171-8. |
| PMID 15081542 |
| The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia. |
| Jones D, Benjamin RJ, Shahsafaei A, Dorfman DM. |
| Blood. 2000 Jan 15;95(2):627-32. |
| PMID 10627472 |
| Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes. |
| Kawada K, Hosogi H, Sonoshita M, Sakashita H, Manabe T, Shimahara Y, Sakai Y, Takabayashi A, Oshima M, Taketo MM. |
| Oncogene. 2007 Jul 12;26(32):4679-88. Epub 2007 Feb 5. |
| PMID 17297455 |
| Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes. |
| Kawada K, Sonoshita M, Sakashita H, Takabayashi A, Yamaoka Y, Manabe T, Inaba K, Minato N, Oshima M, Taketo MM. |
| Cancer Res. 2004 Jun 1;64(11):4010-7. |
| PMID 15173015 |
| An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. |
| Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Giannini S, Cosmi L, Sagrinati C, Mazzinghi B, Orlando C, Maggi E, Marra F, Romagnani S, Serio M, Romagnani P. |
| J Exp Med. 2003 Jun 2;197(11):1537-49. |
| PMID 12782716 |
| Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. |
| Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis I, Baggiolini M, Moser B. |
| J Exp Med. 1996 Sep 1;184(3):963-9. |
| PMID 9064356 |
| Clinical significance of CXCR3 and CXCR4 expression in primary melanoma. |
| Longo-Imedio MI, Longo N, Trevino I, Lazaro P, Sanchez-Mateos P. |
| Int J Cancer. 2005 Dec 10;117(5):861-5. |
| PMID 15981210 |
| Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14, encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin receptors. |
| Marchese A, Heiber M, Nguyen T, Heng HH, Saldivia VR, Cheng R, Murphy PM, Tsui LC, Shi X, Gregor P, et al. |
| Genomics. 1995 Sep 20;29(2):335-44. |
| PMID 8666380 |
| Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. |
| Robledo MM, Bartolome RA, Longo N, Rodruiguez-Frade JM, Mellado M, Longo I, van Muijen GN, Sanchez-Mateos P, Teixido J. |
| J Biol Chem. 2001 Nov 30;276(48):45098-105. Epub 2001 Sep 24. |
| PMID 11571298 |
| CXC chemokines: the regulatory link between inflammation and angiogenesis. |
| Romagnani P, Lasagni L, Annunziato F, Serio M, Romagnani S. |
| Trends Immunol. 2004 Apr;25(4):201-9. |
| PMID 15039047 |
| Up-regulation of the interferon gamma (IFN-gamma)-inducible chemokines IFN-inducible T-cell alpha chemoattractant and monokine induced by IFN-gamma and of their receptor CXC receptor 3 in human renal cell carcinoma. |
| Suyama T, Furuya M, Nishiyama M, Kasuya Y, Kimura S, Ichikawa T, Ueda T, Nikaido T, Ito H, Ishikura H. |
| Cancer. 2005 Jan 15;103(2):258-67. |
| PMID 15578685 |
| Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. |
| Walser TC, Rifat S, Ma X, Kundu N, Ward C, Goloubeva O, Johnson MG, Medina JC, Collins TL, Fulton AM. |
| Cancer Res. 2006 Aug 1;66(15):7701-7. |
| PMID 16885372 |
| CXCL10 promotes invasion-related properties in human colorectal carcinoma cells. |
| Zipin-Roitman A, Meshel T, Sagi-Assif O, Shalmon B, Avivi C, Pfeffer RM, Witz IP, Ben-Baruch A. |
| Cancer Res. 2007 Apr 1;67(7):3396-405. |
| PMID 17409450 |
| Citation |
| This paper should be referenced as such : |
| Taketo, MM ; Kawada, K |
| CXCR3 (chemokine (C-X-C motif) receptor 3) |
| Atlas Genet Cytogenet Oncol Haematol. 2009;13(3):191-193. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/CXCR3ID40224chXq13.html |
| Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ] |
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Subcutaneous panniculitis-like T-cell lymphoma
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| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Feb 28 13:51:23 CET 2018 |
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