| Written | 2009-03 | Hisayuki Nomiyama, Osamu Yoshie |
| Department of Biochemistry, Kumamoto University Medical School, Honjo, Kumamoto 860-0811, Japan (HN); Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan (OY) |
| Identity |
| Alias_names | GPR28 |
| chemokine (C-C motif) receptor 9 | |
| Alias_symbol (synonym) | GPR-9-6 |
| CDw199 | |
| Other alias | C-C CKR-9 |
| CC-CKR-9 | |
| CCR-9 | |
| Ckbeta-15 | |
| CMKBR9 | |
| HGNC (Hugo) | CCR9 |
| LocusID (NCBI) | 10803 |
| Atlas_Id | 44380 |
| Location | 3p21.31 [Link to chromosome band 3p21] |
| Location_base_pair | Starts at 45886504 and ends at 45903175 bp from pter ( according to hg19-Feb_2009) [Mapping CCR9.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 | CCR9 is a G protein-coupled receptor with specificity for a CC chemokine CCL25 (originally described as thymus-expressed chemokine or TECK) and is one of the key molecules in leukocyte homing to gut mucosa. |
| DNA/RNA |
| Note | The gene and mRNA for CCR9 are 16.6 and 2.7 kb in length, respectively. |
 | |
| The CCR9 gene generates two distinct mRNAs. | |
| Description | The CCR9 gene consists of three exons, the second and third exons being the coding-exons. Alternative splicing of the gene generates two distinct mRNAs, CCR9-A and CCR9-B. The CCR9-A cDNA was the first to be cloned. |
| Transcription | The CCR9-A mRNA is encoded by the three exons, while the CCR9-B lacks the sequence derived from the second exon of 49 bp. The CCR9 mRNAs are expressed predominantly in the thymus. Among the cell lines tested, T cell leukemia line MOLT-4 and HTLV-1+ T cells express CCR9 mRNA. The CCR9-A mRNA is expressed at ~10-fold higher levels than CCR9-B mRNA in the cells and cell lines investigated. |
| Pseudogene | None. |
| Protein |
| Note | CCR9-A: 369 amino acids, 42015 Da. CCR9-B: 357 amino acids, 40712 Da. |
| Description | CCR9 is a member of the seven transmembrane G protein-coupled receptor superfamily, and is the single receptor for chemokine CCL25. |
| Expression | CCR9 is present on thymocytes as well as on intraepithelial and lamina propria lymphocytes of the small intestine. A small subset of lymphocytes in the colon is also expressing CCR9. |
| Localisation | Cell membrane; Multi-pass membrane protein. |
| Function | CCR9 mediates chemotaxis to CCL25, which is selectively expressed in the thymus and small intestine, and plays an important role in the recruitment of T cells into gut mucosa. Dendritic cells derived from gut-associated lymphoid tissues as well as retinoic acid have been shown to induce the expression of alpha4beta7 integrin and CCR9 on T cells, resulting in their preferential homing to the gut. Although CCR9 deletion in mice has no major effects on the intrathymic T-cell development, down-regulation of CCR9 on activated CD4+CD8+ double positive thymocytes has been shown to allow the migration of maturing thymocytes from the cortex to the medulla. The EC50 of CCL25 for CCR9-A is somewhat lower than that for CCR9-B. CCR9-A-expressing cells are therefore more responsive to CCL25 than the cells expressing CCR9-B in chemotaxis and calcium influx experiments. |
| Homology | CCR9 is closely related to the chemokine receptors CCR6, CCR7, and CXCR6. |
| Implicated in |
| Note | |
| Entity | T-cell acute lymphocytic leukemia (T-ALL) |
| Oncogenesis | Qiuping et al. (2003) assessed the expression of CCR9 in 21 T-ALL and 17 "T-cell chronic lymphocytic leukemia" (T-CLL) cases, and found that functionally active CCR9 was selectively and frequently expressed on T-ALL CD4+ T cells and was moderately expressed on T-CLL CD4+ T cells. Annels et al. (2004) investigated homing receptor expression on the blast cells of 11 pediatric T-ALL patients. They found that CCR9 and CD103 (alphaE integrin) were expressed at high levels on T-ALL cells of one patient. This patient later switched to a clonally related acute myeloid leukemia during treatment, and the relapse of leukemia was confined to the gut. This study suggests a role of CCR9 in infiltration of leukemic cells into the gut. |
| Entity | Adult T-cell leukemia (ATL) |
| Oncogenesis | ATL frequently invades the gastrointestinal tract. Nagakubo et al. (2007) examined CCR9 expression in five ATL-derived cell lines and 10 blood samples from ATL patients containing leukemic cells at high levels. Although all ATL cell lines were CCR9-positive, fresh ATL cells derived from patients were mostly negative. However, ATL cells became readily positive for CCR9 mRNA after one-day culture in parallel with the expression of Tax mRNA. This study suggests that CCR9 is inducible in ATL cells and may play a role in the high incidence of ATL cell invasion into the gastrointestinal tract. |
| Entity | Melanoma metastasis to the small intestine |
| Oncogenesis | Letsch et al. (2004) assessed CCR9 expression in 20 melanoma cell lines. The CCR9-positive cell lines were established from metastases to small intestine (n = 3), lymph node (n = 4), and skin (n = 1). Only melanoma cell lines derived from small intestinal metastases, however, were responsive to CCL25. This study correlated functional expression of CCR9 with melanoma metastasis to the small intestine. Amersi et al. (2008) assessed CCR9 expression in primary (n = 23) and metastatic (n = 198) melanomas, and melanoma lines derived from small intestinal metastases (n = 8). CCR9 expression was observed in 88 of 102 metastatic melanomas from the small intestine, 8 of 8 melanoma lines derived from small intestine metastasis, but none of 96 metastatic melanomas from other sites. In addition, 11 of 23 primary melanomas were CCR9-positive and 7 of these later developed small intestinal metastases. This study suggests that CCR9 has a role in melanoma metastasis to the small intestine. |
| Entity | Melanoma metastasis |
| Oncogenesis | Seidl et al. (2007) investigated expression of eight chemokine receptors including CCR9 in 51 tissue samples of melanocytic origin. CCR9 mRNA was observed in more than half of the melanocytic lesions including lymph node metastases and visceral metastases. The authors concluded that there is no clear trend toward an association between the CCR9 expression levels and melanoma progression. |
| Entity | Prostate cancer metastasis |
| Oncogenesis | Singh et al. (2004) investigated CCR9 expression in two prostate cancer cell lines. Both cell lines expressed CCR9. This study suggests that expression and activation of CCR9 affect prostate cancer metastasis. |
| Entity | Small intestinal Crohn's disease |
| Oncogenesis | Papadakis et al. (2001) found that CCR9+ T cells were markedly elevated in the peripheral blood of patients with Crohn's disease but not those with purely colonic Crohn's disease. This study suggests selective involvement of CCR9 in the pathogenesis of small bowel Crohn's disease. |
| Bibliography |
| CD46-induced immunomodulatory CD4+ T cells express the adhesion molecule and chemokine receptor pattern of intestinal T cells. |
| Alford SK, Longmore GD, Stenson WF, Kemper C. |
| J Immunol. 2008 Aug 15;181(4):2544-55. |
| PMID 18684945 |
| Activation of CCR9/CCL25 in cutaneous melanoma mediates preferential metastasis to the small intestine. |
| Amersi FF, Terando AM, Goto Y, Scolyer RA, Thompson JF, Tran AN, Faries MB, Morton DL, Hoon DS. |
| Clin Cancer Res. 2008 Feb 1;14(3):638-45. |
| PMID 18245522 |
| Possible link between unique chemokine and homing receptor expression at diagnosis and relapse location in a patient with childhood T-ALL. |
| Annels NE, Willemze AJ, van der Velden VH, Faaij CM, van Wering E, Sie-Go DM, Egeler RM, van Tol MJ, Revesz T. |
| Blood. 2004 Apr 1;103(7):2806-8. Epub 2003 Dec 4. |
| PMID 14656893 |
| PlexinD1 glycoprotein controls migration of positively selected thymocytes into the medulla. |
| Choi YI, Duke-Cohan JS, Ahmed WB, Handley MA, Mann F, Epstein JA, Clayton LK, Reinherz EL. |
| Immunity. 2008 Dec;29(6):888-98. Epub 2008 Nov 27. |
| PMID 19027330 |
| Chemokine receptors in melanoma: CCR9 has a potential role in metastasis to the small bowel. |
| Hwang ST. |
| J Invest Dermatol. 2004 Mar;122(3):xiv-xv. |
| PMID 15086589 |
| Retinoic acid imprints gut-homing specificity on T cells. |
| Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. |
| Immunity. 2004 Oct;21(4):527-38. |
| PMID 15485630 |
| Generation of gut-homing T cells and their localization to the small intestinal mucosa. |
| Johansson-Lindbom B, Agace WW. |
| Immunol Rev. 2007 Feb;215:226-42. (REVIEW) |
| PMID 17291292 |
| The greater chemotactic network for lymphocyte trafficking: chemokines and beyond. |
| Kim CH. |
| Curr Opin Hematol. 2005 Jul;12(4):298-304. (REVIEW) |
| PMID 15928487 |
| Chemokines and the tissue-specific migration of lymphocytes. |
| Kunkel EJ, Butcher EC. |
| Immunity. 2002 Jan;16(1):1-4. (REVIEW) |
| PMID 11825560 |
| Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. |
| Kunkel EJ, Campbell JJ, Haraldsen G, Pan J, Boisvert J, Roberts AI, Ebert EC, Vierra MA, Goodman SB, Genovese MC, Wardlaw AJ, Greenberg HB, Parker CM, Butcher EC, Andrew DP, Agace WW. |
| J Exp Med. 2000 Sep 4;192(5):761-8. |
| PMID 10974041 |
| Functional CCR9 expression is associated with small intestinal metastasis. |
| Letsch A, Keilholz U, Schadendorf D, Assfalg G, Asemissen AM, Thiel E, Scheibenbogen C. |
| J Invest Dermatol. 2004 Mar;122(3):685-90. |
| PMID 15086554 |
| Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. |
| Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH. |
| Nature. 2003 Jul 3;424(6944):88-93. |
| PMID 12840763 |
| T-cell homing specificity and plasticity: new concepts and future challenges. |
| Mora JR, von Andrian UH. |
| Trends Immunol. 2006 May;27(5):235-43. Epub 2006 Mar 31. (REVIEW) |
| PMID 16580261 |
| Expression of CCR9 in HTLV-1+ T cells and ATL cells expressing Tax. |
| Nagakubo D, Jin Z, Hieshima K, Nakayama T, Shirakawa AK, Tanaka Y, Hasegawa H, Hayashi T, Tsukasaki K, Yamada Y, Yoshie O. |
| Int J Cancer. 2007 Apr 1;120(7):1591-7. |
| PMID 17205512 |
| Pivotal role of CCL25 (TECK)-CCR9 in the formation of gut cryptopatches and consequent appearance of intestinal intraepithelial T lymphocytes. |
| Onai N, Kitabatake M, Zhang YY, Ishikawa H, Ishikawa S, Matsushima K. |
| Int Immunol. 2002 Jul;14(7):687-94. |
| PMID 12096027 |
| CCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn's disease. |
| Papadakis KA, Prehn J, Moreno ST, Cheng L, Kouroumalis EA, Deem R, Breaverman T, Ponath PD, Andrew DP, Green PH, Hodge MR, Binder SW, Targan SR. |
| Gastroenterology. 2001 Aug;121(2):246-54. |
| PMID 11487533 |
| Selectively increased expression and functions of chemokine receptor CCR9 on CD4+ T cells from patients with T-cell lineage acute lymphocytic leukemia. |
| Qiuping Z, Qun L, Chunsong H, Xiaolian Z, Baojun H, Mingzhen Y, Chengming L, Jinshen H, Qingping G, Kejian Z, Zhimin S, Xuejun Z, Junyan L, Jinquan T. |
| Cancer Res. 2003 Oct 1;63(19):6469-77. |
| PMID 14559839 |
| CCR9 homes metastatic melanoma cells to the small bowel. |
| Richmond A. |
| Clin Cancer Res. 2008 Feb 1;14(3):621-3. |
| PMID 18245518 |
| Profiles of chemokine receptors in melanocytic lesions: de novo expression of CXCR6 in melanoma. |
| Seidl H, Richtig E, Tilz H, Stefan M, Schmidbauer U, Asslaber M, Zatloukal K, Herlyn M, Schaider H. |
| Hum Pathol. 2007 May;38(5):768-80. Epub 2007 Feb 15. |
| PMID 17306330 |
| Expression and functional role of CCR9 in prostate cancer cell migration and invasion. |
| Singh S, Singh UP, Stiles JK, Grizzle WE, Lillard JW Jr. |
| Clin Cancer Res. 2004 Dec 15;10(24):8743-50. |
| PMID 15623660 |
| Differential homing mechanisms regulate regionalized effector CD8alphabeta+ T cell accumulation within the small intestine. |
| Stenstad H, Svensson M, Cucak H, Kotarsky K, Agace WW. |
| Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10122-7. Epub 2007 Jun 5. |
| PMID 17551016 |
| CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa. |
| Svensson M, Marsal J, Ericsson A, Carramolino L, Broden T, Marquez G, Agace WW. |
| J Clin Invest. 2002 Oct;110(8):1113-21. |
| PMID 12393847 |
| A role for CCR9 in T lymphocyte development and migration. |
| Uehara S, Grinberg A, Farber JM, Love PE. |
| J Immunol. 2002 Mar 15;168(6):2811-9. |
| PMID 11884450 |
| Chemokine receptors and leukocyte trafficking in the mucosal immune system. |
| Williams IR. |
| Immunol Res. 2004;29(1-3):283-92. (REVIEW) |
| PMID 15181289 |
| Mice lacking the CCR9 CC-chemokine receptor show a mild impairment of early T- and B-cell development and a reduction in T-cell receptor gammadelta(+) gut intraepithelial lymphocytes. |
| Wurbel MA, Malissen M, Guy-Grand D, Meffre E, Nussenzweig MC, Richelme M, Carrier A, Malissen B. |
| Blood. 2001 Nov 1;98(9):2626-32. |
| PMID 11675330 |
| The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. |
| Wurbel MA, Philippe JM, Nguyen C, Victorero G, Freeman T, Wooding P, Miazek A, Mattei MG, Malissen M, Jordan BR, Malissen B, Carrier A, Naquet P. |
| Eur J Immunol. 2000 Jan;30(1):262-71. |
| PMID 10602049 |
| CCR9A and CCR9B: two receptors for the chemokine CCL25/TECK/Ck beta-15 that differ in their sensitivities to ligand. |
| Yu CR, Peden KW, Zaitseva MB, Golding H, Farber JM. |
| J Immunol. 2000 Feb 1;164(3):1293-305. |
| PMID 10640743 |
| Cutting edge: identification of the orphan chemokine receptor GPR-9-6 as CCR9, the receptor for the chemokine TECK. |
| Zaballos A, Gutierrez J, Varona R, Ardavin C, Marquez G. |
| J Immunol. 1999 May 15;162(10):5671-5. |
| PMID 10229797 |
| Human G protein-coupled receptor GPR-9-6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. |
| Zabel BA, Agace WW, Campbell JJ, Heath HM, Parent D, Roberts AI, Ebert EC, Kassam N, Qin S, Zovko M, LaRosa GJ, Yang LL, Soler D, Butcher EC, Ponath PD, Parker CM, Andrew DP. |
| J Exp Med. 1999 Nov 1;190(9):1241-56. |
| PMID 10544196 |
| Citation |
| This paper should be referenced as such : |
| Nomiyama, H ; Yoshie, O |
| CCR9 (chemokine (C-C motif) receptor 9) |
| Atlas Genet Cytogenet Oncol Haematol. 2010;14(2):91-94. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/CCR9ID44380ch3p21.html |
| 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 : Mon Dec 10 13:47:02 CET 2018 |
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