CCR9

For the airport in Ontario, Canada, see Creemore Aerodrome.

C-C chemokine receptor type 9 is a protein that in humans is encoded by the CCR9 gene.^[5][6] This gene is mapped to the chemokine receptor gene cluster region. Two alternatively spliced transcript variants have been described.^[6]

CCR9
Identifiers
Aliases	CCR9, CC-CKR-9, CDw199, GPR-9-6, GPR28, C-C motif chemokine receptor 9
External IDs	OMIM: 604738 MGI: 1341902 HomoloGene: 22546 GeneCards: CCR9
Gene location (Human) Chr. Chromosome 3 (human)^[1] Band 3p21.31 Start 45,886,509 bp^[1] End 45,903,174 bp^[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)^[2] Band 9 F4|9 74.33 cM Start 123,507,504 bp^[2] End 123,613,395 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in thymus duodenum sural nerve appendix blood bone marrow spleen monocyte lymph node skeletal muscle tissue Top expressed in thymus blood spleen external carotid artery ascending aorta aortic valve bone marrow duodenum jejunum knee joint More reference expression data BioGPS More reference expression data
Gene ontology Molecular function C-C chemokine receptor activity G protein-coupled receptor activity signal transducer activity chemokine receptor activity chemokine binding C-C chemokine binding Cellular component cell surface integral component of membrane integral component of plasma membrane membrane plasma membrane intracellular anatomical structure external side of plasma membrane Biological process positive regulation of cytosolic calcium ion concentration chemotaxis chemokine-mediated signaling pathway cellular defense response G protein-coupled receptor signaling pathway immune response signal transduction CD8-positive, gamma-delta intraepithelial T cell differentiation calcium-mediated signaling cell chemotaxis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10803 12769 Ensembl ENSG00000173585 ENSMUSG00000029530 UniProt P51686 Q9WUT7 RefSeq (mRNA) NM_001256369 NM_006641 NM_031200 NM_001386447 NM_001386448 NM_001166625 NM_009913 RefSeq (protein) NP_001243298 NP_006632 NP_112477 NP_001160097 NP_034043 Location (UCSC) Chr 3: 45.89 – 45.9 Mb Chr 9: 123.51 – 123.61 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

CCR9 has also recently been designated CDw199 (cluster of differentiation w199).

The protein encoded by this gene is a member of the beta chemokine receptor family. CCR9 is a seven transmembrane protein similar to G protein-coupled receptors.^[7][8][9]

Function

Chemokines and their receptors, such as CCR9 and its binding agonist, are key regulators of thymocyte migration and maturation in normal and inflammatory conditions.^[8] The specific agonist or ligand that binds CCR9 is CCL25 also referred to as TECK^[10] in some literature. The effects of chemokines binding to their specific receptors is generally dependent on the structural placement of the N terminal cysteine(s) amino acids.^[11] Receptors are broken down into 4 family groups CXC, CC, C, and CX3C, because CCR9 has two adjacent cysteines it is a C-C family receptor.^[11] C-C family chemokines (such as CCL25) are often associated with the recruitment of lymphocytes.^[11][8] It has been found that this gene is differentially expressed by T lymphocytes of small intestine and colon, suggesting a role in thymocyte recruitment and development that may permit functional specialization of immune responses in different segments of the gastrointestinal tract.

Clinical significance

The breadth of effects following interactions of CCR9 and its binding ligand CCL25 are vast and not completely understood, however, it is generally thought that CCR9 and CCL25 play substantial roles in cancer proliferation and inflammatory diseases.^[11] The location of CCR9 and CCL25 expression plays a substantial role in how it contributes to diseases.^[11] For example, the high expression of CCL25 in the epithelial lining of the small intestine, has contributed to its strong association and influence on inflammatory disease of the gut such as inflammatory bowel disease.^[11] However, CCR9 and CCL25 have also been associated with other inflammatory conditions such as cardiovascular disease, rheumatoid arthritis, and asthma.^[11][12] The role of CCR9 in cancer lies primarily in its ability to upregulate cell proliferation, metastasis, and the drug resistance.^[12]

Inflammatory Bowel Disease (IBD)

CCR9/CCL25 interactions are known to contribute to the up-regulated migration of memory T cell homing to the gut given high expression of CCL25 in intestinal lining.^[11]  As a result, it is suggested that CCR9 and CCL25 have been a key focus in promoting a balanced pro-inflammatory and anti-inflammatory response in the gut.^[11] It has been observed that decreased expression of CCL25 and CCR9 contributes to macrophage recruitment in the gut as well as inflammatory cytokines which induces the observed inflammation in IBD.^[11] The inflammatory cytokines upregulated in the immune response of IBD are TNF-α, IFN-γ, IL-2, IL-6, IL-17A, and Th1/Th17.^[11] Overall, it is likely that the interactions of CCR9 and CCL25 provide substantial protections against large intestinal inflammation via its ability to regulate inflammation in the gut by balancing the presence of inflammatory cytokines.^[11]

Myocardial Infarction (MI)

CCR9/CCL25 interaction reduction is believed to improve the survival rate, cardiac function, and reduce infarct size following myocardial infarctions.^[11] Additionally, reduced CCR9 expression following myocardial infarctions is also believed to attenuate apoptosis in the cells of the affected cardiac tissue while also reducing inflammation through the down-regulation of inflammatory cytokines including: IL-1β, IL-6, and TNF-α.^[11] Overall, CCR9 and CCL25 are believed to play a key role in mitigating the damage to cardiac tissue following heart attacks, while also aiding cardiac remodeling.^[11] The role CCR9 and CCL25 is thought to have in cardiovascular health has made it a key area of focus in clinical research.^[11]

Cancer

CCR9/CCL25 interaction is believed to significantly influence the cellular functions of cancer cells and ultimately contribute to their proliferation and metastasis.^[12] CCR9 and CCL25 interactions are understood to suppress apoptosis observed by cancer cells.^[12] Apoptosis in cancer cells is  an essential mechanism utilized to mitigate the proliferation of cancer cells.^[12] The suggested reduction in apoptosis observed in cancer cells as a result of CCR9 and CCL25 interactions, ultimately supports the proliferation and metastasis of cancer cells.^[12] The observed proliferative and antiapoptotic effects of CCR9/CCL25 interaction, suggests the potential for targeted therapies that down-regulate CCR9/CCL25 for certain cancers including: leukemia, prostate cancer, breast cancer, ovarian cancer and lung cancer.^[12]

References

1. GRCh38: Ensembl release 89: ENSG00000173585 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000029530 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Zaballos A, Gutiérrez J, Varona R, Ardavín C, Márquez G (May 1999). "Cutting edge: identification of the orphan chemokine receptor GPR-9-6 as CCR9, the receptor for the chemokine TECK". Journal of Immunology. 162 (10): 5671–5675. doi:10.4049/jimmunol.162.10.5671. PMID 10229797. S2CID 21522407.
6. "Entrez Gene: CCR9 chemokine (C-C motif) receptor 9".
7. Schulz O, Hammerschmidt SI, Moschovakis GL, Förster R (May 2016). "Chemokines and Chemokine Receptors in Lymphoid Tissue Dynamics". Annual Review of Immunology. 34 (1): 203–242. doi:10.1146/annurev-immunol-041015-055649. PMID 26907216.
8. Griffith JW, Sokol CL, Luster AD (2014-03-21). "Chemokines and chemokine receptors: positioning cells for host defense and immunity". Annual Review of Immunology. 32 (1): 659–702. doi:10.1146/annurev-immunol-032713-120145. PMID 24655300. S2CID 10579265.
9. Tu Z, Xiao R, Xiong J, Tembo KM, Deng X, Xiong M, et al. (February 2016). "CCR9 in cancer: oncogenic role and therapeutic targeting". Journal of Hematology & Oncology. 9 (1): 10. doi:10.1186/s13045-016-0236-7. PMC 4754913. PMID 26879872.
10. Youn BS, Yu KY, Oh J, Lee J, Lee TH, Broxmeyer HE (June 2002). "Role of the CC chemokine receptor 9/TECK interaction in apoptosis". Apoptosis. 7 (3): 271–276. doi:10.1023/A:1015320321511. PMID 11997671. S2CID 25082118.
11. Wu X, Sun M, Yang Z, Lu C, Wang Q, Wang H, et al. (2021-08-19). "The Roles of CCR9/CCL25 in Inflammation and Inflammation-Associated Diseases". Frontiers in Cell and Developmental Biology. 9: 686548. doi:10.3389/fcell.2021.686548. PMC 8416662. PMID 34490243.
12. Xu B, Deng C, Wu X, Ji T, Zhao L, Han Y, et al. (December 2020). "CCR9 and CCL25: A review of their roles in tumor promotion". Journal of Cellular Physiology. 235 (12): 9121–9132. doi:10.1002/jcp.29782. PMID 32401349. S2CID 218617059.

Further reading

• Youn BS, Kim CH, Smith FO, Broxmeyer HE (October 1999). "TECK, an efficacious chemoattractant for human thymocytes, uses GPR-9-6/CCR9 as a specific receptor". Blood. 94 (7): 2533–2536. doi:10.1182/blood.V94.7.2533.419k37_2533_2536. PMID 10498628.
• Zabel BA, Agace WW, Campbell JJ, Heath HM, Parent D, Roberts AI, et al. (November 1999). "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". The Journal of Experimental Medicine. 190 (9): 1241–1256. doi:10.1084/jem.190.9.1241. PMC 2195678. PMID 10544196.
• Wurbel MA, Philippe JM, Nguyen C, Victorero G, Freeman T, Wooding P, et al. (January 2000). "The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9". European Journal of Immunology. 30 (1): 262–271. doi:10.1002/1521-4141(200001)30:1<262::AID-IMMU262>3.0.CO;2-0. PMID 10602049.
• Yu CR, Peden KW, Zaitseva MB, Golding H, Farber JM (February 2000). "CCR9A and CCR9B: two receptors for the chemokine CCL25/TECK/Ck beta-15 that differ in their sensitivities to ligand". Journal of Immunology. 164 (3): 1293–1305. doi:10.4049/jimmunol.164.3.1293. PMID 10640743.
• Maho A, Bensimon A, Vassart G, Parmentier M (2000). "Mapping of the CCXCR1, CX3CR1, CCBP2 and CCR9 genes to the CCR cluster within the 3p21.3 region of the human genome". Cytogenetics and Cell Genetics. 87 (3–4): 265–268. doi:10.1159/000015443. PMID 10702689. S2CID 1178132.
• Kunkel EJ, Campbell JJ, Haraldsen G, Pan J, Boisvert J, Roberts AI, et al. (September 2000). "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". The Journal of Experimental Medicine. 192 (5): 761–768. doi:10.1084/jem.192.5.761. PMC 2193265. PMID 10974041.
• Papadakis KA, Prehn J, Nelson V, Cheng L, Binder SW, Ponath PD, et al. (November 2000). "The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system". Journal of Immunology. 165 (9): 5069–5076. doi:10.4049/jimmunol.165.9.5069. PMID 11046037.
• Papadakis KA, Landers C, Prehn J, Kouroumalis EA, Moreno ST, Gutierrez-Ramos JC, et al. (July 2003). "CC chemokine receptor 9 expression defines a subset of peripheral blood lymphocytes with mucosal T cell phenotype and Th1 or T-regulatory 1 cytokine profile". Journal of Immunology. 171 (1): 159–165. doi:10.4049/jimmunol.171.1.159. PMID 12816994.
• Qiuping Z, Qun L, Chunsong H, Xiaolian Z, Baojun H, Mingzhen Y, et al. (October 2003). "Selectively increased expression and functions of chemokine receptor CCR9 on CD4+ T cells from patients with T-cell lineage acute lymphocytic leukemia". Cancer Research. 63 (19): 6469–6477. PMID 14559839.
• Singh S, Singh UP, Stiles JK, Grizzle WE, Lillard JW (December 2004). "Expression and functional role of CCR9 in prostate cancer cell migration and invasion". Clinical Cancer Research. 10 (24): 8743–8750. doi:10.1158/1078-0432.CCR-04-0266. PMID 15623660.
• Babu S, Blauvelt CP, Kumaraswami V, Nutman TB (March 2005). "Chemokine receptors of T cells and of B cells in lymphatic filarial infection: a role for CCR9 in pathogenesis". The Journal of Infectious Diseases. 191 (6): 1018–1026. doi:10.1086/427658. PMID 15717282.
• Sen Y, Yongyi B, Yuling H, Luokun X, Li H, Jie X, et al. (October 2005). "V alpha 24-invariant NKT cells from patients with allergic asthma express CCR9 at high frequency and induce Th2 bias of CD3+ T cells upon CD226 engagement". Journal of Immunology. 175 (8): 4914–4926. doi:10.4049/jimmunol.175.8.4914. PMID 16210593.
• Nagakubo D, Jin Z, Hieshima K, Nakayama T, Shirakawa AK, Tanaka Y, et al. (April 2007). "Expression of CCR9 in HTLV-1+ T cells and ATL cells expressing Tax". International Journal of Cancer. 120 (7): 1591–1597. doi:10.1002/ijc.22483. PMID 17205512. S2CID 23891689.
• Olaussen RW, Karlsson MR, Lundin KE, Jahnsen J, Brandtzaeg P, Farstad IN (June 2007). "Reduced chemokine receptor 9 on intraepithelial lymphocytes in celiac disease suggests persistent epithelial activation". Gastroenterology. 132 (7): 2371–2382. doi:10.1053/j.gastro.2007.04.023. PMID 17570212.

External links

• Human CCR9 genome location and CCR9 gene details page in the UCSC Genome Browser.
• . IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2008-06-07. Retrieved 2008-12-03.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.