CCR9

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]

For the airport in Ontario, Canada, see Creemore Aerodrome.
CCR9
Identifiers
AliasesCCR9, CC-CKR-9, CDw199, GPR-9-6, GPR28, C-C motif chemokine receptor 9
External IDsOMIM: 604738 MGI: 1341902 HomoloGene: 22546 GeneCards: CCR9
Orthologs
SpeciesHumanMouse
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 MbChr 9: 123.51 – 123.61 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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.
  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.

Further reading

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