Introduction of CCR-9

CCR-9, also known as cluster of differentiation w199 (CDw199), GPR28 or GPR-9-6, is a member of the beta chemokine receptor family, which in human is encoded by CCR9 gene. CCR-9 is supposed to be a seven transmembrane protein similar to G protein-coupled receptors. It is predominantly found in immature T lymphocytes and on the surface of intestinal cells. The specific ligand of CCR-9 has been identified to be CCL25 (also known as SCYA25 or TECK).

Function of CCR-9 Membrane Protein

It has been indicated that CCR-9 may play a role in the thymocytes recruitment and development and may permit functional specialization of immune responses in different segment of the gastrointestinal tract. The bond of CCR-9 and CCL25 subsequently transduces a signal by increasing the intracellular calcium ions level. CCR9 has also been found to play a role in various cancer, including breast, prostate, ovarian, and lung cancer. The stimulation of CCR9 with its ligand CCL25 promotes metastatic process by supporting cell migration, invasion and modulating MMP (matrix metalloproteinases), the expression of which is required for invasion. Moreover, several studies have suggested that CCR-9 is highly expressed in a range of cancer cells. The interaction of CCR9/CCL25 has been suggesting to activate several signaling pathways in cancer, especially those involved in tumor chemoresistance and metastasis. Accordingly, CCR-9 has been regarded as a potentially targeted molecule for cancer therapy.

Fig.1 Ribbon representation of CCR-9 (cyan) viewed parallel to the membrane (Oswald, 2016).

Application of CCR-9 Membrane Protein in Literature

1. Igaki K., et al. MLN3126, an antagonist of the chemokine receptor CCR9, ameliorates inflammation in a T cell mediated mouse colitis model. Int Immunopharmacol. 2018, 60: 160-169. PubMed ID: 29730559

Authors in this group investigate the efficacy of an orally available small molecular compound, called MLN3126, for inflammatory bowel disease (IBD). The findings indicate that MLN3126 would be a promising orally available CCR9 antagonist to treat colonic IBD.

2. Weingrill R.B., et al. Chemokine (C-C motif) ligand 25 expressed by trophoblast cells and leukocytes bearing its receptor Ccr9: An alliance during embryo implantation? Am J Reprod Immunol. 2018, 79(1). PubMed ID: 29154408

The author of this article hypothesized that trophoblast expression of Ccl25 attracts a specific leukocyte cell population to the implantation site for local regulation. The findings support CR9-axis at the maternal-fetal interface in mice, which may be involved in immune regulatory mechanisms during embryo implantation.

3. Tu Z., et al. CCR9 in cancer: oncogenic role and therapeutic targeting. J Hematol Oncol. 2016, 9: 10. PubMed ID: 26879872

This article focuses on CCR9 induction activity and summarizes what is currently known regarding its role in cancers and its potential application in tumor-targeted therapy.

4. Yokoyama W., et al. Abrogation of CC chemokine receptor 9 ameliorates collagen-induced arthritis of mice. Purinergic Signal. 2014, 16(5): 445. PubMed ID: 25248373

This article reports the interaction between CCL25 and CCR9 may play important roles in cell infiltration into the RA synovial tissues and inflammatory mediator production and suggests that blocking CCL25 or CCR9 may represent a novel safe therapy for RA.

5. Chu P.S., et al. C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. Hepatology. 2013, 58(1): 337-50. PubMed ID: 23460364

This article focuses on revealing the importance of CCR9 positive macrophages in the pathogenesis of acute liver inflammation.

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Reference

1. Oswald C., et al. (2016). Intracellular allosteric antagonism of the CCR9 receptor. Nature. 540 (7633), 462-465.

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