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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 344 | 3p21.31 | CCRL2 | C-C motif chemokine receptor like 2 | |
| Mouse | 7 | 360 | 9 60.92 cM | Ccrl2 | C-C motif chemokine receptor-like 2 | |
| Rat | 7 | 423 | 8q32 | Ccrl2 | C-C motif chemokine receptor like 2 | |
| Previous and Unofficial Names |
| CCR11 | CKRX | CRAM-A | CRAM-B | ACR5 | CCR6 | Chemokine receptor X |
| Database Links |
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| Specialist databases | |
| GPCRdb | ccrl2_human (Hs), ccrl2_mouse (Mm), d3zvm9_rat (Rn) |
| Other databases | |
| Alphafold | O00421 (Hs), O35457 (Mm), D3ZVM9 (Rn) |
| ChEMBL Target | CHEMBL2321627 (Hs) |
| Ensembl Gene | ENSG00000121797 (Hs), ENSMUSG00000043953 (Mm), ENSRNOG00000033234 (Rn) |
| Entrez Gene | 9034 (Hs), 54199 (Mm), 316019 (Rn) |
| Human Protein Atlas | ENSG00000121797 (Hs) |
| KEGG Gene | hsa:9034 (Hs), mmu:54199 (Mm), rno:316019 (Rn) |
| OMIM | 608379 (Hs) |
| Pharos | O00421 (Hs) |
| RefSeq Nucleotide | NM_003965 (Hs), NM_017466 (Mm), NM_001108191 (Rn) |
| RefSeq Protein | NP_003956 (Hs), NP_059494 (Mm), NP_001101661 (Rn) |
| UniProtKB | O00421 (Hs), O35457 (Mm), D3ZVM9 (Rn) |
| Wikipedia | CCRL2 (Hs) |
| Natural/Endogenous Ligands |
| CCL19 {Sp: Human} , CCL19 {Sp: Mouse} |
| Endogenous ligands (Human) |
| chemerin C-terminal peptide, CCL19 (CCL19, Q99731) [3] |
Download all structure-activity data for this target as a CSV file 
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| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Stimulation by CCL19 does not result in typical chemokine-receptor-dependent cellular activation (e.g. calcium mobilization or migration) [15,24-25]. Biotinylated CCL2 binds to CCRL2-expressing HEK293 cells, although radioligand binding was not detected [4,26]. Chemerin blocked the binding of anti-mCCRL2 antibody to mouse peritoneal mast cells, but despite binding to the N-terminal domain of mCCRL2 with high affinity, chemerin elicited no functional response. CCRL2 appears to concentrate bioactive chemerin and facilitate its presentation to ChemR23 on adjacent cells [23,25]. Binding of chemerin to CCRL2 has been demonstrated to trigger adhesion of CMKLR1+ lymphoid cells through an α4β1 integrin/VCAM-1–dependent mechanism therefore CCRl2 plays a role in chemerin-dependent lymphocyte recruitment to inflamed airways, and the regulation of circulating chemerin levels [17]. | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Immunopharmacology Comments |
| CCRL2 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. However, the nomenclature of CCLR2 for this receptor and its classification as a member of the chemokine receptor family is provisional pending confirmation of chemokine binding. |
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| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| CCRL2 surface expression on the pre-B-cell lines Nalm6 and G2 is specifically upregulated in response to the inflammatory chemokine CCL5 (RANTES) [12]. CCRL2 mRNA and protein was rapidly (30 minutes) and transiently (2-4 hours) regulated during dendritic cell maturation [20]. CCRL2 mRNA expression is strongly upregulated in mouse lung after ovalbumin challenge and is localised in macrophages and bronchial epithelium, as shown by immunohistochemistry [19]. | ||||||||
| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| CCRL2 mRNA levels are significantly higher in db/db mouse white adipose tissue, and there is a trend towards increased expression in ob/ob mice, compared to control [9]. | ||||||||||
| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| Clinically-Relevant Mutations and Pathophysiology Comments | ||||||||||||||||||||||||||
| Three single-nucleotide polymorphisms (rs1154428, rs6808835, and rs6791599) in CCRL2 in linkage disequilibrium with CCR5Delta32 are associated with high-density lipoprotein cholesterol in at risk cardiovascular patients, suggesting that chemokine activity influences lipid levels in populations with preexisting cardiovascular disease [13]. | ||||||||||||||||||||||||||
| Gene Expression and Pathophysiology
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| Biologically Significant Variants
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| Biologically Significant Variant Comments | ||||||||||||||||||
| Human CCRL2 has two splice variants: CCRL2A (Acc. NM_003965) and CCRL2B (Acc. NM_001130910). Variant B encodes the predominant isoform, which is localized at the plasma membrane. It is alternatively spliced within the coding region and thus uses an earlier stop codon, as compared with the isoform A. Variant B has a distinct C-terminus and is 14 aa shorter than the isoform A [14]. Splice variants are differentially expressed in B-cells dependent on maturation stage [12]. |
| General Comments |
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A study of the haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes reveals a cluster of four CC-chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2) on chromosome 3p21 [6-7]. CCRL2 neither internalizes its ligands nor transduces signals, but presents bound ligands to functional signaling receptors improving their activity [16,18]. CCRL2-predicted hepatitis C treatment response to pegylated interferon and ribavirin therapy has been verified by RT-qPCR [8]. |
1. An P, Li R, Wang JM, Yoshimura T, Takahashi M, Samudralal R, O'Brien SJ, Phair J, Goedert JJ, Kirk GD et al.. (2011) Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia. PLoS Genet, 7 (10): e1002328. [PMID:22046140]
2. Auer J, Bläss M, Schulze-Koops H, Russwurm S, Nagel T, Kalden JR, Röllinghoff M, Beuscher HU. (2007) Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis. Arthritis Res Ther, 9 (5): R94. [PMID:17875202]
3. Barnea G, Strapps W, Herrada G, Berman Y, Ong J, Kloss B, Axel R, Lee KJ. (2008) The genetic design of signaling cascades to record receptor activation. Proc Natl Acad Sci USA, 105 (1): 64-9. [PMID:18165312]
4. Biber K, Zuurman MW, Homan H, Boddeke HW. (2003) Expression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8. J Leukoc Biol, 74 (2): 243-51. [PMID:12885941]
5. Brouwer N, Zuurman MW, Wei T, Ransohoff RM, Boddeke HW, Biber K. (2004) Induction of glial L-CCR mRNA expression in spinal cord and brain in experimental autoimmune encephalomyelitis. Glia, 46 (1): 84-94. [PMID:14999816]
6. Clark VJ, Dean M. (2004) Characterisation of SNP haplotype structure in chemokine and chemokine receptor genes using CEPH pedigrees and statistical estimation. Hum Genomics, 1 (3): 195-207. [PMID:15588479]
7. Clark VJ, Dean M. (2004) Haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes. Hum Genomics, 1 (4): 255-73. [PMID:15588486]
8. Devitt E, Lawless MW, Sadlier D, A Browne J, Walsh C, Crowe J. (2010) Early viral and peripheral blood mononuclear cell responses to pegylated interferon and ribavirin treatment: the first 24 h. Eur J Gastroenterol Hepatol, 22 (10): 1211-20. [PMID:20631625]
9. Ernst MC, Issa M, Goralski KB, Sinal CJ. (2010) Chemerin exacerbates glucose intolerance in mouse models of obesity and diabetes. Endocrinology, 151 (5): 1998-2007. [PMID:20228173]
10. Fan P, Kyaw H, Su K, Zeng Z, Augustus M, Carter KC, Li Y. (1998) Cloning and characterization of a novel human chemokine receptor. Biochem Biophys Res Commun, 243 (1): 264-8. [PMID:9473515]
11. Galligan CL, Matsuyama W, Matsukawa A, Mizuta H, Hodge DR, Howard OM, Yoshimura T. (2004) Up-regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis. Arthritis Rheum, 50 (6): 1806-14. [PMID:15188357]
12. Hartmann TN, Leick M, Ewers S, Diefenbacher A, Schraufstatter I, Honczarenko M, Burger M. (2008) Human B cells express the orphan chemokine receptor CRAM-A/B in a maturation-stage-dependent and CCL5-modulated manner. Immunology, 125 (2): 252-62. [PMID:18397265]
13. Hyde CL, Macinnes A, Sanders FA, Thompson JF, Mazzarella RA, Faergeman O, van Wijk DF, Wood L, Lira M, Paciga SA. (2010) Genetic association of the CCR5 region with lipid levels in at-risk cardiovascular patients. Circ Cardiovasc Genet, 3 (2): 162-8. [PMID:20130232]
14. Kiss H, Darai E, Kiss C, Kost-Alimova M, Klein G, Dumanski JP, Imreh S. (2002) Comparative human/murine sequence analysis of the common eliminated region 1 from human 3p21.3. Mamm Genome, 13 (11): 646-55. [PMID:12461651]
15. Leick M, Catusse J, Follo M, Nibbs RJ, Hartmann TN, Veelken H, Burger M. (2010) CCL19 is a specific ligand of the constitutively recycling atypical human chemokine receptor CRAM-B. Immunology, 129 (4): 536-46. [PMID:20002784]
16. Merfeld DM, Young LR, Tomko DL, Paige GD. (1991) Spatial orientation of VOR to combined vestibular stimuli in squirrel monkeys. Acta Otolaryngol Suppl, 481: 287-92. [PMID:1927397]
17. Monnier J, Lewén S, O'Hara E, Huang K, Tu H, Butcher EC, Zabel BA. (2012) Expression, regulation, and function of atypical chemerin receptor CCRL2 on endothelial cells. J Immunol, 189 (2): 956-67. [PMID:22696441]
18. Muruganandan S, Roman AA, Sinal CJ. (2010) Role of chemerin/CMKLR1 signaling in adipogenesis and osteoblastogenesis of bone marrow stem cells. J Bone Miner Res, 25 (2): 222-34. [PMID:19929432]
19. Oostendorp J, Hylkema MN, Luinge M, Geerlings M, Meurs H, Timens W, Zaagsma J, Postma DS, Boddeke HW, Biber K. (2004) Localization and enhanced mRNA expression of the orphan chemokine receptor L-CCR in the lung in a murine model of ovalbumin-induced airway inflammation. J Histochem Cytochem, 52 (3): 401-10. [PMID:14966207]
20. Otero K, Vecchi A, Hirsch E, Kearley J, Vermi W, Del Prete A, Gonzalvo-Feo S, Garlanda C, Azzolino O, Salogni L, Lloyd CM, Facchetti F, Mantovani A, Sozzani S. (2010) Nonredundant role of CCRL2 in lung dendritic cell trafficking. Blood, 116 (16): 2942-9. [PMID:20606167]
21. Shimada T, Matsumoto M, Tatsumi Y, Kanamaru A, Akira S. (1998) A novel lipopolysaccharide inducible C-C chemokine receptor related gene in murine macrophages. FEBS Lett, 425 (3): 490-4. [PMID:9563519]
22. Troyer JL, Nelson GW, Lautenberger JA, Chinn L, McIntosh C, Johnson RC, Sezgin E, Kessing B, Malasky M, Hendrickson SL et al.. (2011) Genome-wide association study implicates PARD3B-based AIDS restriction. J Infect Dis, 203 (10): 1491-502. [PMID:21502085]
23. Yoshimura T, Oppenheim JJ. (2008) Chemerin reveals its chimeric nature. J Exp Med, 205 (10): 2187-90. [PMID:18809717]
24. Zabel BA, Allen SJ, Kulig P, Allen JA, Cichy J, Handel TM, Butcher EC. (2005) Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. J Biol Chem, 280 (41): 34661-6. [PMID:16096270]
25. Zabel BA, Nakae S, Zúñiga L, Kim JY, Ohyama T, Alt C, Pan J, Suto H, Soler D, Allen SJ, Handel TM, Song CH, Galli SJ, Butcher EC. (2008) Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis. J Exp Med, 205 (10): 2207-20. [PMID:18794339]
26. Zuurman MW, Heeroma J, Brouwer N, Boddeke HW, Biber K. (2003) LPS-induced expression of a novel chemokine receptor (L-CCR) in mouse glial cells in vitro and in vivo. Glia, 41 (4): 327-36. [PMID:12555200]
target has curated data in GtoImmuPdb
