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CCRL2

Family: Chemokine receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Tissue Distribution
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Biologically Significant Variants
General Comments
References
Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 344 3p21 CCRL2 chemokine (C-C motif) receptor-like 2
Mouse 7 360 9F Ccrl2 chemokine (C-C motif) receptor-like 2
Rat 7 423 8q32 Ccrl2 chemokine (C-C motif) receptor-like 2
Previous and Unofficial Names
chemokine (C-C motif) receptor-like 2
HCR
CRAM-B
CKRX
CRAM-A
CCR11
Cmkbr1l2
L-CCR
CRAM
Chemokine (C-C motif) receptor-like 2
Chemokine receptor X
Putative MCP-1 chemokine receptor
Chemokine receptor CCR11
C-C chemokine receptor-like 2
CCR6
ACR5
Ccrl2_predicted
LOC316019
chemokine (C-C motif) receptor-like 2 (predicted)
1810047I05Rik
Database Links
Ensembl ENSG00000121797 (Hs), ENSMUSG00000043953 (Mm), ENSRNOG00000033234 (Rn)
Entrez Gene 9034 (Hs), 54199 (Mm), 316019 (Rn)
GeneCards CCRL2 (Hs)
GenitoUrinary Development Molecular Anatomy Project Ccrl2 (Mm)
HomoloGene 2948 (Hs)
Human Protein Reference Database 16327 (Hs)
InterPro O00421 (Hs), O35457 (Mm), D3ZVM9 (Rn)
KEGG Gene hsa:9034 (Hs), mmu:54199 (Mm), rno:316019 (Rn)
OMIM 608379 (Hs)
PharmGKB Gene PA26175 (Hs)
PhosphoSitePlus O00421 (Hs), O35457 (Mm)
Protein Ontology (PRO) PRO:000001214 (Hs)
RefSeq Nucleotide NM_003965 (Hs), NM_017466 (Mm), NM_001108191 (Rn)
RefSeq Protein NP_003956 (Hs), NP_059494 (Mm), NP_001101661 (Rn)
TreeFam ENSG00000121797 (Hs), ENSMUSG00000043953 (Mm), ENSRNOG00000033234 (Rn)
UniGene Hs. 535713 (Hs)
UniProt O00421 (Hs), O35457 (Mm), D3ZVM9 (Rn)
Wikipedia CCRL2
Chemokine receptors
Search for 3D structures on the PDB
Search by keyword: Chemokine receptors CCRL2 Search by accession number: O00421, O35457, D3ZVM9
Natural/Endogenous Ligand(s)
CCL19 {Sp: Human} , CCL19 {Sp: Mouse}
Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
CCL19 {Sp: Human} Hs Unknown 7.36 pIC50 14
Agonist Comments
Stimulation by CCL19 does not result in typical chemokine-receptor-dependent cellular activation (e.g. calcium mobilization or migration) [14,21-22]. Biotinylated CCL2 binds to CCRL2-expressing HEK293 cells, although radioligand binding was not detected [3,23]. 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 [20,22].
Tissue Distribution
Spleen, fetal liver, lymph nodes, bone marrow, lung, heart, thymus, placenta
Species:  Human
Technique:  Northern blot
References:  9
Leukocytes
Species:  Human
Technique:  Immunocytochemistry
References:  10
LPS activated macrophages
Species:  Mouse
Technique:  Northern blot
References:  19
Astrocytes, microglia (upregulated after stimulation with LPS)
Species:  Mouse
Technique:  RT-PCR
References:  23
Mast cells
Species:  Mouse
Technique:  Immunohistochemistry
References:  20,22
Activated dendritic cells, macrophages. No expression in eosinophils, T cells
Species:  Mouse
Technique:  Northern blot
References:  18
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) [11]. CCRL2 mRNA and protein was rapidly (30 minutes) and transiently (2-4 hours) regulated during dendritic cell maturation [18]. CCRL2 mRNA expression is strongly upregulated in mouse lung after ovalbumin challenge and is localised in macrophages and bronchial epithelium, as shown by immunohistochemistry [17].
Physiological Functions
Control of excessive airway inflammatory response
Species:  Mouse
Tissue:  Dentritic cells (lung)
References:  18
Physiological Consequences of Altering Gene Expression
CCRL2-deficient mice had significantly reduced passive cutaneous anaphylaxis reactions when a low sensitizing dose of DNP-specific IgE was used (50 ng/ear), suggesting that mCCRL2 ligation normally amplifies the inflammatory response.
Species:  Mouse
Tissue:  Mast cells
Technique:  Gene knockout
References:  20,22
Defective trafficking of antigen-loaded lung dendritic cells to mediastinal lymph nodes in CCRL2 knockout mice, associated with a reduction in lymph node cellularity and reduced priming of T helper cell 2 response
Species:  None
Tissue:  Dendritic cells
Technique:  Gene knockout
References:  18
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 [8].
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2		 MGI:1920904  MP:0010740 abnormal dendritic cell chemotaxis PMID: 20606167 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2		 MGI:1920904  MP:0002148 abnormal hypersensitivity reaction PMID: 20606167 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2		 MGI:1920904  MP:0005466 abnormal T-helper 2 physiology PMID: 20606167 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2		 MGI:1920904  MP:0008673 decreased interleukin-13 secretion PMID: 20606167 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2		 MGI:1920904  MP:0008700 decreased interleukin-4 secretion PMID: 20606167 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2		 MGI:1920904  MP:0008703 decreased interleukin-5 secretion PMID: 20606167 
Ccrl2tm1Lex Ccrl2tm1Lex/Ccrl2tm1Lex
involves: 129S/SvEvBrd * C57BL/6		 MGI:1920904  MP:0005597 decreased susceptibility to type I hypersensitivity reaction PMID: 18794339 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2		 MGI:1920904  MP:0008101 lymph node hypoplasia PMID: 20606167 
Ccrl2tm1Dgen Ccrl2tm1Dgen/Ccrl2tm1Dgen
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1920904  MP:0002169 no abnormal phenotype detected
Clinically-Relevant Mutations and Pathophysiology
Disease:  Pneumocystis pneumonia
Role:  Associated with rapid development of pneumocystis pneumonia (PCP) during AIDS progression
References:  1
Click column headers to sort
Type Species Molecular location Description Reference
non-conservative amino acid change Human F167Y 1
Disease:  Autoimmune encephalomyelitis
Role:  CCRL2 expression is seen in the spinal cord and brain (predominantly astrocytes and microglia) of mice with experimental autoimmune encephalomyelitis
References:  4
Mutations not determined
Role:  CCRL2 predicted hepatitis C treatment response to pegylated interferon and ribavirin therapy verified by RT-qPCR.
References:  7
Mutations not determined
Disease:  Rheumatoid arthritis
Role:  CCRL2 expression is up-regulated in synovial neutrophils of rheumatoid arthritis patients. Inflammatory products present in the synovial fluid activate this receptor, indicating that CCRL2 is a functional receptor that may be involved in the pathogenesis of rheumatoid arthritis
References:  2,10
Mutations not determined
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 [12].
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 [13]. Splice variants are differentially expressed in B-cells dependent on maturation stage [11].
General Comments
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.

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 [5-6]. CCRL2 neither internalizes its ligands nor transduces signals, but presents bound ligands to functional signaling receptors improving their activity [15-16].
Available Assays
DiscoveRx PathHunter® CHO-K1 CCRL2 (Orphan) High Expression β-Arrestin Cell Line Human Cat No. 93-0333C2A
DiscoveRx PathHunter® eXpress CCRL2 CHO-K1 β-Arrestin (Orphan) GPCR Assay Human Cat No. 93-0333E2ACP1

REFERENCES

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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. 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]

4. 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]

5. 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]

6. Clark, VJ; Dean, M. (2004) Haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes. Hum. Genomics, 1 (4): 255-73. [PMID:15588486]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. Yoshimura, T; Oppenheim, JJ. (2008) Chemerin reveals its chimeric nature. J. Exp. Med., 205 (10): 2187-90. [PMID:18809717]

21. 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]

22. 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]

23. 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]

To cite this database page, please use the following:

Amy E. Monaghan.
Chemokine receptors: CCRL2. Last modified on 06/12/2012. Accessed on 20/06/2013. IUPHAR database (IUPHAR-DB), http://iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=78.


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