CCR2 (chemokine (C-C motif) receptor 2)

2011-05-01   Jérôme Moreaux 

Institut de Recherche en Biotherapie, INSERM U847, Hopital Saint-Eloi, CHU de Montpellier, 80 av Augustin Fliche, 34295 Montpellier Cedex 5, France





CCR2 is a member of the beta chemokine receptor family. CCR2 is a seven transmembrane protein similar to G protein-coupled receptors. This gene encodes two isoforms of a receptor for monocyte chemoattractant protein-1, a chemokine which specifically mediates monocyte chemotaxis. Monocyte chemoattractant protein-1 is involved in monocyte infiltration in inflammatory diseases such as rheumatoid arthritis as well as in the inflammatory response against tumors. The receptors encoded by this gene mediate agonist-dependent calcium mobilization and inhibition of adenylyl cyclase. This gene is located in the chemokine receptor gene cluster region including CCR1, CCRL2, CCR3, CCR5 and CCXCR1 on chromosome 3p.
Atlas Image


Size: 7195 bases.
2 isoforms:
- C-C chemokine receptor type 2 isoform A. CCDS43078.1
- C-C chemokine receptor type 2 isoform B. CCDS46813.1


Homo sapiens chemokine (C-C motif) receptor 2 (CCR2), transcript variant A, mRNA: 2689 bp.
Homo sapiens chemokine (C-C motif) receptor 2 (CCR2), transcript variant B, mRNA: 2335 bp.


No pseudogenes have been reported for CCR2.



Chemokine receptors are cytokine receptors found on the surface of cells, which interact with a type of cytokine called a chemokine. They have a 7 transmembrane structure and couple to G-protein for signal transduction within a cell, making them members of a large protein family of G protein-coupled receptors. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium (Ca2+) ions (calcium signaling). This causes cell responses, including the onset of a process known as chemotaxis that traffics the cell to a desired location within the organism. Chemokine receptors share many common structural features; they are composed of about 350 amino acids that are divided into a short and acidic N-terminal end, seven helical transmembrane domains with three intracellular and three extracellular hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues that act as phosphorylation sites during receptor regulation. The first two extracellular loops of chemokine receptors are linked together by disulfide bonding between two conserved cysteine residues. The N-terminal end of a chemokine receptor binds to chemokine(s) and is important for ligand specificity. G-proteins couple to the C-terminal end, which is important for receptor signaling following ligand binding.
Atlas Image
Structure of CCR2. The typical serpentine structure is depicted with three extracellular (top) and three intracellular (bottom) loops and seven transmembrane domains.


374 amino acids; 41915 Da.


Peripheral blood monocytes, activated T cells, B cells and immature dendritic cells.


Cell membrane; multi-pass membrane protein.


Receptor for the MCP-1/CCL2, MCP-3/CCL7 and MCP-4/CCL13 chemokines. Transduces a signal by increasing the intracellular calcium ions level. Alternative coreceptor with CD4 for HIV-1 infection.


CCR2 proteins contains amino acid sequence homology to other C-C chemokines. CCR1 (56%), CCR5 (71%), CCR3 (78%), CCR4 (75%).

Implicated in

Entity name
In a cohort of 80 patients with Multiple Myeloma (MM), patients with active disease showed significant lower expression of CCR1, CCR2 and CXCR4 than patients with non-active disease.
CCR1 and CCR2 are overexpressed in myeloma cells compared to normal B cells. Osteoclasts express genes coding for CCR2 chemokines specifically (CCL2, CCL7, CCL8, and CCL13) and high CCR2 gene expression in myeloma cells is associated with increased bone lesions in MM patients. CCR2 is significantly overexpressed in MM cells compared to normal bone marrow plasma cells. Osteoclasts can directly recruit MMC by CCR2 chemokines production, promote MMC survival, growth, and drug resistance by producing various growth factors. MMC will promote osteoclast progenitor recruitment and differentiation producing CCL3, MIP-1beta, and CXCL12 chemokines, IGF-1, and increasing RANKL production by stromal cells. Osteoclasts are the main cells in the BM environment that produce various CCR2 chemokines enabling malignant plasma cells attraction.
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98 untreated primary neuroblastomas from patients with metastatic disease were analyzed for tumor-infiltrating iNKTs (Valpha24-Jalpha18-invariant natural killer T cells) using RT-PCR and immunofluorescent microscopy. 53% of tumors contained iNKTs. CCR2 is more frequently expressed by iNKT compared to T cells and natural killer cells from blood. iNKTs migrate toward neuroblastoma cells in a CCL2-dependent manner, preferentially infiltrating MYCN nonamplified proto-oncogene tumors that express CCL2.
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MCP-1 may play a role in tumor angiogenesis and early tumor growth of human malignant melanoma by inducing VEGF and inflammatory cytokines production (IL-1alpha and TNFalpha by the tumor-associated macrophages (TAM) and autocrine/paracrine effects on melanoma cells in a mouse model.
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Prostate cancer
The pleiotropic roles of CCL2 in the development of prostate cancer are mediated through its receptor, CCR2. An association between prostate cancer progression and CCR2 expression was demonstrated on tissue microarray specimens of patients. CCR2 mRNA and protein were significantly overexpressed within prostate cancer metastatic tissues compared to localized prostate cancer and benign prostate tissue. CCR2 overexpression was also associated with higher Gleason score and higher clinical pathologic stages.
CCL2 support prostate cancer cell survival via PI3K/AKT in vitro. CCL2 derived from human bone marrow endothelial cells induces PC-3 cell line transendothelial cell migration via activation of the small GTPase Rac. In a cell co-culture system, prostate cancer cell-conditioned medium induces CCL2 overexpression in endothelial cells and osteoblasts. In osteoblasts, this secretion is mediated in part by parathyroid hormone-related protein.
In mouse model, neutralizing antibody against CCL2 inhibits prostate cancer PC-3 and VCaP growth in bone. Same results were obtained with CCL2 knockdown. CCL2 induces surviving expression in prostate cancer cells and protect them from autophagic death.
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Breast cancer
Overexpression of the chemokine CCL2 is frequently associated with advanced tumor stage and metastatic relapse in breast cancer.
Overexpression of CCL2 promotes breast cancer metastasis to both lung and bone in mice. Blocking CCL2 with a neutralizing antibody reduced lung and bone metastases. The enhancement of lung metastases by CCL2 was associated with increased macrophage infiltration. In bone, it was associated with osteoclast differentiation. CCL2 produced by breast tumor cells activates CCR2 positive stromal cells of monocytic origin (including macrophages and preosteoclasts) leading to metastases in lung and bone.
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Esophageal carcinoma
CCL2 is expressed by tumor cells of esophageal squamous cell carcinoma. CCL2 produced by tumor cell and CCR2 expressed on vascular endothelial cells may participate in esophageal carcinoma tumor angiogenesis.
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Gastric cancer
CCL2 produced by human gastric carcinoma cells is involved in angiogenesis via macrophage recruitment and activation via CCR2. CCL2 produced by gastric carcinoma cells induces tumor growth in ectopic xenografts and increased tumorigenicity and induced lymph node metastases and ascites in orthotopic xenografts.


Pubmed IDLast YearTitleAuthors
172611842007Oestrogen receptor negative breast cancers exhibit high cytokine content.Chavey C et al
114681782001Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays.De Vos J et al
179914282008Mutant MCP-1 therapy inhibits tumor angiogenesis and growth of malignant melanoma in mice.Koga M et al
153308992004Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus.Koide N et al
162783812005Monocyte chemoattractant protein-1 transfection induces angiogenesis and tumorigenesis of gastric carcinoma in nude mice via macrophage recruitment.Kuroda T et al
197208362009Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone.Lu X et al
151237432004Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2.Metelitsa LS et al
210976722011Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration.Moreaux J et al
126320672003Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas.Ohta M et al
184397512008The inflammatory chemokines CCL2 and CCL5 in breast cancer.Soria G et al
164613042006Clinical significance of chemokine receptor (CCR1, CCR2 and CXCR4) expression in human myeloma cells: the association with disease activity and survival.Vande Broek I et al
202339972010Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth.Zhang J et al
200051492010CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis.Zhang J et al

Other Information

Locus ID:

NCBI: 729230
MIM: 601267
HGNC: 1603
Ensembl: ENSG00000121807


dbSNP: 729230
ClinVar: 729230
TCGA: ENSG00000121807


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Cytokine-cytokine receptor interactionKEGGhsa04060
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Beta defensinsREACTOMER-HSA-1461957
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class A/1 (Rhodopsin-like receptors)REACTOMER-HSA-373076
Peptide ligand-binding receptorsREACTOMER-HSA-375276
Chemokine receptors bind chemokinesREACTOMER-HSA-380108
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (i) signalling eventsREACTOMER-HSA-418594
Antimicrobial peptidesREACTOMER-HSA-6803157
Interleukin-10 signalingREACTOMER-HSA-6783783

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
173640262007Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites.416
206810572010The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases.137
199042832010Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks.136
123748652002HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels.104
172952032007Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2.103
246393502014CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile.101
177034122007Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes.100
197208362009Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone.92
204837502010Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2.92
116941032001Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data.85


Jérôme Moreaux

CCR2 (chemokine (C-C motif) receptor 2)

Atlas Genet Cytogenet Oncol Haematol. 2011-05-01

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