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

Identity

Other namesCC-CKR-2
CCR2A
CCR2B
CD192
CKR2
CKR2A
CKR2B
CMKBR2
FLJ78302
MCP-1-R
MGC103828
MGC111760
MGC168006
HGNC (Hugo) CCR2
LocusID (NCBI) 729230
Location 3p21.31
Location_base_pair Starts at 46395235 and ends at 46402413 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Note 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.
 
Description 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
Transcription 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.
Pseudogene No pseudogenes have been reported for CCR2.

Protein

Note 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.
 
  Structure of CCR2. The typical serpentine structure is depicted with three extracellular (top) and three intracellular (bottom) loops and seven transmembrane domains.
Description 374 amino acids; 41915 Da.
Expression Peripheral blood monocytes, activated T cells, B cells and immature dendritic cells.
Localisation Cell membrane; multi-pass membrane protein.
Function 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.
Homology CCR2 proteins contains amino acid sequence homology to other C-C chemokines. CCR1 (56%), CCR5 (71%), CCR3 (78%), CCR4 (75%).

Implicated in

Entity Multiple myeloma
Prognosis 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.
Oncogenesis 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.
  
Entity Neuroblastoma
Oncogenesis 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.
  
Entity Melanoma
Oncogenesis 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.
  
Entity Prostate cancer
Prognosis 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.
Oncogenesis 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.
  
Entity Breast cancer
Prognosis Overexpression of the chemokine CCL2 is frequently associated with advanced tumor stage and metastatic relapse in breast cancer.
Oncogenesis 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.
  
Entity Esophageal carcinoma
Oncogenesis 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.
  
Entity Gastric cancer
Oncogenesis 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.
  

External links

Nomenclature
HGNC (Hugo)CCR2   1603
Cards
AtlasCCR2ID964ch3p21
Entrez_Gene (NCBI)CCR2  729230  chemokine (C-C motif) receptor 2
GeneCards (Weizmann)CCR2
Ensembl (Hinxton)ENSG00000121807 [Gene_View]  chr3:46395235-46402413 [Contig_View]  CCR2 [Vega]
ICGC DataPortalENSG00000121807
cBioPortalCCR2
AceView (NCBI)CCR2
Genatlas (Paris)CCR2
WikiGenes729230
SOURCE (Princeton)NM_001123041 NM_001123396
Genomic and cartography
GoldenPath (UCSC)CCR2  -  3p21.31   chr3:46395235-46402413 +  3p21   [Description]    (hg19-Feb_2009)
EnsemblCCR2 - 3p21 [CytoView]
Mapping of homologs : NCBICCR2 [Mapview]
OMIM601267   
Gene and transcription
Genbank (Entrez)AK292685 AK292920 AV715904 BC074751 BC095540
RefSeq transcript (Entrez)NM_001123041 NM_001123396
RefSeq genomic (Entrez)AC_000135 NC_000003 NC_018914 NG_021428 NT_022517 NW_001838877 NW_004929309
Consensus coding sequences : CCDS (NCBI)CCR2
Cluster EST : UnigeneHs.705362 [ NCBI ]
CGAP (NCI)Hs.705362
Alternative Splicing : Fast-db (Paris)GSHG0033960
Alternative Splicing GalleryENSG00000121807
Gene ExpressionCCR2 [ NCBI-GEO ]     CCR2 [ SEEK ]   CCR2 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP41597 (Uniprot)
NextProtP41597  [Medical]
With graphics : InterProP41597
Splice isoforms : SwissVarP41597 (Swissvar)
Domaine pattern : Prosite (Expaxy)G_PROTEIN_RECEP_F1_1 (PS00237)    G_PROTEIN_RECEP_F1_2 (PS50262)   
Domains : Interpro (EBI)Chemokine_CCR2 [organisation]   Chemokine_rcpt [organisation]   GPCR_Rhodpsn [organisation]   GPCR_Rhodpsn_7TM [organisation]  
Related proteins : CluSTrP41597
Domain families : Pfam (Sanger)7tm_1 (PF00001)   
Domain families : Pfam (NCBI)pfam00001   
DMDM Disease mutations729230
Blocks (Seattle)P41597
PDB (SRS)1KAD    1KP1   
PDB (PDBSum)1KAD    1KP1   
PDB (IMB)1KAD    1KP1   
PDB (RSDB)1KAD    1KP1   
Human Protein AtlasENSG00000121807 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP41597
IPIIPI00015137   IPI00218945   IPI00925634   
Protein Interaction databases
DIP (DOE-UCLA)P41597
IntAct (EBI)P41597
FunCoupENSG00000121807
BioGRIDCCR2
InParanoidP41597
Interologous Interaction database P41597
IntegromeDBCCR2
STRING (EMBL)CCR2
Ontologies - Pathways
Ontology : AmiGOblood vessel remodeling  dendritic cell chemotaxis  positive regulation of T-helper 1 type immune response  negative regulation of type 2 immune response  chemokine receptor activity  cytoplasm  cytosol  plasma membrane  plasma membrane  integral component of plasma membrane  cellular calcium ion homeostasis  chemotaxis  inflammatory response  immune response  cellular defense response  G-protein coupled receptor signaling pathway  negative regulation of adenylate cyclase activity  positive regulation of cytosolic calcium ion concentration  JAK-STAT cascade  response to wounding  regulation of vascular endothelial growth factor production  positive regulation of T cell chemotaxis  integral component of membrane  viral process  C-C chemokine receptor activity  negative regulation of angiogenesis  cytokine-mediated signaling pathway  cellular homeostasis  dendrite  CCR2 chemokine receptor binding  positive regulation of interferon-gamma production  positive regulation of interleukin-2 production  T-helper 17 cell chemotaxis  positive regulation of tumor necrosis factor biosynthetic process  protein homodimerization activity  neuronal cell body  perikaryon  negative regulation of eosinophil degranulation  innate immune response  positive regulation of alpha-beta T cell proliferation  perinuclear region of cytoplasm  positive regulation of inflammatory response  positive regulation of T cell activation  chemokine-mediated signaling pathway  positive regulation of monocyte chemotaxis  positive regulation of monocyte chemotaxis  positive regulation of immune complex clearance by monocytes and macrophages  positive regulation of monocyte extravasation  positive regulation of CD8-positive, alpha-beta T cell extravasation  positive regulation of astrocyte chemotaxis  positive regulation of hematopoietic stem cell migration  
Ontology : EGO-EBIblood vessel remodeling  dendritic cell chemotaxis  positive regulation of T-helper 1 type immune response  negative regulation of type 2 immune response  chemokine receptor activity  cytoplasm  cytosol  plasma membrane  plasma membrane  integral component of plasma membrane  cellular calcium ion homeostasis  chemotaxis  inflammatory response  immune response  cellular defense response  G-protein coupled receptor signaling pathway  negative regulation of adenylate cyclase activity  positive regulation of cytosolic calcium ion concentration  JAK-STAT cascade  response to wounding  regulation of vascular endothelial growth factor production  positive regulation of T cell chemotaxis  integral component of membrane  viral process  C-C chemokine receptor activity  negative regulation of angiogenesis  cytokine-mediated signaling pathway  cellular homeostasis  dendrite  CCR2 chemokine receptor binding  positive regulation of interferon-gamma production  positive regulation of interleukin-2 production  T-helper 17 cell chemotaxis  positive regulation of tumor necrosis factor biosynthetic process  protein homodimerization activity  neuronal cell body  perikaryon  negative regulation of eosinophil degranulation  innate immune response  positive regulation of alpha-beta T cell proliferation  perinuclear region of cytoplasm  positive regulation of inflammatory response  positive regulation of T cell activation  chemokine-mediated signaling pathway  positive regulation of monocyte chemotaxis  positive regulation of monocyte chemotaxis  positive regulation of immune complex clearance by monocytes and macrophages  positive regulation of monocyte extravasation  positive regulation of CD8-positive, alpha-beta T cell extravasation  positive regulation of astrocyte chemotaxis  positive regulation of hematopoietic stem cell migration  
Pathways : KEGGCytokine-cytokine receptor interaction    Chemokine signaling pathway   
Protein Interaction DatabaseCCR2
Wikipedia pathwaysCCR2
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)CCR2
snp3D : Map Gene to Disease729230
SNP (GeneSNP Utah)CCR2
SNP : HGBaseCCR2
Genetic variants : HAPMAPCCR2
Exome VariantCCR2
1000_GenomesCCR2 
ICGC programENSG00000121807 
Somatic Mutations in Cancer : COSMICCCR2 
CONAN: Copy Number AnalysisCCR2 
Mutations and Diseases : HGMDCCR2
Mutations and Diseases : intOGenCCR2
Genomic VariantsCCR2  CCR2 [DGVbeta]
dbVarCCR2
ClinVarCCR2
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM601267   
MedgenCCR2
GENETestsCCR2
Disease Genetic AssociationCCR2
Huge Navigator CCR2 [HugePedia]  CCR2 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneCCR2
Homology/Alignments : Family Browser (UCSC)CCR2
Phylogenetic Trees/Animal Genes : TreeFamCCR2
Chemical/Protein Interactions : CTD729230
Chemical/Pharm GKB GenePA26167
Clinical trialCCR2
Cancer Resource (Charite)ENSG00000121807
Other databases
Probes
Litterature
PubMed402 Pubmed reference(s) in Entrez
CoreMineCCR2
iHOPCCR2
OncoSearchCCR2

Bibliography

Identifying intercellular signaling genes expressed in malignant plasma cells by using complementary DNA arrays.
De Vos J, Couderc G, Tarte K, Jourdan M, Requirand G, Delteil MC, Rossi JF, Mechti N, Klein B.
Blood. 2001 Aug 1;98(3):771-80.
PMID 11468178
 
Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas.
Ohta M, Kitadai Y, Tanaka S, Yoshihara M, Yasui W, Mukaida N, Haruma K, Chayama K.
Int J Oncol. 2003 Apr;22(4):773-8.
PMID 12632067
 
Significance of macrophage chemoattractant protein-1 expression and macrophage infiltration in squamous cell carcinoma of the esophagus.
Koide N, Nishio A, Sato T, Sugiyama A, Miyagawa S.
Am J Gastroenterol. 2004 Sep;99(9):1667-74.
PMID 15330899
 
Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2.
Metelitsa LS, Wu HW, Wang H, Yang Y, Warsi Z, Asgharzadeh S, Groshen S, Wilson SB, Seeger RC.
J Exp Med. 2004 May 3;199(9):1213-21.
PMID 15123743
 
Monocyte chemoattractant protein-1 transfection induces angiogenesis and tumorigenesis of gastric carcinoma in nude mice via macrophage recruitment.
Kuroda T, Kitadai Y, Tanaka S, Yang X, Mukaida N, Yoshihara M, Chayama K.
Clin Cancer Res. 2005 Nov 1;11(21):7629-36.
PMID 16278381
 
Clinical significance of chemokine receptor (CCR1, CCR2 and CXCR4) expression in human myeloma cells: the association with disease activity and survival.
Vande Broek I, Leleu X, Schots R, Facon T, Vanderkerken K, Van Camp B, Van Riet I.
Haematologica. 2006 Feb;91(2):200-6.
PMID 16461304
 
Oestrogen receptor negative breast cancers exhibit high cytokine content.
Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, Boissiere F, Laune D, Roques S, Lazennec G.
Breast Cancer Res. 2007;9(1):R15.
PMID 17261184
 
Mutant MCP-1 therapy inhibits tumor angiogenesis and growth of malignant melanoma in mice.
Koga M, Kai H, Egami K, Murohara T, Ikeda A, Yasuoka S, Egashira K, Matsuishi T, Kai M, Kataoka Y, Kuwano M, Imaizumi T.
Biochem Biophys Res Commun. 2008 Jan 11;365(2):279-84. Epub 2007 Nov 6.
PMID 17991428
 
The inflammatory chemokines CCL2 and CCL5 in breast cancer.
Soria G, Ben-Baruch A.
Cancer Lett. 2008 Aug 28;267(2):271-85. Epub 2008 Apr 24. (REVIEW)
PMID 18439751
 
Chemokine (C-C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone.
Lu X, Kang Y.
J Biol Chem. 2009 Oct 16;284(42):29087-96. Epub 2009 Aug 31.
PMID 19720836
 
Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth.
Zhang J, Lu Y, Pienta KJ.
J Natl Cancer Inst. 2010 Apr 21;102(8):522-8. Epub 2010 Mar 16. (REVIEW)
PMID 20233997
 
CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis.
Zhang J, Patel L, Pienta KJ.
Cytokine Growth Factor Rev. 2010 Feb;21(1):41-8. Epub 2009 Dec 14. (REVIEW)
PMID 20005149
 
Osteoclast-gene expression profiling reveals osteoclast-derived CCR2 chemokines promoting myeloma cell migration.
Moreaux J, Hose D, Kassambara A, Reme T, Moine P, Requirand G, Goldschmidt H, Klein B.
Blood. 2011 Jan 27;117(4):1280-90. Epub 2010 Nov 19.
PMID 21097672
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written05-2011Jérôme Moreaux
Institut de Recherche en Biotherapie, INSERM U847, Hopital Saint-Eloi, CHU de Montpellier, 80 av Augustin Fliche, 34295 Montpellier Cedex 5, France

Citation

This paper should be referenced as such :
Moreaux, J
CCR2 (chemokine (C-C motif) receptor 2)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(11):938-941.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/CCR2ID964ch3p21.html

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indexed on : Sat Oct 4 13:08:00 CEST 2014

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