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CXCR3 (chemokine (C-X-C motif) receptor 3)

Written2008-04Makoto Mark Taketo, Kenji Kawada
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan

(Note : for Links provided by Atlas : click)

Identity

Other namesCD182
CD183
CKR-L2
CMKAR3
CXC-R3
CXCR-3
GPR9
IP10
IP10-R
Mig-R
MigR
HGNC (Hugo) CXCR3
LocusID (NCBI) 2833
Atlas_Id 40224
Location Xq13.1  [Link to chromosome band Xq13]
Location_base_pair Starts at 70835766 and ends at 70838367 bp from pter ( according to hg19-Feb_2009)  [Mapping CXCR3.png]
Note CXCR3 is a G protein-coupled receptor with selectivity for three chemokines, termed IP10 (CXCL10), Mig (CXCL9) and I-TAC (CXCL11). IP10, Mig and I-TAC belong to the structural subfamily of CXC chemokines, in which a single amino acid residue separates the first two of four highly conserved Cys residues. Binding of chemokines to CXCR3 induces cellular responses that are involved in leukocyte traffic, most notably integrin activation, cytoskeletal changes and chemotactic migration. A hallmark of CXCR3 is its prominent expression in in vitro cultured effector/memory T cells, and in T cells present in many types of inflamed tissues. In addition, IP10, Mig and I-TAC are commonly produced by local cells in inflammatory lesions, suggesting that CXCR3 and its chemokines participate in the recruitment of inflammatory cells.

DNA/RNA

Note CXCR3-A is a receptor for CXCL9, CXCL10 and CXCL11 and mediates the proliferation of human mesangial cells. CXCR3-B is a receptor for CXCL4 and also mediates the inhibitory activities of CXCL9, CXCL10 and CXCL11 on the growth of human microvascular endothelial cells. CXCR3-B may play a role in angiogenesis.
 
  The CXCR3 gene generates two distinct mRNAs.
Description Alternative splicing of the CXCR3 gene generates two distinct chemokine receptors. The CXCR3 gene generates two distinct mRNAs, resulting from alternative splicing of three different exons. The already known CXCR3, renamed CXCR3-A,results from splicing of a single intron. The first exon encodes 4 amino acids and the second exon encodes the remaining 312 amino acids. The recently identified splicing variant, CXCR3-B,results from an alternative splicing between the same donor site used by the known CXCR3-A and a novel acceptor site localized 233 base pairs upstream of the CXCR3-A acceptor site. This novel exon (exon2) encodes 51 different amino acids, which are selectively expressed in CXCR3-B.
Transcription CXCR3-A and CXCR3-B transcripts of 1.6 and 1.8 kb, respectively.

Protein

Description Size: 368 amino acids; 40660 Da.
Expression CXCR3-A and CXCR3-B are mainly expressed in the heart, kidney, liver and skeletal muscle. CXCR3-A is also expressed in the placenta.
Localisation Cell membrane; Multi-pass membrane protein.
Function Dijkstra et al. showed that human CCL21, in the absence of its primary receptor, CCR7, is a functional ligand for CXCR3, inducing chemotaxis in adult microglial cells, but not in kidney epithelial cells. CCL21 signaling through CXCR3 depends on the cellular background in which CXCR3 is expressed.
Lasagni et al. found that both CXCR3-A and CXCR3-B bound CXCL9, CXCL10, and CXCL11, but only CXCR3-B bound CXCL4 (PF4), following expression in a microvascular endothelial cell line. Overexpression of CXCR3-A induced an increase in endothelial cell survival, whereas overexpression of CXCR3-B upregulated apoptotic pathways. CXCR3B-specific monoclonal antibodies reacted with neoplastic tissue endothelial cells, providing evidence that CXCR3-B is expressed in vivo and may account for the angiostatic effects of CXC chemokines.

Implicated in

Note
Entity Melanoma
Prognosis Forty primary melanomas were analyzed. 57% of the tumors expressed CXCR3 and 35% expressed CXCR4 on the melanoma cells. Co-expression of both CXCR3 and CXCR4 conferred a significantly poorer outcome similar to the expression of CXCR4 alone.
Oncogenesis Several human melanoma cell lines as well as melanoma cells on macroscopically infiltrated lymph nodes express the chemokine receptors CXCR3 and CXCR4.
In a murine model with B16F10 melanoma cells, reduced CXCR3 expression by antisense RNA showed significantly reduced metastatic activities to lymph nodes.
  
Entity Breast cancer
Oncogenesis Activation of Ras in MDA-MB-435 and MCF-7 breast cancer cells promotes CXCL10 expression and down-regulates CXCR3-B expression to promote tumor cell proliferation.
In a murine model of metastatic breast cancer, a small molecular weight antagonist of CXCR3 inhibits lung metastasis.
  
Entity Colon cancer
Prognosis In 92 colon cancer samples, 31 samples (33.7%) expressed CXCR3 on cancer epithelial cells. The patients with CXCR3-positive tumors had a significantly poorer prognosis than those with CXCR3-negative tumors. In addition, the patients with tumors dobly positive for CXCR3 and CXCR4 had a significantly poorer prognosis than those with tumors positive only for CXCR4 or doubly negative.
Oncogenesis In a murine model of metastatic colon cancer, overexpression of CXCR3 significantly promotes lymph node metastasis, although metastasis to the liver or lung was unaffected.
  
Entity Renal cell carcinoma
Oncogenesis Real-time RT-PCR analysis showed that expression levels of I-TAC, Mig, and CXCR3 in RCC tissues were greater 14.9 times, 30.3 times, and 9.9 times, respectively, compared with the levels in the corresponding normal kidney tissues.
  
Entity B-cell Lymphoma
Oncogenesis CXCR3 expression was seen in 37 of 39 cases of chronic lymphocytic leukemia / small lymphocytic lymphoma, whereas mantle cell lymphoma (30 cases), follicular lymphoma (27 cases) and small noncleaved cell lymphoma (8 cases) were negative in all but 2 cases.
  

Bibliography

Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14, encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin receptors.
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Genomics. 1995 Sep 20;29(2):335-44.
PMID 8666380
 
Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes.
Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis I, Baggiolini M, Moser B.
J Exp Med. 1996 Sep 1;184(3):963-9.
PMID 9064356
 
The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia.
Jones D, Benjamin RJ, Shahsafaei A, Dorfman DM.
Blood. 2000 Jan 15;95(2):627-32.
PMID 10627472
 
Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells.
Dwinell MB, Lugering N, Eckmann L, Kagnoff MF.
Gastroenterology. 2001 Jan;120(1):49-59.
PMID 11208713
 
Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells.
Robledo MM, Bartolome RA, Longo N, Rodruiguez-Frade JM, Mellado M, Longo I, van Muijen GN, Sanchez-Mateos P, Teixido J.
J Biol Chem. 2001 Nov 30;276(48):45098-105. Epub 2001 Sep 24.
PMID 11571298
 
An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4.
Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Giannini S, Cosmi L, Sagrinati C, Mazzinghi B, Orlando C, Maggi E, Marra F, Romagnani S, Serio M, Romagnani P.
J Exp Med. 2003 Jun 2;197(11):1537-49.
PMID 12782716
 
The expression of the chemokine receptor CXCR3 and its ligand, CXCL10, in human breast adenocarcinoma cell lines.
Goldberg-Bittman L, Neumark E, Sagi-Assif O, Azenshtein E, Meshel T, Witz IP, Ben-Baruch A.
Immunol Lett. 2004 Mar 29;92(1-2):171-8.
PMID 15081542
 
Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes.
Kawada K, Sonoshita M, Sakashita H, Takabayashi A, Yamaoka Y, Manabe T, Inaba K, Minato N, Oshima M, Taketo MM.
Cancer Res. 2004 Jun 1;64(11):4010-7.
PMID 15173015
 
CXC chemokines: the regulatory link between inflammation and angiogenesis.
Romagnani P, Lasagni L, Annunziato F, Serio M, Romagnani S.
Trends Immunol. 2004 Apr;25(4):201-9.
PMID 15039047
 
Clinical significance of CXCR3 and CXCR4 expression in primary melanoma.
Longo-Imedio MI, Longo N, Trevino I, Lazaro P, Sanchez-Mateos P.
Int J Cancer. 2005 Dec 10;117(5):861-5.
PMID 15981210
 
Up-regulation of the interferon gamma (IFN-gamma)-inducible chemokines IFN-inducible T-cell alpha chemoattractant and monokine induced by IFN-gamma and of their receptor CXC receptor 3 in human renal cell carcinoma.
Suyama T, Furuya M, Nishiyama M, Kasuya Y, Kimura S, Ichikawa T, Ueda T, Nikaido T, Ito H, Ishikura H.
Cancer. 2005 Jan 15;103(2):258-67.
PMID 15578685
 
Ras-induced modulation of CXCL10 and its receptor splice variant CXCR3-B in MDA-MB-435 and MCF-7 cells: relevance for the development of human breast cancer.
Datta D, Flaxenburg JA, Laxmanan S, Geehan C, Grimm M, Waaga-Gasser AM, Briscoe DM, Pal S.
Cancer Res. 2006 Oct 1;66(19):9509-18.
PMID 17018607
 
Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer.
Walser TC, Rifat S, Ma X, Kundu N, Ward C, Goloubeva O, Johnson MG, Medina JC, Collins TL, Fulton AM.
Cancer Res. 2006 Aug 1;66(15):7701-7.
PMID 16885372
 
Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes.
Kawada K, Hosogi H, Sonoshita M, Sakashita H, Manabe T, Shimahara Y, Sakai Y, Takabayashi A, Oshima M, Taketo MM.
Oncogene. 2007 Jul 12;26(32):4679-88. Epub 2007 Feb 5.
PMID 17297455
 
CXCL10 promotes invasion-related properties in human colorectal carcinoma cells.
Zipin-Roitman A, Meshel T, Sagi-Assif O, Shalmon B, Avivi C, Pfeffer RM, Witz IP, Ben-Baruch A.
Cancer Res. 2007 Apr 1;67(7):3396-405.
PMID 17409450
 

Citation

This paper should be referenced as such :
Taketo, MM ; Kawada, K
CXCR3 (chemokine (C-X-C motif) receptor 3)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(3):191-193.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CXCR3ID40224chXq13.html


External links

Nomenclature
HGNC (Hugo)CXCR3   4540
Cards
AtlasCXCR3ID40224chXq13
Entrez_Gene (NCBI)CXCR3  2833  C-X-C motif chemokine receptor 3
AliasesCD182; CD183; CKR-L2; CMKAR3; 
GPR9; IP10-R; Mig-R; MigR
GeneCards (Weizmann)CXCR3
Ensembl hg19 (Hinxton)ENSG00000186810 [Gene_View]  chrX:70835766-70838367 [Contig_View]  CXCR3 [Vega]
Ensembl hg38 (Hinxton)ENSG00000186810 [Gene_View]  chrX:70835766-70838367 [Contig_View]  CXCR3 [Vega]
ICGC DataPortalENSG00000186810
TCGA cBioPortalCXCR3
AceView (NCBI)CXCR3
Genatlas (Paris)CXCR3
WikiGenes2833
SOURCE (Princeton)CXCR3
Genomic and cartography
GoldenPath hg19 (UCSC)CXCR3  -     chrX:70835766-70838367 -  Xq13   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)CXCR3  -     Xq13   [Description]    (hg38-Dec_2013)
EnsemblCXCR3 - Xq13 [CytoView hg19]  CXCR3 - Xq13 [CytoView hg38]
Mapping of homologs : NCBICXCR3 [Mapview hg19]  CXCR3 [Mapview hg38]
OMIM300574   
Gene and transcription
Genbank (Entrez)AF469635 AK313679 AY242128 BC034403 DQ892460
RefSeq transcript (Entrez)NM_001142797 NM_001504
RefSeq genomic (Entrez)NC_000023 NC_018934 NG_029076 NT_011651 NW_004929443
Consensus coding sequences : CCDS (NCBI)CXCR3
Cluster EST : UnigeneHs.198252 [ NCBI ]
CGAP (NCI)Hs.198252
Alternative Splicing GalleryENSG00000186810
Gene ExpressionCXCR3 [ NCBI-GEO ]   CXCR3 [ EBI - ARRAY_EXPRESS ]   CXCR3 [ SEEK ]   CXCR3 [ MEM ]
Gene Expression Viewer (FireBrowse)CXCR3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2833
GTEX Portal (Tissue expression)CXCR3
Protein : pattern, domain, 3D structure
UniProt/SwissProtP49682 (Uniprot)
NextProtP49682  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP49682
Splice isoforms : SwissVarP49682 (Swissvar)
PhosPhoSitePlusP49682
Domaine pattern : Prosite (Expaxy)G_PROTEIN_RECEP_F1_1 (PS00237)    G_PROTEIN_RECEP_F1_2 (PS50262)   
Domains : Interpro (EBI)Chemokine_CXCR3    Chemokine_rcpt    GPCR_Rhodpsn    GPCR_Rhodpsn_7TM   
Domain families : Pfam (Sanger)7tm_1 (PF00001)   
Domain families : Pfam (NCBI)pfam00001   
DMDM Disease mutations2833
Blocks (Seattle)CXCR3
SuperfamilyP49682
Human Protein AtlasENSG00000186810
Peptide AtlasP49682
HPRD02936
IPIIPI00027754   IPI00640020   IPI00651732   IPI00953042   
Protein Interaction databases
DIP (DOE-UCLA)P49682
IntAct (EBI)P49682
FunCoupENSG00000186810
BioGRIDCXCR3
STRING (EMBL)CXCR3
ZODIACCXCR3
Ontologies - Pathways
QuickGOP49682
Ontology : AmiGOangiogenesis  negative regulation of endothelial cell proliferation  regulation of leukocyte migration  receptor activity  chemokine receptor activity  cytoplasm  cytosol  plasma membrane  plasma membrane  integral component of plasma membrane  apoptotic process  movement of cell or subcellular component  chemotaxis  inflammatory response  cell adhesion  cell surface receptor signaling pathway  G-protein coupled receptor signaling pathway  G-protein coupled receptor signaling pathway  positive regulation of cytosolic calcium ion concentration  positive regulation of cell proliferation  external side of plasma membrane  T cell chemotaxis  C-X-C chemokine receptor activity  negative regulation of angiogenesis  calcium-mediated signaling  chemokine binding  C-X-C chemokine binding  positive regulation of cAMP metabolic process  positive regulation of cAMP-mediated signaling  positive regulation of angiogenesis  positive regulation of transcription from RNA polymerase II promoter  positive regulation of chemotaxis  positive regulation of release of sequestered calcium ion into cytosol  chemokine-mediated signaling pathway  chemokine (C-C motif) ligand 11 production  negative regulation of execution phase of apoptosis  positive regulation of execution phase of apoptosis  
Ontology : EGO-EBIangiogenesis  negative regulation of endothelial cell proliferation  regulation of leukocyte migration  receptor activity  chemokine receptor activity  cytoplasm  cytosol  plasma membrane  plasma membrane  integral component of plasma membrane  apoptotic process  movement of cell or subcellular component  chemotaxis  inflammatory response  cell adhesion  cell surface receptor signaling pathway  G-protein coupled receptor signaling pathway  G-protein coupled receptor signaling pathway  positive regulation of cytosolic calcium ion concentration  positive regulation of cell proliferation  external side of plasma membrane  T cell chemotaxis  C-X-C chemokine receptor activity  negative regulation of angiogenesis  calcium-mediated signaling  chemokine binding  C-X-C chemokine binding  positive regulation of cAMP metabolic process  positive regulation of cAMP-mediated signaling  positive regulation of angiogenesis  positive regulation of transcription from RNA polymerase II promoter  positive regulation of chemotaxis  positive regulation of release of sequestered calcium ion into cytosol  chemokine-mediated signaling pathway  chemokine (C-C motif) ligand 11 production  negative regulation of execution phase of apoptosis  positive regulation of execution phase of apoptosis  
Pathways : BIOCARTAIL12 and Stat4 Dependent Signaling Pathway in Th1 Development [Genes]    NO2-dependent IL 12 Pathway in NK cells [Genes]    mCalpain and friends in Cell motility [Genes]    Selective expression of chemokine receptors during T-cell polarization [Genes]   
Pathways : KEGGCytokine-cytokine receptor interaction    Chemokine signaling pathway   
REACTOMEP49682 [protein]
REACTOME PathwaysR-HSA-380108 Chemokine receptors bind chemokines [pathway]
REACTOME PathwaysR-HSA-418594 G alpha (i) signalling events [pathway]
NDEx Network
Atlas of Cancer Signalling NetworkCXCR3
Wikipedia pathwaysCXCR3
Orthology - Evolution
OrthoDB2833
GeneTree (enSembl)ENSG00000186810
Phylogenetic Trees/Animal Genes : TreeFamCXCR3
Homologs : HomoloGeneCXCR3
Homology/Alignments : Family Browser (UCSC)CXCR3
Gene fusions - Rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerCXCR3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CXCR3
dbVarCXCR3
ClinVarCXCR3
1000_GenomesCXCR3 
Exome Variant ServerCXCR3
ExAC (Exome Aggregation Consortium)CXCR3 (select the gene name)
Genetic variants : HAPMAP2833
Genomic Variants (DGV)CXCR3 [DGVbeta]
Mutations
ICGC Data PortalCXCR3 
TCGA Data PortalCXCR3 
Broad Tumor PortalCXCR3
OASIS PortalCXCR3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCXCR3 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CXCR3
DgiDB (Drug Gene Interaction Database)CXCR3
DoCM (Curated mutations)CXCR3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CXCR3 (select a term)
intoGenCXCR3
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
Diseases
DECIPHER (Syndromes)X:70835766-70838367  ENSG00000186810
CONAN: Copy Number AnalysisCXCR3 
Mutations and Diseases : HGMDCXCR3
OMIM300574   
MedgenCXCR3
Genetic Testing Registry CXCR3
NextProtP49682 [Medical]
TSGene2833
GENETestsCXCR3
Huge Navigator CXCR3 [HugePedia]
snp3D : Map Gene to Disease2833
BioCentury BCIQCXCR3
ClinGenCXCR3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2833
Chemical/Pharm GKB GenePA35049
Clinical trialCXCR3
Miscellaneous
canSAR (ICR)CXCR3 (select the gene name)
Probes
Litterature
PubMed217 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCXCR3
EVEXCXCR3
GoPubMedCXCR3
iHOPCXCR3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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