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

2008-04-01   Makoto Mark Taketo  , Kenji Kawada  

Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo, Kyoto 606-8501, Japan

Identity

HGNC
CXCR3
LOCATION
Xq13.1
LOCUSID
2833
ALIAS
CD182,CD183,CKR-L2,CMKAR3,CXC-R3,CXCR-3,GPR9,IP10,IP10-R,Mig-R,MigR

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.
Atlas Image
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.

Proteins

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

Entity name
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 name
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 name
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 name
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 name
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.

Article Bibliography

Pubmed IDLast YearTitleAuthors
170186072006Ras-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 et al
112087132001Regulated production of interferon-inducible T-cell chemoattractants by human intestinal epithelial cells.Dwinell MB et al
150815422004The expression of the chemokine receptor CXCR3 and its ligand, CXCL10, in human breast adenocarcinoma cell lines.Goldberg-Bittman L et al
106274722000The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia.Jones D et al
172974552007Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes.Kawada K et al
151730152004Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes.Kawada K et al
127827162003An 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 et al
90643561996Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes.Loetscher M et al
159812102005Clinical significance of CXCR3 and CXCR4 expression in primary melanoma.Longo-Imedio MI et al
86663801995Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14, encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin receptors.Marchese A et al
115712982001Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells.Robledo MM et al
150390472004CXC chemokines: the regulatory link between inflammation and angiogenesis.Romagnani P et al
155786852005Up-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 et al
168853722006Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer.Walser TC et al
174094502007CXCL10 promotes invasion-related properties in human colorectal carcinoma cells.Zipin-Roitman A et al

Other Information

Locus ID:

NCBI: 2833
MIM: 300574
HGNC: 4540
Ensembl: ENSG00000186810

Variants:

dbSNP: 2833
ClinVar: 2833
TCGA: ENSG00000186810
COSMIC: CXCR3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000186810ENST00000373691P49682
ENSG00000186810ENST00000373693P49682

Expression (GTEx)

0
5
10
15
20
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Cytokine-cytokine receptor interactionKEGGhsa04060
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
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

Protein levels (Protein atlas)

Not detected
Low
Medium
High
cerebral cortex
cerebellum
hippocampus
caudate
thyroid gland
parathyroid gland
adrenal gland
bronchus
lung
oral mucosa
salivary gland
esophagus
stomach 1
stomach 2
duodenum
colon
rectum
liver
gallbladder
pancreas
kidney
urinary bladder
testis
epididymis
seminal vesicle
prostate
vagina
ovary
fallopian tube
endometrium 1
endometrium 2
cervix, uterine
placenta
breast
heart muscle
smooth muscle
skeletal muscle
soft tissue 1
soft tissue 2
adipose tissue
skin 1
skin 2
appendix
spleen
lymph node
tonsil
bone marrow

References

Pubmed IDYearTitleCitations
379378172024The IFN-γ-CXCL9/CXCL10-CXCR3 axis in vitiligo: Pathological mechanism and treatment.4
379522162024The CXCL10-CXCR3 axis plays an important role in Kawasaki disease.0
383074102024Hyperactivation of β-catenin signal in hepatocellular carcinoma recruits myeloid-derived suppressor cells through PF4-CXCR3 axis.2
379378172024The IFN-γ-CXCL9/CXCL10-CXCR3 axis in vitiligo: Pathological mechanism and treatment.4
379522162024The CXCL10-CXCR3 axis plays an important role in Kawasaki disease.0
383074102024Hyperactivation of β-catenin signal in hepatocellular carcinoma recruits myeloid-derived suppressor cells through PF4-CXCR3 axis.2
364725882023Cxcr3 constrains pancreatic cancer dissemination through instructing T cell fate.0
364740022023IL-2/GM-CSF enhances CXCR3 expression in CAR-T cells via the PI3K/AKT and ERK1/2 pathways.3
366074762023Reciprocal expression of the immune response genes CXCR3 and IFI44L as module hubs are associated with patient survivals in primary central nervous system lymphoma.2
366213492023Clinical Significance of the Pre-Transplant CXCR3 and CCR6 Expression on T Cells In Kidney Graft Recipients.0
367509662023CXCR3 predicts the prognosis of endometrial adenocarcinoma.0
368988512023EBV-positive pyothorax-associated lymphoma expresses CXCL9 and CXCL10 chemokines that attract cytotoxic lymphocytes via CXCR3.2
375426612023CXCL9 and its Receptor CXCR3, an Important Link Between Inflammation and Cardiovascular Risks in RA Patients.4
364725882023Cxcr3 constrains pancreatic cancer dissemination through instructing T cell fate.0
364740022023IL-2/GM-CSF enhances CXCR3 expression in CAR-T cells via the PI3K/AKT and ERK1/2 pathways.3

Citation

Makoto Mark Taketo ; Kenji Kawada

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

Atlas Genet Cytogenet Oncol Haematol. 2008-04-01

Online version: http://atlasgeneticsoncology.org/gene/40224