CXCR1 (chemokine (C-X-C motif) receptor 1)

2013-06-01   Sivan Sapoznik , Stav Kozlovski , Gal Markel 

Identity

HGNC
LOCATION
2q35
LOCUSID
ALIAS
C-C,C-C-CKR-1,CD128,CD181,CDw128a,CKR-1,CMKAR1,IL8R1,IL8RA,IL8RBA
FUSION GENES

DNA/RNA

Description

The CXCR1 gene (il8ra) is 4149 bp long and is composed of two exons, one of them included in the coding region (1053 bp) CXCR1 has 165 known SNPs; many of them correlate with disease states.
Genetic locus: CXCR1, together with its homolog CXCR2 (76% amino acids identity) and its pseudogene (il8rp), reside in chromosome 2q34-35. The high homology and close chromosomal localization between the three genes suggest gene duplications.

Transcription

Transcripts: primer extension analysis revealed two start sites for CXCR1 (Sprenger et al., 1995). In addition, neutrophils contain two transcripts of CXCR1 (2.0 and 4.0 kb) which result from the usage of alternative poly adenylation signals.
Transcription regulators: PU.1, which belongs to the ets family of transcription factors, is a major activator of CXCR1 expression (Wilkinson and Navarro, 1999). HIF1 and NF-kappaB mediate the transcription of CXCR1 under hypoxia in prostate cancer cells (Maxwell et al., 2007). CXCR1 mRNA expression is also regulated by G-CSF (Lloyd et al., 1995).

Pseudogene

Conservation during evolution: the CXCR1 gene was present in the common ancestor of chordates and has orthologs in diverse species, from lizards and Xenopus to primates. There is a high level of homology between CXCR1 from human, rabbit, rat, and mouse. The sequencing of the coding region of CXCR1 in worldwide human populations and 5 representative nonhuman primate species revealed accelerated protein evolution in the human lineage, mainly at the N-terminal ligand/receptor recognition domain (Liu et al., 2005).

Proteins

Description

350 amino acids, 39791 Da.
CXCR1 is a G protein coupled receptor (GPCR), composed of seven transmembrane (TM) helices, an N-terminal ligand binding domain and a signaling cytoplasmic tail.

Expression

Expression in tissues: according to SAGE (serial analysis of gene expression), CXCR1 is mainly expressed in the bone marrow, retina, heart, lungs and in the placenta.
Expression in cell types: CXCR1 is expressed on a wide variety of cell types, including neutrophils, monocytes, CD8 T cells, mast cells, basophils, natural killer cells, keratinocytes, fibroblasts, neurons, endothelial cells, and melanocytes.
Expression regulators: CXCR1 was found to be up-regulated by IL6, by a yet-unknown mechanism (Eikawa et al., 2010).

Localisation

CXCR1 resides in the plasma membrane and transduces signals into the cell (figure 1).
Atlas Image
Figure 1.

Function

Upon binding to its ligands, CXCR1 transduces signals via the phosphatidylinositol-calcium second messenger system and plays an important role in acute inflammation. IL-8 (CXCL8), the main ligand of CXCR1, is a powerful neutrophil chemotactic factor and its binding to CXCR1 induces activation and migration of neutrophils (Holmes et al., 1991; Liu et al., 2005). In neutrophils, receptor activation also stimulates the release of granule enzymes and the generation of superoxide in respiratory burst (Jones et al., 1996). In addition to its effect on immune cells, CXCR1 may be important in regulating vasculogenesis and consequent tumor growth (Strieter et al., 1995). The signaling pathway of CXCR1 as a G protein coupled receptor is presented in figure 1. Noteworthy, CXCR1 signaling also activates monomeric, low molecular weight G proteins of the Ras and Rho families (Laudanna et al., 1996).
Ligand selectivity: CXCR1 displays a relatively narrow selectivity and high preference for IL-8. At low affinity it also binds MGSA/GRO.

Implicated in

Entity name
Melanoma
Note
Highly expressed by melanoma cells and and mediates their proliferation and invasiveness in vitro and tumor growth in mice experiments (Singh et al., 2009). Recently, it was shown as a potential target for T cell engineering, a finding which highly impacts on adoptive cell immune-therapy for melanoma patients (Sapoznik et al., 2012).
Entity name
Breast cancer
Note
CXCR1 is over-expressed in tumor and cascular endothelial cells, as shown by immunohistochemistry studies on a cohort of 50 breast cancer patients performed by Miller et al. (Miller et al., 1998). Recently, Singh and his colleagues showed that CXCR1 as well as CXCR2 are important mediators of breast cancer stem-like cells activity. Furthermore, blockade of CXCR1 and CXCR2 adds to the inhibitory effect of HER2-targeted therapy on these cells and may potentially serve as a novel therapeutic strategy for breast cancer (Singh et al., 2013).
Note
CXCR1 is over-expressed in colorectal cancer cells (Abolhassani et al., 2008) and antagonists of CXCR1 and CXCR2 inhibit liver metastases of human colon cancer in a murine model (Varney et al., 2011). Interestingly, based on two large cohorts of population incident studies, Bondurant and his colleagues were recently able to show that SNPs in genes connected with the IL8 pathway (including CXCR1 and CXCR2) are associated with higher risk of both colon and rectal cancers (Bondurant et al., 2013).
Entity name
Prostate cancer
Note
CXCR1 is over-expressed in tumor cells from human prostate biopsies (Murphy et al., 2005). Depletion of CXCR1 by RNA interference in androgen-independent human prostate cancer cells induces cell death and reduced proliferation in vitro (Shamaladevi et al., 2009). In consistence with that, down- regulation of CXCR1 by shRNA or by a specific antagonist lead to inhibition of human xenograft growth in immune-deficient mice (Shamaladevi et al., 2009; Liu et al., 2012).
Entity name
Nasopharyngeal carcinoma
Note
Immune-histochemical analysis of 30 patients with nasopharyngeal carcinoma proved that its expression in tumor tissue significantly correlates with a shorter overall survival rate. Thus it is an indicator of poor prognosis in nasopharyngeal carcinoma (Horikawa et al., 2005).
Entity name
Chronic obstractive pulmonary disease (COPD)
Note
CXCR1 polymorphisms are identified polymorphisms associated with COPD and asthma, as shown by Stemmler et al. by screening 50 COPD patients (Stemmler et al., 2005). Pignatti and colleagues found that neutrophilic asthma patients have similar expression levels of CXCR1 as COPD patients and that CXCR1 expression is negatively correlated with the inflammatory infiltrate in the airways (Pignatti et al., 2005).
Entity name
Urinary tract infection recurrent
Note
CXCR1 was first identified as a candidate gene for urinary tract infections when Godaly et al showed that mIL-8Rh mutant mice developed acute pyelonephiritis with severe renal scattering (Godaly et al., 2001). Lundstedt et al. have afterwards identified two sequence variants which were shown to impair transcription of CXCR1 and led to reduced levels of the CXCR1 protein in children prone to urinary tract infections (Lundstedt et al., 2007).
Entity name
Psoriasis
Note
A single study by Arenberger et al showed in a small cohort of psoriasis patients that CXCR1 is slightly though significantly over-expressed in polymorphonuclear leukocyte infiltration in the epidermis as compared to normal volunteers (Arenberger et al., 1992).

Bibliography

Pubmed IDLast YearTitleAuthors
190109172008Leptin receptor-related immune response in colorectal tumors: the role of colonocytes and interleukin-8.Abolhassani M et al
13612771992Interleukin-8 receptors in normal and psoriatic polymorphonuclear leukocytes.Arenberger P et al
226742962013Interleukin genes and associations with colon and rectal cancer risk and overall survival.Bondurant KL et al
210481142010Enrichment of Foxp3+ CD4 regulatory T cells in migrated T cells to IL-6- and IL-8-expressing tumors through predominant induction of CXCR1 by IL-6.Eikawa S et al
114043742001Neutrophil recruitment, chemokine receptors, and resistance to mucosal infection.Godaly G et al
18407011991Structure and functional expression of a human interleukin-8 receptor.Holmes WE et al
156303682005Expression of interleukin-8 receptor A predicts poor outcome in patients with nasopharyngeal carcinoma.Horikawa T et al
86928781996Different functions for the interleukin 8 receptors (IL-8R) of human neutrophil leukocytes: NADPH oxidase and phospholipase D are activated through IL-8R1 but not IL-8R2.Jones SA et al
85849341996Role of Rho in chemoattractant-activated leukocyte adhesion through integrins.Laudanna C et al
230190132012G31P, an antagonist against CXC chemokine receptors 1 and 2, inhibits growth of human prostate cancer cells in nude mice.Liu X et al
162059792005Molecular evolution of CXCR1, a G protein-coupled receptor involved in signal transduction of neutrophils.Liu Y et al
74993111995Granulocyte-colony stimulating factor and lipopolysaccharide regulate the expression of interleukin 8 receptors on polymorphonuclear leukocytes.Lloyd AR et al
177861972007A genetic basis of susceptibility to acute pyelonephritis.Lundstedt AC et al
175333742007HIF-1 and NF-kappaB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells.Maxwell PJ et al
95680591998Expression of interleukin-8 receptors on tumor cells and vascular endothelial cells in human breast cancer tissue.Miller LJ et al
159303472005Nonapical and cytoplasmic expression of interleukin-8, CXCR1, and CXCR2 correlates with cell proliferation and microvessel density in prostate cancer.Murphy C et al
156375522005Downmodulation of CXCL8/IL-8 receptors on neutrophils after recruitment in the airways.Pignatti P et al
224416572012CXCR1 as a novel target for directing reactive T cells toward melanoma: implications for adoptive cell transfer immunotherapy.Sapoznik S et al
198615392009CXC receptor-1 silencing inhibits androgen-independent prostate cancer.Shamaladevi N et al
231498202013Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms.Singh JK et al
194016892009CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion.Singh S et al
85301631995Promoter analysis of the human interleukin-8 receptor genes, IL-8RA and IL-8RB.Sprenger H et al
157726812005Association of interleukin-8 receptor alpha polymorphisms with chronic obstructive pulmonary disease and asthma.Stemmler S et al
75390291995Role of C-X-C chemokines as regulators of angiogenesis in lung cancer.Strieter RM et al
210359462011Small molecule antagonists for CXCR2 and CXCR1 inhibit human colon cancer liver metastases.Varney ML et al
98678621999PU.1 regulates the CXCR1 promoter.Wilkinson NC et al

Other Information

Locus ID:

NCBI: 3577
MIM: 146929
HGNC: 6026
Ensembl: ENSG00000163464

Variants:

dbSNP: 3577
ClinVar: 3577
TCGA: ENSG00000163464
COSMIC: CXCR1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000163464ENST00000295683P25024

Expression (GTEx)

0
100
200
300
400
500
600
700
800

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Epithelial cell signaling in Helicobacter pylori infectionKEGGko05120
Cytokine-cytokine receptor interactionKEGGhsa04060
Epithelial cell signaling in Helicobacter pylori infectionKEGGhsa05120
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
EndocytosisKEGGko04144
EndocytosisKEGGhsa04144
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
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
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
Neutrophil degranulationREACTOMER-HSA-6798695

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
235250412013Layer V cortical neurons require microglial support for survival during postnatal development.189
230861462012Structure of the chemokine receptor CXCR1 in phospholipid bilayers.153
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
180592792007Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease.89
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
275782142016The CXCL8-CXCR1/2 pathways in cancer.84
246788122014The CXCL8/IL-8 chemokine family and its receptors in inflammatory diseases.77
241394012013Staphylococcus aureus leukotoxin ED targets the chemokine receptors CXCR1 and CXCR2 to kill leukocytes and promote infection.67
250813832014The IL-8/CXCR1 axis is associated with cancer stem cell-like properties and correlates with clinical prognosis in human pancreatic cancer cases.58
164110612006Polymorphisms in inflammation-related genes and risk of gastric cancer (Finland).47

Citation

Sivan Sapoznik ; Stav Kozlovski ; Gal Markel

CXCR1 (chemokine (C-X-C motif) receptor 1)

Atlas Genet Cytogenet Oncol Haematol. 2013-06-01

Online version: http://atlasgeneticsoncology.org/gene/40966/cxcr1-(chemokine-(c-x-c-motif)-receptor-1)