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CXCR2

Official Full Name
C-X-C motif chemokine receptor 2
Organism
Homo sapiens
GeneID
3579
Background
The protein encoded by this gene is a member of the G-protein-coupled receptor family. This protein is a receptor for interleukin 8 (IL8). It binds to IL8 with high affinity, and transduces the signal through a G-protein activated second messenger system. This receptor also binds to chemokine (C-X-C motif) ligand 1 (CXCL1/MGSA), a protein with melanoma growth stimulating activity, and has been shown to be a major component required for serum-dependent melanoma cell growth. This receptor mediates neutrophil migration to sites of inflammation. The angiogenic effects of IL8 in intestinal microvascular endothelial cells are found to be mediated by this receptor. Knockout studies in mice suggested that this receptor controls the positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. This gene, IL8RA, a gene encoding another high affinity IL8 receptor, as well as IL8RBP, a pseudogene of IL8RB, form a gene cluster in a region mapped to chromosome 2q33-q36. Alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Nov 2009]
Synonyms
CD182; IL8R2; IL8RA; IL8RB; CMKAR2; WHIMS2; CDw128b;
Bio Chemical Class
GPCR rhodopsin
Protein Sequence
MEDFNMESDSFEDFWKGEDLSNYSYSSTLPPFLLDAAPCEPESLEINKYFVVIIYALVFLLSLLGNSLVMLVILYSRVGRSVTDVYLLNLALADLLFALTLPIWAASKVNGWIFGTFLCKVVSLLKEVNFYSGILLLACISVDRYLAIVHATRTLTQKRYLVKFICLSIWGLSLLLALPVLLFRRTVYSSNVSPACYEDMGNNTANWRMLLRILPQSFGFIVPLLIMLFCYGFTLRTLFKAHMGQKHRAMRVIFAVVLIFLLCWLPYNLVLLADTLMRTQVIQETCERRNHIDRALDATEILGILHSCLNPLIYAFIGQKFRHGLLKILAIHGLISKDSLPKDSRPSFVGSSSGHTSTTL
Open
Disease
Asthma, Chronic obstructive pulmonary disease, Cystic fibrosis, Fungal infection, Gout, Hidradenitis suppurativa, Indeterminate colitis, Liver vascular disorder, Medical/surgical procedure injury, Melanoma, Myelodysplastic syndrome, Pain, Psoriasis, Schizophrenia, Solid tumour/cancer, Transplant rejection, Ulcerative colitis
Approved Drug
2 +
Clinical Trial Drug
12 +
Discontinued Drug
3 +

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Detailed Information

The CXCR2 gene belongs to the CXC chemokine receptor family and is a seven-transmembrane G protein-coupled receptor first identified in 1991. Particularly in immunological response, CXCR2 is very important in many physiological and pathological mechanisms. Mostly via binding to chemokines including IL-8 (interleukin-8), the protein produced by this gene is a vital regulator of leukocyte migration and inflammatory response, therefore helping to control neutrophil migration and contribute to the development of different disorders.

Structure and Function of CXCR2

The CXCR2 receptor protein plays a vital role in immune response through its interaction with various chemokines. By interacting with G proteins, this is a typical G protein-coupled receptor (GPCR) that starts intracellular signaling. Though mostly an IL-8 receptor, CXCR2 may also bind additional CXC chemokines including CXCL1, CXCL2, and CXCL3, therefore setting off a sequence of intracellular biological events.

CXCR2 is expressed in neutrophils, endothelial cells, and tumor cells. Neutrophils travel to inflammatory areas where they serve their immunological surveillance and defense roles upon CXCR2 activation. Under several physiological and pathological states, CXCR2 also shows its wide biological activities in processes like tumor development and angiogenesis.

Regulation and Expression of the CXCR2 Gene

Located on chromosome 2q34-q35, the CXCR2 gene forms a cluster with the CXCR1 gene. Crucially for CXCR2 expression control, its promoter region has a distinctive TATA box and many transcription factor binding sites including Sp1 and AP-2. Studies reveal many elements influence CXCR2 expression: oxygen levels, intracellular signaling pathways, and transcription factor binding.

In hypoxic conditions, for example, CXCR2 expression is commonly elevated through HIF-1 and NF-κB activation of transcription factors. Certain microRNAs (miRNAs) also control CXCR2 expression by targeting its mRNA, therefore influencing its stability or translation efficiency and hence CXCR2 expression levels.

Figure 1: MRNAs regulate CXCR2 expression, influencing diseases such as cancer, ischemic stroke, and neuropathic pain.Figure 1. miRNAs regulate CXCR2 expression. (Korbecki J, et al., 2022)

CXCR2 and Immune Response

Extensive research highlights CXCR2's critical role in the immune system, particularly in inflammation. The main immune cells in charge of clearing pathogens during infection and inflammation are neutrophils. With IL-8 as the main natural ligand, CXCR2 helps neutrophils identify infection or damage sites during their migration to infected or inflammatory regions.

Increased CXCR2 expression causes too strong neutrophil migration in chronic inflammatory illnesses like rheumatoid arthritis, asthma, and Crohn's disease, hence aggravating inflammation and tissue damage. Promoting tumor development and metastases within the tumor microenvironment, CXCR2 is also associated with tumor immune evasion.

Role of CXCR2 in Tumor Immunity

Recent studies show CXCR2's significance extends beyond inflammation to tumor growth, metastasis, and immune evasion. Lung, liver, and breast malignancies among other types of cancer have elevated CXCR2 expression. CXCR2 draws neutrophils to tumor locations in the tumor microenvironment, hence increasing angiogenesis that fuels and oxygenates tumor development. By means of several tumor-associated chemokines, CXCR2 also improves tumor cell motility and metastases, therefore enabling immune surveillance escape.

CXCR2 is thought to be a target in various cancer therapies. By specifically targeting CXCR2 or its ligands, tumor angiogenesis, metastases, and immune evasion may be sufficiently stopped, hence enhancing anti-tumor treatments. Currently in clinical studies, many small molecule inhibitors aiming at CXCR2 show great potential.

Signaling Mechanism of CXCR2

As a G protein-coupled receptor, CXCR2's signaling mechanism is complex. Upon activation, CXCR2 interacts with G proteins to activate downstream pathways. It primarily engages the Gαi protein with pathways like PI3K-Akt and the phosphoinositol-calcium second messenger system, regulating cell migration, proliferation, and differentiation.

G protein βγ subunits are vital in CXCR2 signaling, activating phospholipase C (PLC-β) to promote calcium release, affecting cell movement and function. CXCR2 signaling also involves intracellular protein kinases, like protein kinase C (PKC), crucial for receptor desensitization and internalization processes.

Moreover, CXCR2 interacts with numerous other receptors and molecules beyond single pathways, forming a complex "chemical synapse" that defines CXCR2's functions and mechanisms in different cell types.

CXCR2 Gene Mutations and Disease

CXCR2 gene mutations are closely linked to various diseases. CXCR2 deficiencies or functional abnormalities can lead to immune system disorders, causing immune-related diseases. For instance, CXCR2 knockout mice exhibit severe neutropenia, underscoring CXCR2's role in normal immune functions. Moreover, CXCR2 mutations are associated with congenital immune deficiencies, cancers, and inflammatory diseases.

Specific CXCR2 mutations may alter ligand binding affinity or signaling efficiency, triggering distinct pathological responses. Understanding CXCR2 gene mutations and mechanisms can provide theoretical bases for early diagnosis, treatment, and prevention of related diseases.

The potential of CXCR2 as a Therapeutic Target

CXCR2's pivotal role in numerous diseases presents it as a potential therapeutic target. Strategies focus on inhibiting ligand binding or disrupting its signaling pathways to mitigate CXCR2's adverse effects in inflammation and tumor progression.

For instance, various small molecule CXCR2 antagonists development shown excellent therapeutic results in preclinical research. These antagonists competitively block CXCR2 ligand binding, therefore reducing inflammation and limiting too strong neutrophil migration. Furthermore providing novel cancer therapeutic approaches, CXCR2 antagonists reduce tumor angiogenesis and metastases.

References:

  1. Korbecki J, Kupnicka P, et al. CXCR2 Receptor: Regulation of Expression, Signal Transduction, and Involvement in Cancer. Int J Mol Sci. 2022 Feb 16;23(4):2168.
  2. Lazennec G, Rajarathnam K, et al. CXCR2 chemokine receptor - a master regulator in cancer and physiology. Trends Mol Med. 2024 Jan;30(1):37-55.
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