CXCR4
GeneName
CXCR4
Summary
CXCR4, also known as CXCR-4, LAP3, or the SDF-1 receptor, is a 40kDa G protein-coupled receptor that is predominantly expressed on the surface of various immune cells, including T cells, B cells, and dendritic cells. It plays a pivotal role in mediating cell migration and chemotaxis in response to its ligand, CXCL12, and is involved in several biological processes such as brain development, neurogenesis, and immune responses. CXCR4 is localised to the plasma membrane and is associated with various cellular components, including early and late endosomes, lysosomes, and cytoplasmic vesicles. Its functions extend to binding with chemokines and acting as a co-receptor for certain viruses, facilitating their entry into host cells.
Importance
CXCR4 is relevant to: - Cancer metastasis, as it directs the migration of cancer cells to distant sites, influencing tumour progression. - HIV infection, where it serves as a co-receptor for viral entry into host cells, making it a target for antiviral therapies. - Autoimmune diseases due to its role in regulating immune cell trafficking and inflammatory responses. - Neurodegenerative diseases, given its involvement in neurogenesis and myelin maintenance, highlighting its potential in neuroprotective strategies.
Top Products
For researchers investigating CXCR4, we highly recommend the top-selling recombinant monoclonal antibody, Anti-CXCR4 antibody [UMB2] (ab124824). This antibody has been validated for use in a variety of applications, including flow cytometry (FC), western blotting (WB), immunohistochemistry (IHC), and immunocytochemistry (ICC), making it a versatile tool for your research needs. With 284 citations, it is well-regarded in the scientific community, reflecting its reliability and effectiveness in CXCR4 detection. The CXCR4 peptide ELISA Kit (ab256223) is an excellent option for researchers looking to measure CXCR4 levels in their samples.
Abcam Product Citation Summary
The data indicates a significant focus on the role of CXCR4 in various cancer contexts, particularly in human renal cell carcinoma and colorectal cancer. The use of immunohistochemistry and western blotting across multiple studies highlights the importance of CXCR4 in understanding tumour biology, metastasis prediction, and cellular interactions. Additionally, studies involving mouse models provide insights into the developmental and pathological roles of CXCR4 in tissues such as the hippocampus and bone marrow.
Abcam Product Citation Table
Domain
The amino-terminus is critical for ligand binding. Residues in all four extracellular regions contribute to HIV-1 coreceptor activity.
The P-X-P-P motif is phosphorylated in response to ligand binding, promoting. association with beta-arrestin ARRB1.
Function
Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation (PubMed:10074102, PubMed:10452968, PubMed:10644702, PubMed:10825158, PubMed:18799424, PubMed:20048153, PubMed:20505072, PubMed:24912431, PubMed:28978524, PubMed:8752280, PubMed:8752281). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase (PubMed:16725153, PubMed:17197449, PubMed:18799424, PubMed:39093700). CXCR4 is coupled to G(i) G alpha proteins and mediates inhibition of adenylate cyclase (PubMed:17197449, PubMed:39093700). Involved in the AKT signaling cascade (PubMed:24912431). Plays a role in regulation of cell migration, e.g. during wound healing (PubMed:28978524). Also acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels (PubMed:20228059). Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). Involved in hematopoiesis and in cardiac ventricular septum formation (By similarity). Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells (By similarity). Involved in cerebellar development; in the CNS, could mediate hippocampal-neuron surviva (By similarity).
(Microbial infection) Acts as a coreceptor (CD4 being the primary receptor) for human immunodeficiency virus-1/HIV-1 X4 isolates and as a primary receptor for some HIV-2 isolates. Promotes Env-mediated fusion of the virus (PubMed:10074122, PubMed:10756055, PubMed:8849450, PubMed:8929542, PubMed:9427609).
Involvement in disease
WHIM syndrome 1
WHIMS1
An autosomal dominant immunologic disease characterized by neutropenia, hypogammaglobulinemia and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis.
None
The disease is caused by variants affecting the gene represented in this entry.
CXCR4 mutations play a role in the pathogenesis of Waldenstroem macroglobulinemia (WM) and influence disease presentation and outcome, as well as response to therapy. WM is a B-cell lymphoma characterized by accumulation of malignant lymphoplasmacytic cells in the bone marrow, lymph nodes and spleen, and hypersecretion of monoclonal immunoglobulin M (IgM). Excess IgM production results in serum hyperviscosity, tissue infiltration, and autoimmune-related pathology.
Post-translational modifications
Phosphorylated on agonist stimulation (PubMed:20048153, PubMed:37209686). Phosphorylation of the P-X-P-P motif promotes association with beta-arrestin ARRB1, leading to receptor desensitization and negative regulation of G-protein coupled receptor signaling (PubMed:37209686). Phosphorylation at Ser-324 and Ser-325 leads to recruitment of ITCH, ubiquitination and protein degradation (PubMed:14602072, PubMed:19116316).
Ubiquitinated after ligand binding, leading to its degradation (PubMed:28978524). Ubiquitinated by ITCH at the cell membrane on agonist stimulation (PubMed:14602072, PubMed:34927784). The ubiquitin-dependent mechanism, endosomal sorting complex required for transport (ESCRT), then targets CXCR4 for lysosomal degradation. This process is dependent also on prior Ser-/Thr-phosphorylation in the C-terminal of CXCR4. Also binding of ARRB1 to STAM negatively regulates CXCR4 sorting to lysosomes though modulating ubiquitination of SFR5S.
Sulfation on Tyr-21 is required for efficient binding of CXCL12/SDF-1alpha and promotes its dimerization. Tyr-7 and Tyr-12 are sulfated in a sequential manner after Tyr-21 is almost fully sulfated, with the binding affinity for CXCL12/SDF-1alpha increasing with the number of sulfotyrosines present. Sulfotyrosines Tyr-7 and Tyr-12 occupy clefts on opposing CXCL12 subunits, thus bridging the CXCL12 dimer interface and promoting CXCL12 dimerization.
O- and N-glycosylated. Asn-11 is the principal site of N-glycosylation. There appears to be very little or no glycosylation on Asn-176. N-glycosylation masks coreceptor function in both X4 and R5 laboratory-adapted and primary HIV-1 strains through inhibiting interaction with their Env glycoproteins. The O-glycosylation chondroitin sulfate attachment does not affect interaction with CXCL12/SDF-1alpha nor its coreceptor activity.
Sequence Similarities
Belongs to the G-protein coupled receptor 1 family.
Tissue Specificity
Expressed in numerous tissues, such as peripheral blood leukocytes, spleen, thymus, spinal cord, heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, cerebellum, cerebral cortex and medulla (in microglia as well as in astrocytes), brain microvascular, coronary artery and umbilical cord endothelial cells. Isoform 1 is predominant in all tissues tested.
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Cell junction
- Early endosome
- Late endosome
- Lysosome
- In unstimulated cells, diffuse pattern on plasma membrane (PubMed:10452968, PubMed:14602072, PubMed:21540189). On agonist stimulation, colocalizes with ITCH at the plasma membrane where it becomes ubiquitinated (PubMed:14602072). In the presence of antigen, distributes to the immunological synapse forming at the T-cell-APC contact area, where it localizes at the peripheral and distal supramolecular activation cluster (SMAC) (PubMed:20215400).
Alternative names
CD184, C-X-C chemokine receptor type 4, CXC-R4, CXCR-4, FB22, Fusin, HM89, LCR1, Leukocyte-derived seven transmembrane domain receptor, Lipopolysaccharide-associated protein 3, NPYRL, Stromal cell-derived factor 1 receptor, LESTR, LAP-3, LPS-associated protein 3, SDF-1 receptor, CXCR4
Database links
swissprot:P61073 entrezGene:7852 omim:162643
Other research areas
- Cardiovascular
- Immunology & Infectious Disease
- Oncology