CXCR4

This gene encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. The protein has 7 transmembrane regions and is located on the cell surface. It acts with the CD4 protein to support HIV entry into cells and is also highly expressed in breast cancer cells. Mutations in this gene have been associated with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq]

C-X-C Motif Chemokine Receptor 4

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:10452968, PubMed:28978524, PubMed:18799424, PubMed:24912431).

Involved in the AKT signaling cascade (PubMed:24912431).

Plays a role in regulation of cell migration, e.g. during wound healing (PubMed:28978524).

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. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival (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:8849450, PubMed:8929542, PubMed:9427609, PubMed:10074122, PubMed:10756055).

Activation of MAPK activity Source: ProtInc
Apoptotic process Source: ProtInc
Axon guidance Source: Reactome
Brain development Source: GO_Central
Calcium-mediated signaling Source: MGI
Cardiac muscle contraction Source: Ensembl
Cell chemotaxis Source: GO_Central
Cellular response to cytokine stimulus Source: UniProtKB
Cellular response to drug Source: Ensembl
CXCL12-activated CXCR4 signaling pathway Source: UniProtKB
Dendritic cell chemotaxis Source: BHF-UCL
Detection of mechanical stimulus involved in sensory perception of pain Source: Ensembl
Detection of temperature stimulus involved in sensory perception of pain Source: Ensembl
Endothelial cell differentiation Source: Ensembl
Endothelial tube morphogenesis Source: Ensembl
Entry into host Source: Reactome
Epithelial cell development Source: Ensembl
Fusion of virus membrane with host plasma membrane Source: Reactome
G protein-coupled receptor signaling pathway Source: UniProtKB
Immune response Source: GO_Central
Inflammatory response Source: ProtInc
Myelin maintenance Source: BHF-UCL
Neurogenesis Source: GO_Central
Neuron migration Source: Ensembl
Neuron recognition Source: Ensembl
Positive regulation of chemotaxis Source: Ensembl
Positive regulation of cold-induced thermogenesis Source: YuBioLab
Positive regulation of cytosolic calcium ion concentration Source: GO_Central
Positive regulation of dendrite extension Source: Ensembl
Positive regulation of macrophage migration inhibitory factor signaling pathway Source: ARUK-UCL
Positive regulation of mesenchymal stem cell migration Source: Ensembl
Positive regulation of oligodendrocyte differentiation Source: BHF-UCL
Positive regulation of vascular wound healing Source: Ensembl
Regulation of calcium ion transport Source: Ensembl
Regulation of cell adhesion Source: UniProtKB
Regulation of chemotaxis Source: UniProtKB
Regulation of programmed cell death Source: Ensembl
Regulation of viral process Source: Ensembl
Response to activity Source: Ensembl
Response to hypoxia Source: UniProtKB
Response to morphine Source: Ensembl
Response to ultrasound Source: Ensembl
Response to virus Source: ProtInc
Telencephalon cell migration Source: Ensembl

Early endosome; Late endosome; Cell membrane; Lysosome; Cell junction. In unstimulated cells, diffuse pattern on plasma membrane. On agonist stimulation, colocalizes with ITCH at the plasma membrane where it becomes ubiquitinated. 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).

WHIM syndrome (WHIMS):
Immunodeficiency 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.
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.

Extracellular: 1-38
Helical: 39-63
Cytoplasmic: 64-77
Helical: 78-99
Extracellular: 100-110
Helical: 111-130
Cytoplasmic: 131-154
Helical: 155-174
Extracellular: 175-195
Helical: 196-216
Cytoplasmic: 217-241
Helical: 242-261
Extracellular: 262-282
Helical: 283-302
Cytoplasmic: 303-352

Phosphorylated on agonist stimulation. Rapidly phosphorylated on serine and threonine residues in the C-terminal. Phosphorylation at Ser-324 and Ser-325 leads to recruitment of ITCH, ubiquitination and protein degradation.
Ubiquitinated after ligand binding, leading to its degradation (PubMed:28978524). Ubiquitinated by ITCH at the cell membrane on agonist stimulation. 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.