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)

Monomer. Can form homodimers (PubMed:20929726). Interacts with CD164 (PubMed:17077324).

Interacts (when phosphorylated) with ARRB1; the interaction is associated with internalization of the receptor and short-term desensitization to the ligand (PubMed:37209686). Interacts with ARRB2; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and allows activation of MAPK1 and MAPK3. Interacts with ARR3; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and modulates calcium mobilization (PubMed:20048153).

Interacts with RNF113A; the interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and subsequent degradation (PubMed:28978524). Interacts (via the cytoplasmic C-terminal) with ITCH (via the WW domains I and II); the interaction, enhanced by CXCL12, promotes CXCR4 ubiquitination and leads to its degradation. Interacts with extracellular ubiquitin.

Interacts with DBN1; this interaction is enhanced by antigenic stimulation. Following LPS binding, may form a complex with GDF5, HSP90AA1 and HSPA8

(Microbial infection) Interacts with HIV-1 surface protein gp120 and Tat

(Microbial infection) Interacts with HHV-8 protein ORF K4 (PubMed:25612609)

(Microbial infection) May interact with human cytomegalovirus/HHV-5 protein UL78

(Microbial infection) Interacts with Staphylococcus aureus protein SSL10

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

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

• 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.

• Unknown disease