C-X-C chemokine receptor type 4
Also known as: CXCR4
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. 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. CXCR4 is coupled to G(i) G alpha proteins and mediates inhibition of adenylate cyclase. Involved in the AKT signaling cascade. Plays a role in regulation of cell migration, e.g. during wound healing. Also acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels. Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes. 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).
Classification
- Family (Pfam)
- PF00001 7tm_1, PF12109 CXCR4_N
- InterPro
- CCR1-9-like, Chemokine_CXCR4_N_dom, Chemokine_rcpt, CXCR4/ACKR2, GPCR_Rhodpsn, GPCR_Rhodpsn_7TM
- Functional cluster
- G Protein-Coupled Receptors
Experimental structures · PDB · 30
- 2K03 NMR
- 2K04 NMR
- 2K05 NMR
- 2N55 NMR
- 3ODU X-ray 2.50A
- 3OE0 X-ray 2.90A
- 3OE6 X-ray 3.20A
- 3OE8 X-ray 3.10A
- 3OE9 X-ray 3.10A
- 4RWS X-ray 3.10A
- 8GP3 EM 4.80A
- 8I0Q EM 4.45A
- … and 18 more
A predicted model is available from AlphaFold.
Gene Ontology · 45
- GO:0070161 anchoring junction
- GO:0031252 cell leading edge
- GO:0009986 cell surface
- GO:0005737 cytoplasm
- GO:0031410 cytoplasmic vesicle
- GO:0005769 early endosome
- GO:0009897 external side of plasma membrane
- GO:0070062 extracellular exosome
- GO:0005770 late endosome
- GO:0005764 lysosome
- GO:0005886 plasma membrane
- GO:0032991 protein-containing complex
- GO:0003779 actin binding
- GO:0019957 C-C chemokine binding
- GO:0016493 C-C chemokine receptor activity
- GO:0016494 C-X-C chemokine receptor activity
- GO:0038147 C-X-C motif chemokine 12 receptor activity
- GO:0015026 coreceptor activity
- GO:0004930 G protein-coupled receptor activity
- GO:0032027 myosin light chain binding
- GO:0043130 ubiquitin binding
- GO:0031625 ubiquitin protein ligase binding
- GO:0001618 virus receptor activity
- GO:0007193 adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway
- GO:0006915 apoptotic process
- GO:0007420 brain development
- GO:0019722 calcium-mediated signaling
- GO:0060326 cell chemotaxis
- GO:0071345 cellular response to cytokine stimulus
- GO:0038160 CXCL12-activated CXCR4 signaling pathway
- GO:0002407 dendritic cell chemotaxis
- GO:0007186 G protein-coupled receptor signaling pathway
- GO:0006955 immune response
- GO:0006954 inflammatory response
- GO:0043217 myelin maintenance
- GO:0022008 neurogenesis
- GO:0030335 positive regulation of cell migration
- GO:0120162 positive regulation of cold-induced thermogenesis
- GO:0007204 positive regulation of cytosolic calcium ion concentration
- GO:2000448 positive regulation of macrophage migration inhibitory factor signaling pathway
- GO:0048714 positive regulation of oligodendrocyte differentiation
- GO:1904018 positive regulation of vasculature development
- GO:0030155 regulation of cell adhesion
- GO:0001666 response to hypoxia
- GO:0009615 response to virus
Disease associations
- WHIM syndrome 1 MONDO:8000006
Drugs targeting this protein · 7
- PLERIXAFOR partial agonist
- CTCE-9908 antagonist
- BURIXAFOR antagonist
- MSX-122 antagonist
- BALIXAFORTIDE antagonist
- MOTIXAFORTIDE antagonist
- MAVORIXAFOR antagonist
Neighborhood · nearest proteins
Related proteins · sequence + function similarity
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
- C-X-C chemokine receptor type 4 1.00
Co-cited proteins · studied together in the literature
- Stromal cell-derived factor 1 5 shared papers
- C-X-C chemokine receptor type 4 1 shared papers
- Staphylococcal superantigen-like 10 1 shared papers
- C-X-C chemokine receptor type 4 1 shared papers
- Sialomucin core protein 24 1 shared papers
- Protein UL78 1 shared papers
- Drebrin 1 shared papers
- C-C chemokine receptor type 5 2 shared papers
- Viral macrophage inflammatory protein 2 1 shared papers
- E3 ubiquitin-protein ligase RNF113A 1 shared papers
- Envelope glycoprotein gp160 1 shared papers
- Envelope glycoprotein gp160 1 shared papers
Literature · 58 cited papers
- Cryo-EM structure of monomeric CXCL12-bound CXCR4 in the active state. Cell Rep. · 2024
- Structural snapshots uncover a key phosphorylation motif in GPCRs driving beta-arrestin activation. Mol. Cell · 2023
- ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is downregulated in breast cancer. EMBO Rep. · 2022
- RING finger protein 113A regulates C-X-C chemokine receptor type 4 stability and signaling. Am. J. Physiol. · 2017
- Structural biology. Crystal structure of the chemokine receptor CXCR4 in complex with a viral chemokine. Science · 2015
- The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom's Macroglobulinemia. Leukemia · 2015
- Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood · 2014
- The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood · 2014
- Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
- Human cytomegalovirus-encoded UL33 and UL78 heteromerize with host CCR5 and CXCR4 impairing their HIV coreceptor activity. Blood · 2012
- Down-modulation of the G-protein-coupled estrogen receptor, GPER, from the cell surface occurs via a trans-Golgi-proteasome pathway. J. Biol. Chem. · 2011
- Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science · 2010
- … and 46 more in the literature graph