Atypical Chemokine Receptor 3/CXC Chemokine Receptor 7 Antibodies

Atypical chemokine receptor 3 (ACKR3), formerly known as CXCR7, is a seven-transmembrane receptor whose principal endogenous chemokine ligands are CXCL12 and CXCL11. ACKR3 recruits β-arrestins upon ligand binding and generally lacks conventional G protein signaling. It constitutively cycles between the plasma membrane and intracellular compartments, internalizing bound chemokines and directing them toward degradation. Phosphorylation of the receptor’s C-terminal tail by G protein-coupled receptor kinases regulates scavenging, which can occur independently of β-arrestins in some experimental systems. By controlling local CXCL12 availability, ACKR3 shapes chemokine gradients and modulates CXCR4-dependent cell migration. ACKR3 expression has been reported in vascular endothelial cells, selected neuronal populations, and several types of solid tumors. Its scavenging activity contributes to developmental cell migration and has been implicated in vascular remodeling and tumor progression. The oral small-molecule antagonist ACT-1004-1239 has been evaluated in phase 1 studies, in which it increased circulating concentrations of biologically active CXCL12. No ACKR3-selective drug is currently approved for therapeutic use. Efficient ligand sequestration by ACKR3 critically depends on GRK2 and GRK5 mediated phosphorylation of carboxyl-terminal serine350/threonine352 (pS350/pT352-ACKR3/CXCR7) and serine355/serine360 (pS355/pS360-ACKR3/CXCR7) but not on β-arrestin recruitment. This phosphorylation motif is highly conserved across a variety of species including mouse, rat and human. For more information on ACKR3 pharmacology please refer to the IUPHAR database. For further reading refer to:

Saaber F, Schütz D, Miess E, Abe P, Desikan S, Ashok Kumar P, Balk S, Huang K, Beaulieu JM, Schulz S, Stumm R. ACKR3 Regulation of Neuronal Migration Requires ACKR3 Phosphorylation, but Not β-Arrestin. Cell Rep. 2019 Feb 5;26(6):1473-1488.e9. doi: 10.1016/j.celrep.2019.01.049. PubMed PMID: 30726732.

Sánchez-Alcañiz JA, Haege S, Mueller W, Pla R, Mackay F, Schulz S, López-Bendito G, Stumm R, Marín O. Cxcr7 controls neuronal migration by regulating chemokine responsiveness. Neuron. 2011 Jan 13;69(1):77-90. doi: 10.1016/j.neuron.2010.12.006. PubMed PMID: 21220100.

Hoffmann F, Müller W, Schütz D, Penfold ME, Wong YH, Schulz S, Stumm R. Rapid uptake and degradation of CXCL12 depend on CXCR7 carboxyl-terminal serine/threonine residues. J Biol Chem. 2012 Aug 17;287(34):28362-77. doi: 10.1074/jbc.M111.335679. Epub 2012 Jun 26. PubMed PMID: 22736769; PubMed Central PMCID: PMC3436560.