Atypical chemokine receptor 3 (ACKR3) (ACKR3)

Atypical chemokine receptor 3 (ACKR3), historically known as CXCR7 or RDC1, is a member of the G protein-coupled receptor (GPCR) family that functions as a non-canonical or "atypical" receptor. Unlike classical GPCRs, ACKR3 does not activate heterotrimeric G proteins but instead signals primarily through beta-arrestin-mediated pathways and acts as a high-affinity scavenger for the chemokines CXCL12 (SDF-1) and CXCL11 (I-TAC) [1, 3, 5]. By internalizing and degrading these ligands, ACKR3 regulates their extracellular concentrations and shapes the chemokine gradients necessary for cell migration and tissue development [4, 16]. In disease, ACKR3 is frequently overexpressed in various cancers and tumor-associated vasculature, where it promotes tumor growth, survival, and metastasis, often by modulating the activity of the canonical receptor CXCR4 [1, 4, 12]. It also plays critical roles in cardiovascular development, neuroinflammation, and as a coreceptor for certain HIV/SIV strains [2, 11, 36]. Therapeutic strategies targeting ACKR3 include small-molecule antagonists and neutralizing antibodies, which are being investigated for their potential to inhibit tumor progression and promote remyelination in autoimmune diseases like multiple sclerosis [30, 31, 37].

Other names

CXCR7RDC1RDC-1CMKOR1GPR159Chemokine orphan receptor 1C-X-C chemokine receptor type 7GPCR-RDC

Antagonism of chemokine binding, inhibition of chemokine scavenging, and modulation of beta-arrestin-mediated signaling pathways.