ACKR3

ACKR3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 7SK6, 7SK5
Identifiers
Aliases	ACKR3, CMKOR1, CXC-R7, CXCR-7, CXCR7, GPR159, RDC-1, RDC1, atypical chemokine receptor 3
External IDs	OMIM: 610376; MGI: 109562; HomoloGene: 22419; GeneCards: ACKR3; OMA:ACKR3 - orthologs
Gene location (Human) Chr. Chromosome 2 (human) Band 2q37.3 Start 236,567,787 bp End 236,582,354 bp
Gene location (Mouse) Chr. Chromosome 1 (mouse) Band 1 D|1 45.28 cM Start 90,131,702 bp End 90,144,473 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in synovial joint vena cava tendon of biceps brachii cartilage tissue skin of hip saphenous vein pericardium synovial membrane tibial arteries mucosa of paranasal sinus Top expressed in medial ganglionic eminence renal corpuscle medullary collecting duct endocardial cushion aortic valve stria vascularis ascending aorta ciliary body myocardium of ventricle iris More reference expression data BioGPS More reference expression data
Gene ontology Molecular function C-X-C chemokine receptor activity G protein-coupled receptor activity coreceptor activity C-X-C chemokine binding signal transducer activity chemokine binding scavenger receptor activity protein binding C-C chemokine receptor activity C-C chemokine binding Cellular component cytoplasm integral component of membrane recycling endosome endosome intracellular membrane-bounded organelle membrane plasma membrane cell surface early endosome perinuclear region of cytoplasm clathrin-coated pit nucleus external side of plasma membrane Biological process chemokine-mediated signaling pathway receptor internalization negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage vasculogenesis multicellular organism development chemotaxis cell adhesion angiogenesis positive regulation of ERK1 and ERK2 cascade viral process signal transduction positive regulation of mesenchymal stem cell migration G protein-coupled receptor signaling pathway immune response positive regulation of cytosolic calcium ion concentration calcium-mediated signaling cell chemotaxis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 57007 12778 Ensembl ENSG00000144476 ENSMUSG00000044337 UniProt P25106 P56485 RefSeq (mRNA) NM_001047841 NM_020311 NM_001271607 NM_007722 RefSeq (protein) NP_064707 NP_001258536 NP_031748 Location (UCSC) Chr 2: 236.57 – 236.58 Mb Chr 1: 90.13 – 90.14 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Atypical chemokine receptor 3 also known as C-X-C chemokine receptor type 7 (CXCR-7) and G-protein coupled receptor 159 (GPR159) is a protein that in humans is encoded by the ACKR3 gene.

This gene encodes a G protein-coupled receptor family member. It belongs to the chemokine receptor family of GPCRs. Within this family, ACKR3 is classified as a class A GPCR. This GPCR protein was earlier thought to be a receptor for vasoactive intestinal peptide (VIP) and was considered to be an orphan receptor. It is now classified as a chemokine receptor able to bind the chemokines CXCL12/SDF-1 and CXCL11. The protein is also a coreceptor for human immunodeficiency viruses (HIV). Translocations involving this gene and HMGA2 on chromosome 12 have been observed in lipomas. Alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. Whereas some reports claim that the receptor induces signaling following ligand binding, recent findings in zebrafish suggest that CXCR7 functions primarily by sequestering the chemokine CXCL12.

Another study has provided evidence that ligand binding to CXCR7 activates MAP kinases through Beta-arrestins, and thus has functions beyond ligand sequestration.

ACKR3 has also been shown to sequester endogenous opioid peptides and is thought to modulate their activity.

Nomenclature

In 2013, the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology subcommittee for chemokine receptors reevaluated C-X-C chemokine receptor type 7 (CXCR7) and classified it as an atypical chemokine receptor, leading to its renaming as atypical chemokine receptor 3 (ACKR3). Additional names that have been mentioned in the literature, albeit less frequently, include GPR159 and Orphan receptor RDC1, the latter being a term primarily found in older literature.

Function

ACKR3 stands out as an atypical receptor due to its β-arrestin-biased signaling nature. In the case of a β-arrestin-biased receptor like ACKR3, when it is treated with an unbiased ligand, it triggers signaling pathways solely mediated by β-arrestin. What sets ACKR3 apart is its absence of G-protein involvement, which distinguishes it from typical GPCRs.

Despite being considered atypical, the functions of ACKR3 do not imply that it acts as a completely inactive receptor for CXCL12. On the contrary, extensive literature supports the notion of ACKR3 engaging in active signaling, which is believed to rely on arrestin-mediated mechanisms. Nevertheless, its role as a decoy receptor for CXCL12/SDF1 is well-established. This is evident by the significantly higher affinity of CXCL12 binding to ACKR3/CXCR7 compared to CXCR4, along with its constant internalization facilitated by the recruitment of β-arrestin, without known downstream signaling events.

Ligands

In addition to CXCL12, ACKR3 engages with multiple ligands, encompassing CXCL11, macrophage inhibitory factor (MIF), adrenomedullin (ADM), opioid peptides such as nociceptin, dynorphin, and enkephalin, as well as the viral chemokine vCCL2/viral macrophage inflammatory protein-II.

Inhibition of ACKR3 by ligands such as the peptide LIH383 (FGGFMRRK-NH₂) and the small molecules conolidine, RTI-5152-12, and VUF15485 increases opioid peptide activity and produces analgesic and antidepressant effects in animal studies.

Interactions

ACKR3 and CXCR4 have been shown to interact, different possibilities regarding the involvement of ACKR3 and CXCR4 in CXCL12 signaling:

A) ACKR3 can attenuate CXCR4 signaling by forming heterodimers with CXCR4. While this interaction was initially observed in cells with CXCR7 overexpression, it has rarely been observed with endogenous CXCR7.

B) Multiple cell types demonstrate that either ACKR3 or CXCR4 controls specific cell functions (e.g., migration, proliferation). The distinct regulation of these functions occurs through one of the receptors.

C) Synergistic effects between CXCR4 and ACKR3 have been observed in many cases, suggesting that cellular responses to CXCL12 require the presence of both receptors. Whether receptor heterodimerization is responsible for these synergistic effects remains uncertain.

D) In addition to synergistic effects, a few studies have shown additive effects of ACKR3 and CXCR4 on specific cell functions. However, it has not been experimentally tested whether receptor heterodimerization is necessary for these additive effects. E) Within specific cell types, CXCR4, ACKR3, and CXCR4/ACKR3 heterodimers control distinct cell functions. This pattern appears to be a common arrangement of the CXCL12 system in various types of stem and progenitor cells.

External links

• Human ACKR3 genome location and ACKR3 gene details page in the UCSC Genome Browser.

Further reading

• Nagata S, Ishihara T, Robberecht P, Libert F, Parmentier M, Christophe J, Vassart G (March 1992). "RDC1 may not be VIP receptor". Trends in Pharmacological Sciences. 13 (3): 102–103. doi:10.1016/0165-6147(92)90037-7. PMID 1315461.
• Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG (September 1991). "Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor". Genomics. 11 (1): 225–227. doi:10.1016/0888-7543(91)90125-X. PMID 1662665.
• Sreedharan SP, Robichon A, Peterson KE, Goetzl EJ (June 1991). "Cloning and expression of the human vasoactive intestinal peptide receptor". Proceedings of the National Academy of Sciences of the United States of America. 88 (11): 4986–4990. Bibcode:1991PNAS...88.4986S. doi:10.1073/pnas.88.11.4986. PMC 51792. PMID 1675791.
• Law NM, Rosenzweig SA (May 1994). "Characterization of the G-protein linked orphan receptor GPRN1/RDC1". Biochemical and Biophysical Research Communications. 201 (1): 458–465. doi:10.1006/bbrc.1994.1723. PMID 8198609.
• Shimizu N, Soda Y, Kanbe K, Liu HY, Mukai R, Kitamura T, Hoshino H (January 2000). "A putative G protein-coupled receptor, RDC1, is a novel coreceptor for human and simian immunodeficiency viruses". Journal of Virology. 74 (2): 619–626. doi:10.1128/JVI.74.2.619-626.2000. PMC 111581. PMID 10623723.
• Broberg K, Zhang M, Strömbeck B, Isaksson M, Nilsson M, Mertens F, et al. (August 2002). "Fusion of RDC1 with HMGA2 in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15". International Journal of Oncology. 21 (2): 321–326. doi:10.3892/ijo.21.2.321. PMID 12118328.
• Infantino S, Moepps B, Thelen M (February 2006). "Expression and regulation of the orphan receptor RDC1 and its putative ligand in human dendritic and B cells". Journal of Immunology. 176 (4): 2197–2207. doi:10.4049/jimmunol.176.4.2197. PMID 16455976.
• Burns JM, Summers BC, Wang Y, Melikian A, Berahovich R, Miao Z, et al. (September 2006). "A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development". The Journal of Experimental Medicine. 203 (9): 2201–2213. doi:10.1084/jem.20052144. PMC 2118398. PMID 16940167.
• Proost P, Mortier A, Loos T, Vandercappellen J, Gouwy M, Ronsse I, et al. (July 2007). "Proteolytic processing of CXCL11 by CD13/aminopeptidase N impairs CXCR3 and CXCR7 binding and signaling and reduces lymphocyte and endothelial cell migration". Blood. 110 (1): 37–44. doi:10.1182/blood-2006-10-049072. PMID 17363734.
• Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, et al. (October 2007). "CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature". Proceedings of the National Academy of Sciences of the United States of America. 104 (40): 15735–15740. Bibcode:2007PNAS..10415735M. doi:10.1073/pnas.0610444104. PMC 1994579. PMID 17898181.
• Boldajipour B, Mahabaleshwar H, Kardash E, Reichman-Fried M, Blaser H, Minina S, et al. (February 2008). "Control of chemokine-guided cell migration by ligand sequestration". Cell. 132 (3): 463–473. doi:10.1016/j.cell.2007.12.034. hdl:11858/00-001M-0000-0012-DDE5-7. PMID 18267076.
• Takaya K, Asou T, Kishi K (June 2022). "Selective Elimination of Senescent Fibroblasts by Targeting the Cell Surface Protein ACKR3". International Journal of Molecular Sciences. 23 (12): 6531. doi:10.3390/ijms23126531. PMC 9223754. PMID 35742971.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.