atypical chemokine receptor 3; C-X-C chemokine receptor type 7; CXC-R7; CXCR-7; chemokine orphan receptor 1; G-protein coupled receptor 159; G-protein coupled receptor RDC1 homolog; RDC-1 (ACKR3, CMKOR1, CXCR7, GPR159, RDC1)

Function

• atypical chemokine receptor
• controls chemokine levels & localization via high-affinity chemokine binding uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis
• also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor
• acts as a receptor for chemokines CXCL11 & CXCL12/SDF1
• chemokine binding does not activate G-protein-mediated signal transduction but instead induces beta-arrestin recruitment, leading to ligand internalization & activation of MAPK signaling pathway
• required for regulation of CXCR4 protein levels in migrating interneurons, thereby adapting their chemokine responsiveness
• in glioma cells, transduces signals via MEK/ERK pathway, mediating resistance to apoptosis
• promotes cell growth & survival
• plays a regulatory role in CXCR4-mediated activation of cell surface integrins by CXCL12
• required for heart valve development
• the Ser/Thr residues in the C-terminal cytoplasmic tail may be phosphorylated
• ubiquitinated on Lys in its C-terminal cytoplasmic tail & is essential for correct trafficking from & to the cell membrane
• deubiquitinated by CXCL12-stimulation (reversible)
• homodimer
• can form heterodimers with CXCR4
• heterodimerization may regulate CXCR4 signaling activity
• interacts with ARRB1 & ARRB2

Structure

• the C-terminal cytoplasmic tail, plays a key role in:
  • correct trafficking to the cell membrane
  • recruitment of beta-arrestin
  • ubiquitination,
  • chemokine scavenging & signaling functions
• the Ser/Thr residues & the Lys residues in the C-terminal cytoplasmic tail are essential for beta-arrestin recruitment & ubiquitination respectively
• belongs to the G-protein coupled receptor 1 family atypical chemokine receptor subfamily

Compartment

• cell membrane; multi-pass membrane protein
• cytoplasm, perinuclear region. early endosome, recycling endosome
• predominantly localizes to endocytic vesicles, & upon stimulation by the ligand is internalized via clathrin-coated pits in a beta-arrestin-dependent manner
• once internalized, the ligand dissociates from the receptor, & is targeted to degradation while the receptor is recycled back to the cell membrane

Expression

• expressed in monocytes, basophils, B-cells, umbilical vein endothelial cells & B-lymphoblastoid cells
• lower expression detected in CD4+ T-cell & NK cells
• in brain, detected in endothelial cells & capillaries, & in mature neurons of the frontal cortex & hippocampus
• expressed in tubular formation in the kidney
• highly expressed in astroglial tumor endothelial, microglial & glioma cells
• expressed at low levels in normal CD34+ progenitor cells, but at very high levels in several myeloid malignant cell lines
• expressed in breast carcinomas but not in normal breast tissue (at protein level)
• up-regulated during cell differentiation in glioma cells

Pathology

• acts as coreceptor with CXCR4 for a restricted number of HIV1 isolates
• not involved in cell migration, adhesion or proliferation of normal hematopoietic progenitors but activated by CXCL11 in malignant hemapoietic cells, leading to phosphorylation of ERK1/2 (MAPK3/MAPK1) & enhanced cell adhesion & migration

Notes

originally thought to be receptor for VIP

More general terms

• atypical chemokine receptor
• CXC chemokine receptor
• glycoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=57007
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:57007
• OMIM: https://mirror.omim.org/entry/610376
• UniProt: http://www.uniprot.org/uniprot/P25106.html