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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
Note: originally thought to be receptor for VIP [4]
General
atypical chemokine receptor; chemokine-scavenging receptor; chemokine decoy receptor
CXC chemokine receptor
glycoprotein
Properties
SIZE: entity length = 362 aa
MW = 41 kD
COMPARTMENT: cytoplasm
cell nucleus
MOTIF: exoplasmic domain {1-40}
MOTIF: N-glycosylation site {N13}
N-glycosylation site {N22}
N-glycosylation site {N39}
transmembrane domain {41-61}
cytoplasmic loop {62-81}
transmembrane domain {82-102}
exoplasmic loop {103-118}
MOTIF: cysteine residue {C117}
MODIFICATION: cysteine residue {C196}
transmembrane domain {119-139}
cytoplasmic loop {140-162}
transmembrane domain {163-183}
exoplasmic loop {184-213}
MOTIF: cysteine residue {C196}
MODIFICATION: cysteine residue {C117}
transmembrane domain {214-234}
cytoplasmic loop {235-252}
transmembrane domain {253-273}
exoplasmic loop {274-296}
transmembrane domain {297-319}
cytoplasmic domain {320-362}
MOTIF: C-terminal cytoplasmic tail {324-362}
Database Correlations
OMIM 610376
UniProt P25106
Pfam PF00001
Entrez Gene 57007
Kegg hsa:57007
References
- UniProt :accession P25106
- Atlas of genetics & cytogenetics in oncology & haematology
http://atlasgeneticsoncology.org/genes/CMKOR1ID40108ch2q37.html
- Wikipedia; CXC chemokine receptors entry
http://en.wikipedia.org/wiki/CXC_chemokine_receptors
- Sreedharan SP, Robichon A, Peterson KE, Goetzl EJ.
Cloning and expression of the human vasoactive intestinal
peptide receptor.
Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4986-90
PMID: 1675791