atypical chemokine receptor 2; C-C chemokine receptor 10; C-C chemokine receptor D6; chemokine receptor CCR-10; chemokine receptor CCR-9; chemokine-binding protein 2; chemokine-binding protein D6 (ACKR2, CCBP2, CCR10, CMKBR9, D6)

Introduction

The best characterized of the atypical chemokine receptors

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 including CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL22, CCL23, CCL24, SCYA2/MCP-1, SCY3/MIP-1-alpha, SCYA5/RANTES & SCYA7/MCP-3
• upon active ligand stimulation, activates a beta-arrestin 1 (ARRB1)-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) through a RAC1-PAK1-LIMK1 signaling pathway
  • activation of this pathway results in up- regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake & degradation
• by scavenging chemokines in tissues, on the surfaces of lymphatic vessels, & in placenta, plays a role in the resolution (termination) of the inflammatory response & in regulation of adaptive immune responses
• role in immune silencing of macrophages during resolution of inflammation
• acts as a regulator of inflammatory leukocyte interactions with lymphatic endothelial cells
• required for immature/mature dendritic cells discrimination by lymphatic endothelial cells
• phosphorylated on Ser in the C-terminal cytoplasmic tail
• suppresses development of chemically induced skin tumors

Structure

• the C-terminal cytoplasmic tail controls its phosphorylation, stability, intracellular trafficking itinerary, & chemokine scavenging properties
• belongs to the G-protein coupled receptor 1 family atypical chemokine receptor subfamily

Compartment

• early endosome. recycling endosome. cell membrane
• predominantly localizes to endocytic vesicles
• upon ligand stimulation, internalized via clathrin-coated pits
• once internalized, the ligand dissociates from the receptor, & is targeted to degradation while the receptor is recycled back to the cell membrane

Expression

• found in endothelial cells lining afferent lymphatics in dermis & lymph nodes
• also found in lymph nodes subcapsular & medullary sinuses, tonsillar lymphatic sinuses & lymphatics in mucosa & submucosa of small & large intestine & appendix
• expressed on apoptotic neutrophils (at protein level)
• expressed primarily in placenta & fetal liver,
• found at very low levels in the lung & lymph node
• induced by interleukin-6 & interferon-gamma

Pathology

• found in some malignant vascular tumors
• expressed at high levels in Kaposi sarcoma

More general terms

• atypical chemokine receptor
• CC chemokine receptor
• glycoprotein

Additional terms

• G-protein coupled receptor 2 (GPR2)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1238
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:1238
• OMIM: https://mirror.omim.org/entry/602648
• UniProt: http://www.uniprot.org/uniprot/O00590.html