Trends in Molecular Medicine
ReviewCXCR7 impact on CXCL12 biology and disease
Section snippets
Identifying CXCR7 and its ligands, the chemokines CXCL12 and CXCL11
The seven-transmembrane G-protein-coupled receptor (GPCR) (see Glossary) CXCR7, initially thought to be an inactive member of the family, was originally isolated from a dog thyroid cDNA library and named RDC1 [1]. Shortly thereafter, the human and mouse RDC1 orthologs were identified and found to have more than 90% similarity between their amino acid sequences [2]. In recent years, RDC1 was renamed CXCR7, according to the current chemokine receptor nomenclature 3, 4. The human and mouse CXCR7
CXCR7 structure, activation, and signaling
Chemokines transmit their signals through seven-transmembrane receptors (7-TMRs), proteins with a series of seven-transmembrane helices connected by extracellular and intracellular loops. The Asp-Arg-Tyr (DRY) motif, which is present in the intracellular loop (ICL)-2 of most 7-TMRs appears to control chemotaxis in CXCR4 and CCR5 63, 64 and modulates Gαi activation 64, 65, although these results are challenged by others [63]. Instead of the canonical Asp-Arg-Tyr-Leu-Ala-Ile-Val (DRYLAIV) motif
CXCR7 function in health and disease
7-TMRs are the most commonly targeted receptor class for therapeutics. However, research on CXCR7 function has been significantly delayed because it was considered an orphan receptor and was only recognized as an HIV co-receptor (its first attributed function) much later than CXCR4 [33]. Several tools have recently been developed to study CXCR7 function and signaling: the novel selective antagonists CCX733 and CCX754 [3], which might be improved anticancer treatments 94, 95; agonist-like CCX771
Concluding remarks and future perspectives
CXCR7 is a chemokine receptor that actively signals through the β-arrestin pathway, independently of G protein coupling, and thus it should be more approximately designated as a β-arrestin-coupled receptor. CXCR7 is actively recycled to the membrane, a process that regulates the levels of extracellular CXCL12, the expression of CXCR4, and the CXCL12/CXCR4/G protein signaling pathway. In addition, CXCR7 forms heterodimers with CXCR4 in vitro, although their heterodimerization in vivo remains to
Acknowledgment
We especially thank Dr José Luis Rodriguez-Fernández for his critical reading of this manuscript and all the comments and suggestions. This work was supported by grants from Ministerio de Ciencia e Innovación BFU2010-19144 (to C.C.) and by Instituto de Salud Carlos III-Redes Temáticas de Investigación Cooperativa en Salud (ISCIII-RETICS) RD08/0075/0002 (to L.S-M and C.C.).
Glossary
- Angiogenesis
- formation of new blood vessels from pre-existing vessels. It is a fundamental step towards an aggressive tumor phenotype.
- Arrestins
- multifunctional adaptor proteins that regulate desensitization and signaling by transmembrane receptors, such as GPCRs or 7-TMRs.
- Chemokine
- a family of chemotactic cytokines (approximately 8–17 kDa) that orchestrate the directional migration to selected tissues of a wide spectrum of cells, regulating physiological functions such as immune surveillance,
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