Review
CXCR7 impact on CXCL12 biology and disease

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It is known that the chemokine receptor CXCR7 (RDC1) can be engaged by both chemokines CXCL12 (SDF-1) and CXCL11 (I-TAC), but the exact expression pattern and function of CXCR7 is controversial. CXCR7 expression seems to be enhanced during pathological inflammation and tumor development, and emerging data suggest this receptor is an attractive therapeutic target for autoimmune diseases and cancer. CXCR7/CXCR4 heterodimerization, β-arrestin-mediated signaling, and modulation of CXCL12 responsiveness by CXCR7 suggest that the monogamous CXCR4/CXCL12 signaling axis is an oversimplified model that needs to be revisited. Consequently, research into CXCR7 biology is of great interest and further studies are warranted. This review summarizes recent findings about the CXCR7 receptor and analyses its impact on understanding the roles of CXCL12 biology in health 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,

References (126)

  • R.D. Berahovich

    Nonspecific CXCR7 antibodies

    Immunol. Lett.

    (2010)
  • B. Boldajipour

    Control of chemokine-guided cell migration by ligand sequestration

    Cell

    (2008)
  • C. Delgado-Martin

    CXCL12 uses CXCR4 and a signaling core formed by bifunctional Akt, Erk1/2 and mTORC1 to control simultaneously chemotaxis and survival in mature dendritic cells

    J. Biol. Chem.

    (2011)
  • J. Wang

    The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer

    J. Biol. Chem.

    (2008)
  • S.L. Madden

    Vascular gene expression in nonneoplastic and malignant brain

    Am. J. Pathol.

    (2004)
  • J. Monnier

    CXCR7 is upregulated in human and murine hepatocellular carcinoma and is specifically expressed by endothelial cells

    Eur. J. Cancer

    (2012)
  • M. Hao

    Role of chemokine receptor CXCR7 in bladder cancer progression

    Biochem. Pharmacol.

    (2012)
  • A. Ladoux et al.

    Coordinated upregulation by hypoxia of adrenomedullin and one of its putative receptors (RDC-1) in cells of the rat blood–brain barrier

    J. Biol. Chem.

    (2000)
  • B. Schonemeier

    Enhanced expression of the CXCl12/SDF-1 chemokine receptor CXCR7 after cerebral ischemia in the rat brain

    J. Neuroimmunol.

    (2008)
  • J. Roland

    Role of the intracellular domains of CXCR4 in SDF-1-mediated signaling

    Blood

    (2003)
  • Y.A. Berchiche

    Direct assessment of CXCR4 mutant conformations reveals complex link between receptor structure and Gαi activation

    J. Biol. Chem.

    (2007)
  • M. Thelen et al.

    CXCR7, CXCR4 and CXCL12: an eccentric trio?

    J. Neuroimmunol.

    (2008)
  • M.H. Ulvmar

    Atypical chemokine receptors

    Exp. Cell Res.

    (2011)
  • M. Thelen

    Chemokine receptor oligomerization: functional considerations

    Curr. Opin. Pharmacol.

    (2010)
  • B. Lagane

    CXCR4 dimerization and β-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome

    Blood

    (2008)
  • A. Levoye

    CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling

    Blood

    (2009)
  • X. Deupi et al.

    Structural insights into agonist-induced activation of G-protein-coupled receptors

    Curr. Opin. Struct. Biol.

    (2011)
  • Y. Percherancier

    Bioluminescence resonance energy transfer reveals ligand-induced conformational changes in CXCR4 homo- and heterodimers

    J. Biol. Chem.

    (2005)
  • K.E. Luker

    Imaging ligand-dependent activation of CXCR7

    Neoplasia

    (2009)
  • P. Proost

    Proteolytic processing of CXCL11 by CD13/aminopeptidase N impairs CXCR3 and CXCR7 binding and signaling and reduces lymphocyte and endothelial cell migration

    Blood

    (2007)
  • F.M. Decaillot

    CXCR7/CXCR4 heterodimer constitutively recruits β-arrestin to enhance cell migration

    J. Biol. Chem.

    (2011)
  • Y. Wang

    CXCR4 and CXCR7 have distinct functions in regulating interneuron migration

    Neuron

    (2011)
  • G. Valentin

    The chemokine SDF1a coordinates tissue migration through the spatially restricted activation of Cxcr7 and Cxcr4b

    Curr. Biol.

    (2007)
  • E.J. Whalen

    Therapeutic potential of β-arrestin- and G protein-biased agonists

    Trends Mol. Med.

    (2011)
  • S.K. Shenoy et al.

    β-Arrestin-mediated receptor trafficking and signal transduction

    Trends Pharmacol. Sci.

    (2011)
  • J.A. Sánchez-Alcañiz

    Cxcr7 controls neuronal migration by regulating chemokine responsiveness

    Neuron

    (2011)
  • E. Palmesino

    Differences in CXCR4-mediated signaling in B cells

    Immunobiology

    (2006)
  • T. Sasado

    Distinct contributions of CXCR4b and CXCR7/RDC1 receptor systems in regulation of PGC migration revealed by medaka mutants kazura and yanagi

    Dev. Biol.

    (2008)
  • F. Libert

    Selective amplification and cloning of four new members of the G protein-coupled receptor family

    Science

    (1989)
  • M. Heesen

    Cloning and chromosomal mapping of an orphan chemokine receptor: mouse RDC1

    Immunogenetics

    (1998)
  • J.M. Burns

    A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development

    J. Exp. Med.

    (2006)
  • S.P. Sreedharan

    Cloning and expression of the human vasoactive intestinal peptide receptor

    Proc. Natl. Acad. Sci. U.S.A.

    (1991)
  • S. Nagata

    RDC1 may not be VIP receptor

    Trends Pharmacol. Sci.

    (1992)
  • L.M. McLatchie

    RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor

    Nature

    (1998)
  • M.P. Crump

    Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1

    EMBO J.

    (1997)
  • C.T. Veldkamp

    The monomer–dimer equilibrium of stromal cell-derived factor-1 (CXCL 12) is altered by pH, phosphate, sulfate, and heparin

    Protein Sci.

    (2005)
  • L.J. Drury

    Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways

    Proc. Natl. Acad. Sci. U.S.A.

    (2011)
  • P. Ray

    Secreted CXCL12 (SDF-1) forms dimers under physiologic conditions

    Biochem. J.

    (2012)
  • C.T. Veldkamp

    Structural basis of CXCR4 sulfotyrosine recognition by the chemokine SDF-1/CXCL12

    Sci. Signal.

    (2008)
  • A. Muller

    Involvement of chemokine receptors in breast cancer metastasis

    Nature

    (2001)
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