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Review ArticleMinireview

Functions of the CXCL12 Receptor ACKR3/CXCR7—What Has Been Perceived and What Has Been Overlooked

Christian Koch and Jürgen Engele
Molecular Pharmacology November 2020, 98 (5) 577-585; DOI: https://doi.org/10.1124/molpharm.120.000056
Christian Koch
Institute of Anatomy, University of Leipzig, Medical Faculty, Leipzig, Germany
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Jürgen Engele
Institute of Anatomy, University of Leipzig, Medical Faculty, Leipzig, Germany
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Abstract

The CXCL12 system is central to the development of many organs and is further crucially engaged in pathophysiological processes underlying cancer, inflammation, and cardiovascular disorders. This disease-associated role presently focuses major interest on the two CXCL12 receptors, CXCR4 and atypical chemokine receptor 3 (ACKR3)/CXCR7, as promising therapeutic targets. Major obstacles in these ongoing efforts are confusing reports on the differential use of either ACKR3/CXCR7 and/or CXCR4 across various cells as well as on the specific function(s) of ACKR3/CXCR7. Although basically no doubts remain that CXCR4 represents a classic chemokine receptor, functions assigned to ACKR3/CXCR7 range from those of a strictly silent scavenger receptor eventually modulating CXCR4 signaling to an active and independent signaling receptor. In this review, we depict a thorough analysis of our present knowledge on different modes of organization and functions of the cellular CXCL12 system. We further highlight the potential role of ACKR3/CXCR7 as a “crosslinker” of different receptor systems. Finally, we discuss mechanisms with the potency to impinge on the cellular organization of the CXCL12 system and hence might represent additional future therapeutic targets.

SIGNIFICANCE STATEMENT Delineating the recognized functions of atypical chemokine receptor 3 and CXCR4 in CXCL12 signaling is central to the more detailed understanding of the role of the CXCL12 system in health and disease and will help to guide future research efforts.

Footnotes

    • Received May 5, 2020.
    • Accepted July 31, 2020.
  • This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. There are no financial conflicts of interest to disclose.

  • https://doi.org/10.1124/molpharm.120.000056.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 98 (5)
Molecular Pharmacology
Vol. 98, Issue 5
1 Nov 2020
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Review ArticleMinireview

ACKR3 Functions

Christian Koch and Jürgen Engele
Molecular Pharmacology November 1, 2020, 98 (5) 577-585; DOI: https://doi.org/10.1124/molpharm.120.000056

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Review ArticleMinireview

ACKR3 Functions

Christian Koch and Jürgen Engele
Molecular Pharmacology November 1, 2020, 98 (5) 577-585; DOI: https://doi.org/10.1124/molpharm.120.000056
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  • Article
    • Abstract
    • Introduction
    • Atypical Functions of ACKR3—ACKR3 as a CXCL12 Scavenger
    • Is Suppression of CXCR4 Signaling Another Atypical Function of ACKR3?
    • Active Functions of ACKR3—Cell-Specific Use of ACKR3 and CXCR4 to Control Distinct Cell Functions
    • Evidence that ACKR3 and CXCR4 Form a Functional Receptor in Distinct Cell Types
    • Within the Same Cell ACKR3 and CXCR4 Control Different Cell Functions
    • ACKR3 as a Crosslinker of Different Receptor Systems
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