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Mol Pharmacol. 2019 Dec;96(6):778-793. doi: 10.1124/mol.118.115477. Epub 2019 May 15.

Context-Dependent Signaling of CXC Chemokine Receptor 4 and Atypical Chemokine Receptor 3.

Author information

1
IGF, CNRS, Inserm, Université de Montpellier, Montpellier, France (J.H., T.D., J.-P.P.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.V., A.I., M.J.L., C.H.); Institute for Molecular Cell Biology, Centre for Molecular Biomedicine, University Hospital Jena, Friedrich Schiller University Jena, Jena, Germany (C.P.V., C.H.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (D.C., G.M.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom (B.C., S.J.B., S.J.H.); and Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., S.J.B., S.J.H.).
2
IGF, CNRS, Inserm, Université de Montpellier, Montpellier, France (J.H., T.D., J.-P.P.); Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.P.V., A.I., M.J.L., C.H.); Institute for Molecular Cell Biology, Centre for Molecular Biomedicine, University Hospital Jena, Friedrich Schiller University Jena, Jena, Germany (C.P.V., C.H.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (A.I., M.J.L.); Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (D.C., G.M.); Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom (B.C., S.J.B., S.J.H.); and Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, United Kingdom (B.C., S.J.B., S.J.H.) carsten.hoffmann@med.uni-jena.de.

Abstract

G protein-coupled receptors (GPCRs) are regulated by complex molecular mechanisms, both in physiologic and pathologic conditions, and their signaling can be intricate. Many factors influence their signaling behavior, including the type of ligand that activates the GPCR, the presence of interacting partners, the kinetics involved, or their location. The two CXC-type chemokine receptors, CXC chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3), both members of the GPCR superfamily, are important and established therapeutic targets in relation to cancer, human immunodeficiency virus infection, and inflammatory diseases. Therefore, it is crucial to understand how the signaling of these receptors works to be able to specifically target them. In this review, we discuss how the signaling pathways activated by CXCR4 and ACKR3 can vary in different situations. G protein signaling of CXCR4 depends on the cellular context, and discrepancies exist depending on the cell lines used. ACKR3, as an atypical chemokine receptor, is generally reported to not activate G proteins but can broaden its signaling spectrum upon heteromerization with other receptors, such as CXCR4, endothelial growth factor receptor, or the α 1-adrenergic receptor (α 1-AR). Also, CXCR4 forms heteromers with CC chemokine receptor (CCR) 2, CCR5, the Na+/H+ exchanger regulatory factor 1, CXCR3, α 1-AR, and the opioid receptors, which results in differential signaling from that of the monomeric subunits. In addition, CXCR4 is present on membrane rafts but can go into the nucleus during cancer progression, probably acquiring different signaling properties. In this review, we also provide an overview of the currently known critical amino acids involved in CXCR4 and ACKR3 signaling.

PMID:
31092552
DOI:
10.1124/mol.118.115477

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