Context-dependent signaling of CXC chemokine receptor 4 and atypical chemokine receptor 3

G protein-coupled receptors (GPCRs) are regulated by complex molecular mechanisms, both in physiological and pathological conditions, and their signalling can be intricate. Many factors influence their signalling behaviour, 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 CXCR4 and ACKR3, both members of the GPCR superfamily, are important and established therapeutic targets in relation to cancer, HIV infection and inflammatory diseases. Therefore, it is crucial to understand how the signalling of these receptors works to be able to specifically target them. In this review, we discuss how the signalling pathways activated by CXCR4 and ACKR3 can vary in different situations. G protein signalling 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 signalling spectrum upon heteromerisation with other receptors, such as CXCR4, endothelial growth factor receptor (EGFR) or the α1-adrenergic receptor (α1-AR). Also, CXCR4 forms heteromers with CCR2, CCR5, the Na+/H+ exchanger regulatory factor 1 (NHERF1), CXCR3, α1-AR and the opioid receptors, which results in differential signalling to 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 signalling properties. In this review, we also provide an overview of the currently known critical amino acids involved in CXCR4 and ACKR3 signalling