Abstract
CXCR4 and its ligand CXCL12 mediate the homing of progenitor cells in the bone marrow and their recruitment to sites of injury, as well as affect processes such as cell arrest, survival, and angiogenesis. CXCL12 was long thought to be the sole CXCR4 ligand, but more recently the atypical chemokine macrophage migration inhibitory factor (MIF) was identified as an alternative, non-cognate ligand for CXCR4 and shown to mediate chemotaxis and arrest of CXCR4-expressing T-cells. This has complicated the understanding of CXCR4-mediated signaling and associated biological processes. Compared to CXCL12/CXCR4-induced signaling, only few details are known on MIF/CXCR4-mediated signaling and it remains unclear to which extent MIF and CXCL12 reciprocally influence CXCR4 binding and signaling. Furthermore, the atypical chemokine receptor 3 (ACKR3) (previously CXCR7) has added to the complexity of CXCR4 signaling due to its ability to bind CXCL12 and MIF, and to evoke CXCL12- and MIF-triggered signaling independently of CXCR4. Also, extracellular ubiquitin (eUb) and the viral protein gp120 (HIV) have been reported as CXCR4 ligands, whereas viral chemokine vMIP-II (Herpesvirus) and human β3-defensin (HBD-3) have been identified as CXCR4 antagonists. This review will provide insight into the diversity and inter-connections in the CXCR4 receptor/ligand family. We will discuss signaling pathways initiated by binding of CXCL12 vs. MIF to CXCR4, elaborate on how ACKR3 affects CXCR4 signaling, and summarize biological functions of CXCR4 signaling mediated by CXCL12 or MIF. Also, we will discuss eUb and gp120 as alternative ligands for CXCR4, and describe vMIP-II and HBD-3 as antagonists for CXCR4. Detailed insight into biological effects of CXCR4 signaling und underlying mechanisms, including diversity of CXCR4 ligands and inter-connections with other (chemokine) receptors, is clinically important, as the CXCR4 antagonist AMD3100 has been approved as stem cell mobilizer in specific disease settings.
Highlights
The CXC chemokine receptor CXCR4 is well known for its role in the homing of progenitor cells into the bone marrow
Co-expression of CXCR4 with atypical chemokine receptor 3 (ACKR3) resulted in heterodimerization independent of ligand binding [219]. This was associated with a constitutive recruitment of β-arrestin-2 to the CXCR4/ACKR3 complex, with simultaneous down-regulation of Gαi-mediated signaling as shown by a cyclic AMP (cAMP) reporter gene assay as read-out of Gαi signaling [123] (Box 4; Figure 2)
Decaillot et al postulated that the CXCR4/ACKR3 heterodimer down-tunes classical CXCL12/CXCR4-triggered G protein-coupled signaling by preferentially triggering the recruitment of β-arrestin and inducing β-arrestin-mediated signaling pathways, including activation of the MAP kinases ERK1/2, p38 and SAPK
Summary
The CXC chemokine receptor CXCR4 is well known for its role in the homing of progenitor cells into the bone marrow. With respect to the “site two” interaction important for receptor signaling, the crystal structure of CXCR4 in complex with the antagonistic peptide CVX15 was suggested to reveal a “site two” interaction of the CXCL12 N-terminus (aa 1–8 KPVSLSYR) with CXCR4, with preliminary modeling studies suggesting that CXCL12 Lys-1 could integrate into the CXCR4 binding pocket and interact with available acidic aa [24]. The CXCL12/CXCR4 axis is involved in a plethora of biological processes, including, for example, progenitor cell homing and mobilization, neutrophil homeostasis, embryonic development, and angiogenesis These biological effects are mediated by complex signaling mechanisms, including classical GPCR signaling, β-arrestin recruitment, or the activation of the JAK/signal transducer and activator of transcription (STAT) pathway. Related to its role in angiogenesis, chemotaxis [100, 101], and cell proliferation [100, 102], CXCL12/CXCR4 signaling has been linked to different pathologies including tumor progression and metastasis, as discussed in more detail later
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
