The peculiarities of the SDF-1/CXCL12 system: in some cells, CXCR4 and CXCR7 sing solos, in others, they sing duets

Abstract

The chemokine SDF-1/CXCL12 induces and modulates major steps of ontogenesis, regeneration and tumorigenesis. Depending on the organ or tissue, CXCL12 serves as a proliferation or cell survival factor, influences differentiation, induces adhesion and/or regulates cell migration. These functions are mediated by the two chemokine receptors, CXCR4 and CXCR7. Whereas CXCR4 is still viewed as the sole G-protein-activating and, hence, signaling receptor for CXCL12, CXCR7 is regarded as a non-classic scavenging or decoy receptor that modulates the function of CXCR4. However, this view might be too limited, since evidence has accumulated favoring a cell-type-specific mode of CXCL12 signaling. In addition to the "classic" CXCL12 signaling mode via CXCR4, CXCR4 and CXCR7 have to form a receptor unit for successful CXCL12 signaling in some cells. Moreover, examples exist whereby CXCL12 receptors split functions or switch roles, such that CXCR7 (instead of CXCR4) mediates signal transduction. The obvious lack of a universal mode of CXCL12 signaling urges a re-evaluation of the role of this chemokine in development, health and disease. This review depicts the exceptional characteristics of CXCL12-induced signal transduction in various cells and organs, points out remaining controversies and mentions consequences for therapeutic interventions.

CXCR4 Antagonist AMD3100 Suppresses the Long-Term Abnormal Structural Changes of Newborn Neurons in the Intraventricular Kainic Acid Model of Epilepsy

“…Subsequent work suggested that CXCR7 was involved in several functions of SDF-1 and regulated CXCL12-CXCR4-induced cellular responses [86][87][88]. In contrast to its inhibitory effect on the SDF-1/CXCR4 interaction, AMD3100 acts as an inverse agonist for CXCR7 and positively modulates the SDF-1/CXCR7 interaction [89].…”

Requirement of CXCL12-CXCR7 signaling for CD20− CD138− double-negative population in lymphoplasmacytic lymphoma

“…28 Recent report demonstrated that the signal from CXCR4 is common to that of CXCR7. 26 Since not all LPL cases possessed driver mutation at CXCR4, 27 several cases of LPL might utilize signals from CXCR7.…”

“…CXCL12 is the ligand of CXCR7, binds to CXCR4 as well as CXCR7, and both receptors are closely related according to reported modes of CXCL12-CXCR4/CXCR7 signaling. 26 Then, the expression level of CXCR4 was also examined in sorted CD20 − CD138 − , CD20 + CD138 − and CD20 + CD138 + cells. In contrast to CXCR7, the expression level of CXCR4 was low and comparable among examined subpopulations ( Figure 3).…”

CXCR7 expression disrupts endothelial cell homeostasis and causes ligand-dependent invasion

“…9,20,21 Several recent studies have also reported a non-scavenging function of CXCR7 in specific cell types. 22 Similarly, our previous experiments in EC showed that (1) endogenously produced CXCR7 ligands were required for CXCR7-mediated degradation of pRb and (2) CXCR3 and CXCR4 protein levels were low or absent (respectively) in this context and were not affected by CXCR7 expression. 18 Therefore, we concluded that our gain-of-function phenotypes were a result of CXCR7 signaling and that CXCR7 can function as a bona fide chemokine receptor in EC, making its EC-specific expression in solid tumors of particular interest and significance.…”