CXCR7 Functions as a Scavenger for CXCL12 and CXCL11

Abstract

BackgroundCXCR7 (RDC1), the recently discovered second receptor for CXCL12, is phylogenetically closely related to chemokine receptors, but fails to couple to G-proteins and to induce typical chemokine receptor mediated cellular responses. The function of CXCR7 is controversial. Some studies suggest a signaling activity in mammalian cells and zebrafish embryos, while others indicate a decoy activity in fish. Here we investigated the two propositions in human tissues.Methodology/Principal FindingsWe provide evidence and mechanistic insight that CXCR7 acts as specific scavenger for CXCL12 and CXCL11 mediating effective ligand internalization and targeting of the chemokine cargo for degradation. Consistently, CXCR7 continuously cycles between the plasma membrane and intracellular compartments in the absence and presence of ligand, both in mammalian cells and in zebrafish. In accordance with the proposed activity as a scavenger receptor CXCR7-dependent chemokine degradation does not become saturated with increasing ligand concentrations. Active CXCL12 sequestration by CXCR7 is demonstrated in adult mouse heart valves and human umbilical vein endothelium.Conclusions/SignificanceThe finding that CXCR7 specifically scavenges CXCL12 suggests a critical function of the receptor in modulating the activity of the ubiquitously expressed CXCR4 in development and tumor formation. Scavenger activity of CXCR7 might also be important for the fine tuning of the mobility of hematopoietic cells in the bone marrow and lymphoid organs.

The presumed atypical chemokine receptor CXCR7 signals through Gi/o proteins in primary rodent astrocytes and human glioma cells

“…It has been originally assumed that CXCR7 would represent a silent or a scavenger chemokine receptor which modulates the function of CXCR4 (Boldajipour et al, 2008;Levoye et al, 2009;Naumann et al, 2010;Rajagopal et al, 2010a;Sierro et al, 2007). This view was recently challenged by the demonstration that CXCR7 controls growth, adhesion, and transendothelial migration of several types of tumor cells (Burns et al, 2006;Grymula et al, 2010;Miao et al, 2007;Wang et al, 2008;Zabel et al, 2009) and actively mediates SDF-1-dependent signaling involved in the control of either growth or differentiation of primary astrocytes, Schwann cells, and oligodendroglial precursors (G€ ottle et al, 2010;.…”

“…Studies on the migration of primordial germ cells further revealed that CXCR7 controls CXCR4-mediated cell migration by sequestering extracellular SDF-1 and, hence, shaping the extracellular chemokine gradient (Boldajipour et al, 2008). More recently, this scavenger function was additionally highlighted by the demonstration of a constant cycling of CXCR7 between the plasma membrane and intracellular compartments as well as a nonsaturating binding of SDF-1 to CXCR7 (Naumann et al, 2010). Intriguingly, despite this atypical function, CXCR7 induces cell signaling in various types of tumor cells and controls their growth, adhesion, and transendothelial migration (Burns et al, 2006;Grymula et al, 2010;Miao et al, 2007;Wang et al, 2008;Zabel et al, 2009).…”

Antagonism of CXCR7 attenuates chronic hypoxia–induced pulmonary hypertension

“…The signaling pathways that are activated following the binding of CXCR7 to its ligands are still controversial. Indeed, some studies suggest that CXCR7 is a nonsignaling, decoy receptor that scavenges and degrades chemokine ligands (28,29). However, although there is evidence to suggest that CXCR7 does not signal through classical G-protein-mediated pathways (14,28), many studies have demonstrated an important role of this receptor in physiological and pathological processes (9,25,(30)(31)(32).…”

β-arrestin control of late endosomal sorting facilitates decoy receptor function and chemokine gradient formation

“…Cxcr7 function is important for heart development (Sierro et al, 2007), interneuron migration (Sánchez-Alcañiz et al, 2011;Wang et al, 2011), leukocyte trafficking (Cruz-Orengo et al, 2011) and for promoting breast and lung tumorigenesis (Miao et al, 2007;Luker et al, 2012). Some of these in vivo studies, as well as those conducted in vitro (Luker et al, 2010;Naumann et al, 2010), are consistent with the idea that Cxcr7 serves as a receptor that effectively scavenges Cxcl12a and does not influence downstream signaling pathways (reviewed by Mantovani et al, 2006). Despite its importance in controlling Cxcl12 activity in the tissue, the molecular mechanisms promoting the decoy function of Cxcr7 are unknown.…”