Limits...
CXCR7 functions as a scavenger for CXCL12 and CXCL11.

Naumann U, Cameroni E, Pruenster M, Mahabaleshwar H, Raz E, Zerwes HG, Rot A, Thelen M - PLoS ONE (2010)

Bottom Line: We 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.In accordance with the proposed activity as a scavenger receptor CXCR7-dependent chemokine degradation does not become saturated with increasing ligand concentrations.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland.

ABSTRACT

Background: CXCR7 (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 findings: We 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/significance: The 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.

Show MeSH

Related in: MedlinePlus

Ligand-independent cycling of CXCR7 in zebrafish embryos.In embryos expressing CXCR7-EGFP the receptor localizes at the plasma membrane (grey mark in lower panels) and intracellular vesicles (white dot). Time laps (time stamps) images shows that the vesicles are in contact with the membrane internalize and recycle back to the membrane. Internalization and cycling of CXCR7-EGF is similar in the presence (control–MO) or absence of CXCL12 (CXCL12–MO), underling the ligand independent mechanism. For the complete time laps see supplementary movies S1 cont and S2 CXCL12.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2820091&req=5

pone-0009175-g005: Ligand-independent cycling of CXCR7 in zebrafish embryos.In embryos expressing CXCR7-EGFP the receptor localizes at the plasma membrane (grey mark in lower panels) and intracellular vesicles (white dot). Time laps (time stamps) images shows that the vesicles are in contact with the membrane internalize and recycle back to the membrane. Internalization and cycling of CXCR7-EGF is similar in the presence (control–MO) or absence of CXCL12 (CXCL12–MO), underling the ligand independent mechanism. For the complete time laps see supplementary movies S1 cont and S2 CXCL12.

Mentions: In zebrafish contradicting opinions on the role of CXCR7 have been reported, suggesting a signaling [17] versus a scavenger function [19]. To investigate this controversy, we followed the subcellular localization of the receptor in zebrafish cells. CXCR7-EGFP (CXCR7 tagged at the C-terminus with EGFP) was expressed in embryos alone or in combination with a morpholino oligonucleotide suppressing CXCL12 expression [19], [21]. Figure 5 shows frames from time-lapse movies (Supplementary Information, movies S1 (control - MO) and S2 (CXCL12-MO)) which document the spontaneous pinching off from the plasma membrane of CXCR7 containing endosomes and their re-association with the membrane. The movement of CXCR7 appears independent of the presence of CXCL12 indicating that CXCR7 can, in agreement with its proposed scavenger function, spontaneously cycle from and back to the plasma membrane in zebrafish embryonic cells. Boldajipour et al. [19] proposed that by removing CXCL12 at the posterior side CXCR7 sharpens the chemotactic gradient promoting CXCR4-dependent migration of primordial germ cells. The present observation provides an explanation for the efficiency of CXCR7 in supporting CXCR4-mediated migration of primordial germ cells and is consistent with the view that CXCR7 that is expressed by somatic cells functions as a scavenger.


CXCR7 functions as a scavenger for CXCL12 and CXCL11.

Naumann U, Cameroni E, Pruenster M, Mahabaleshwar H, Raz E, Zerwes HG, Rot A, Thelen M - PLoS ONE (2010)

Ligand-independent cycling of CXCR7 in zebrafish embryos.In embryos expressing CXCR7-EGFP the receptor localizes at the plasma membrane (grey mark in lower panels) and intracellular vesicles (white dot). Time laps (time stamps) images shows that the vesicles are in contact with the membrane internalize and recycle back to the membrane. Internalization and cycling of CXCR7-EGF is similar in the presence (control–MO) or absence of CXCL12 (CXCL12–MO), underling the ligand independent mechanism. For the complete time laps see supplementary movies S1 cont and S2 CXCL12.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2820091&req=5

pone-0009175-g005: Ligand-independent cycling of CXCR7 in zebrafish embryos.In embryos expressing CXCR7-EGFP the receptor localizes at the plasma membrane (grey mark in lower panels) and intracellular vesicles (white dot). Time laps (time stamps) images shows that the vesicles are in contact with the membrane internalize and recycle back to the membrane. Internalization and cycling of CXCR7-EGF is similar in the presence (control–MO) or absence of CXCL12 (CXCL12–MO), underling the ligand independent mechanism. For the complete time laps see supplementary movies S1 cont and S2 CXCL12.
Mentions: In zebrafish contradicting opinions on the role of CXCR7 have been reported, suggesting a signaling [17] versus a scavenger function [19]. To investigate this controversy, we followed the subcellular localization of the receptor in zebrafish cells. CXCR7-EGFP (CXCR7 tagged at the C-terminus with EGFP) was expressed in embryos alone or in combination with a morpholino oligonucleotide suppressing CXCL12 expression [19], [21]. Figure 5 shows frames from time-lapse movies (Supplementary Information, movies S1 (control - MO) and S2 (CXCL12-MO)) which document the spontaneous pinching off from the plasma membrane of CXCR7 containing endosomes and their re-association with the membrane. The movement of CXCR7 appears independent of the presence of CXCL12 indicating that CXCR7 can, in agreement with its proposed scavenger function, spontaneously cycle from and back to the plasma membrane in zebrafish embryonic cells. Boldajipour et al. [19] proposed that by removing CXCL12 at the posterior side CXCR7 sharpens the chemotactic gradient promoting CXCR4-dependent migration of primordial germ cells. The present observation provides an explanation for the efficiency of CXCR7 in supporting CXCR4-mediated migration of primordial germ cells and is consistent with the view that CXCR7 that is expressed by somatic cells functions as a scavenger.

Bottom Line: We 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.In accordance with the proposed activity as a scavenger receptor CXCR7-dependent chemokine degradation does not become saturated with increasing ligand concentrations.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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland.

ABSTRACT

Background: CXCR7 (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 findings: We 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/significance: The 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.

Show MeSH
Related in: MedlinePlus