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Cell Rep. 2019 Feb 5;26(6):1473-1488.e9. doi: 10.1016/j.celrep.2019.01.049.

ACKR3 Regulation of Neuronal Migration Requires ACKR3 Phosphorylation, but Not β-Arrestin.

Author information

1
Institute of Pharmacology and Toxicology, Jena University Hospital, 07747 Jena, Germany.
2
Department of Pharmacology and Toxicology, University of Toronto, Toronto M5S 1A8, ON, Canada.
3
Institute of Pharmacology and Toxicology, Jena University Hospital, 07747 Jena, Germany. Electronic address: ralf.stumm@med.uni-jena.de.

Abstract

Phosphorylation of heptahelical receptors is thought to regulate G protein signaling, receptor endocytosis, and non-canonical signaling via recruitment of β-arrestins. We investigated chemokine receptor functionality under phosphorylation-deficient and β-arrestin-deficient conditions by studying interneuron migration in the embryonic cortex. This process depends on CXCL12, CXCR4, G protein signaling and on the atypical CXCL12 receptor ACKR3. We found that phosphorylation was crucial, whereas β-arrestins were dispensable for ACKR3-mediated control of CXCL12 levels in vivo. Cortices of mice expressing phosphorylation-deficient ACKR3 exhibited a major interneuron migration defect, which was accompanied by excessive activation and loss of CXCR4. Cxcl12-overexpressing mice mimicked this phenotype. Excess CXCL12 caused lysosomal CXCR4 degradation, loss of CXCR4 responsiveness, and, ultimately, similar motility defects as Cxcl12 deficiency. By contrast, β-arrestin deficiency caused only a subtle migration defect mimicked by CXCR4 gain of function. These findings demonstrate that phosphorylation regulates atypical chemokine receptor function without β-arrestin involvement in chemokine sequestration and non-canonical signaling.

KEYWORDS:

ACKR; ACKR3; CXCL12; CXCR4; CXCR7; G protein-coupled receptor kinase; GRK; atypical chemokine receptor; internalization; interneuron; migration; phosphorylation; β-arrestin

PMID:
30726732
DOI:
10.1016/j.celrep.2019.01.049
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