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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.

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Institute of Pharmacology and Toxicology, Jena University Hospital, 07747 Jena, Germany.
Department of Pharmacology and Toxicology, University of Toronto, Toronto M5S 1A8, ON, Canada.
Institute of Pharmacology and Toxicology, Jena University Hospital, 07747 Jena, Germany. Electronic address:


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.


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

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