ACKR3 Regulation of Neuronal Migration Requires ACKR3 Phosphorylation, but Not ß-Arrestin.
Cell Rep
; 26(6): 1473-1488.e9, 2019 02 05.
Article
em En
| MEDLINE
| ID: mdl-30726732
ABSTRACT
Phosphorylation of heptahelical receptors is thought to regulate G protein signaling, receptor endocytosis, and non-canonical signaling via recruitment of ß-arrestins. We investigated chemokine receptor functionality under phosphorylation-deficient and ß-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 ß-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, ß-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 ß-arrestin involvement in chemokine sequestration and non-canonical signaling.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Movimento Celular
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Receptores CXCR
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Interneurônios
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2019
Tipo de documento:
Article