CFTR mutation enhances Dishevelled degradation and results in impairment of Wnt-dependent hematopoiesis.
Cell Death Dis
; 9(3): 275, 2018 02 15.
Article
em En
| MEDLINE
| ID: mdl-29449653
ABSTRACT
Mutations of cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) with a multitude of clinical manifestations. Some CF patients develop clinically significant anemia, suggesting that CFTR may regulate hematopoiesis. Here, we report that cftr mutant zebrafish model exhibits primitive and definitive hematopoietic defects with impaired Wnt signaling. Cftr is found to interact, via its PDZ-binding domain (PDZBD), with Dishevelled (Dvl), a key component of Wnt signaling required for hematopoietic progenitor specification, thus protecting Dvl from Dapper1 (Dpr1)-induced lysosomal degradation. Defective hematopoiesis and impaired Wnt signaling in cftr mutant can be rescued by overexpression of wild-type or channel function-defective G551D mutant CFTR with an intact PDZBD, but not Cftr with mutations in the PDZBD. Analysis of human database ( http//r2.amc.nl ) shows that CFTR is positively correlated with DVL2 and Wnt-related hematopoietic factors in human blood system. The results reveal a previously unrecognized role of CFTR, which is independent of its channel function, in regulating DVL degradation and thus Wnt signaling required for hematopoiesis in both zebrafish and humans, providing an explanation for the anemic phenotype of CF patients.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peixe-Zebra
/
Regulador de Condutância Transmembrana em Fibrose Cística
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Proteínas de Peixe-Zebra
/
Via de Sinalização Wnt
/
Hematopoese
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Proteínas de Membrana
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Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China