The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis.
Nat Commun
; 10(1): 6, 2019 01 02.
Article
em En
| MEDLINE
| ID: mdl-30602778
ABSTRACT
Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluation in IPF. Here we demonstrate that rapamycin-insensitive mTORC1 signaling via 4E-BP1 is a critical pathway for TGF-ß1 stimulated collagen synthesis in human lung fibroblasts, whereas canonical PI3K/Akt signaling is not required. The importance of mTORC1 signaling was confirmed by CRISPR-Cas9 gene editing in normal and IPF fibroblasts, as well as in lung cancer-associated fibroblasts, dermal fibroblasts and hepatic stellate cells. The inhibitory effect of ATP-competitive mTOR inhibition extended to other matrisome proteins implicated in the development of fibrosis and human disease relevance was demonstrated in live precision-cut IPF lung slices. Our data demonstrate that the mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Colágeno
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Proteínas Adaptadoras de Transdução de Sinal
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Fator de Crescimento Transformador beta1
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Fibroblastos
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Alvo Mecanístico do Complexo 1 de Rapamicina
Tipo de estudo:
Etiology_studies
/
Guideline
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article