ERBIN deficiency links STAT3 and TGF-ß pathway defects with atopy in humans.
J Exp Med
; 214(3): 669-680, 2017 03 06.
Article
em En
| MEDLINE
| ID: mdl-28126831
ABSTRACT
Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-ß activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-ß signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3mut ) or a loss-of-function mutation in ERBB2IP (ERBB2IPmut ) have evidence of deregulated TGF-ß signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3-ERBIN-SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-ß. In turn, cell-intrinsic deregulation of TGF-ß signaling is associated with increased functional IL-4Rα expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4Rα/GATA3 axis in vitro. These findings link increased TGF-ß pathway activation in ERBB2IPmut and STAT3mut patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Fator de Crescimento Transformador beta
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Proteínas Adaptadoras de Transdução de Sinal
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Fator de Transcrição STAT3
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Hipersensibilidade
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article