TGFß1 rapidly activates Src through a non-canonical redox signaling mechanism.
Arch Biochem Biophys
; 568: 1-7, 2015 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-25585026
ABSTRACT
Transforming growth factor-ß1 (TGF-ß) is involved in multiple cellular processes through Src activation. In the canonical pathway, Src activation is initiated by pTyr530 dephosphorylation followed by a conformational change allowing Tyr419 auto-phosphorylation. A non-canonical pathway in which oxidation of cysteine allows bypassing of pTyr530 dephosphorylation has been reported. Here, we examined how TGF-ß activates Src in H358 cells, a small cell lung carcinoma cell line. TGF-ß increased Src Tyr419 phosphorylation, but surprisingly, Tyr530 phosphorylation was increased rather than decreased. Vanadate, a protein tyrosine phosphatase inhibitor, stimulated Src activation itself, but rather than inhibiting Src activation by TGF-ß, activation by vanadate was additive with TGF-ß showing that pTyr530 dephosphorylation was not required. Thus, the involvement of the non-canonical oxidative activation was suspected. TGF-ß increased extracellular H2O2 transiently while GSH-ester and catalase abrogated Src activation by TGF-ß. Apocynin, a NADPH oxidase inhibitor, inhibited TGF-ß-stimulated H2O2 production. Furthermore, mutation of cysteines to alanine, 248C/A, 277C/A, or 501C/A abrogated, while 490C/A significantly reduced, TGF-ß-mediated Src activation. Taken together, the results indicate that TGF-ß-mediated Src activation operates largely through a redox dependent mechanism, resulting from enhanced H2O2 production through an NADPH oxidase and that cysteines 248, 277, 490, and 501 are critical for this activation.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Quinases da Família src
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Fator de Crescimento Transformador beta1
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Carcinoma de Pequenas Células do Pulmão
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Neoplasias Pulmonares
Limite:
Humans
Idioma:
En
Revista:
Arch Biochem Biophys
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos