H2O2-induced phosphorylation of ERK1/2 and PKB requires tyrosine kinase activity of insulin receptor and c-Src.
Antioxid Redox Signal
; 7(7-8): 1014-20, 2005.
Article
en En
| MEDLINE
| ID: mdl-15998256
Hydrogen peroxide (H2O2) mimics many physiological responses of insulin, and increased H2O2 generation via the Nox-4 subunit of NAD(P)H oxidase was recently demonstrated to serve as a critical early step in the insulin signaling pathway. Exogenously added H2O2 has also been shown to activate several key components of the insulin signaling cascade. H2O2-induced signaling responses have been found to be associated with the activation of receptor and nonreceptor protein tyrosine kinases (PTK), including the insulin receptor (IR)-beta subunit. Therefore, in the present studies on Chinese hamster ovary cells overexpressing wild-type IR-PTK (CHO-IR) or a PTK-inactive form of IR (CHO-1018), we investigated whether IR-PTK plays a role in H2O2-induced signaling events. Treatment of CHO-IR cells with H2O2 increased the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (PKB), and glycogen synthase kinase-3beta while enhancing tyrosine phosphorylation of the IR-beta subunit and the p85 subunit of phosphatidylinositol 3-kinase (PI3K). Compared with CHO-IR cells, the stimulatory effect of H2O2 on ERK1/2 and PKB was partially reduced in CHO-1018 cells. However, pharmacological inhibition of Src family PTK by 4-amino-5-(4-chlorophenyl)-7-(tert-butyl)pyrazolo[3,4-d]pyrimidine (PP-2) almost completely blocked H2O2-stimulated phosphorylation of the p85 subunit of PI3K, ERK1/2, and PKB. Moreover, H2O2, but not insulin, induced Tyr-418 phosphorylation of Src, which was also suppressed by PP-2. Taken together, these data suggest that both IR-PTK and Src family PTKs contribute to H2O2-induced signaling in CHO-IR cells albeit IR-PTK has a less dominant role in this process.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptor de Insulina
/
Proteínas Proto-Oncogénicas pp60(c-src)
/
Proteínas Proto-Oncogénicas
/
Proteínas Serina-Treonina Quinasas
/
Quinasas MAP Reguladas por Señal Extracelular
/
Peróxido de Hidrógeno
Límite:
Animals
Idioma:
En
Revista:
Antioxid Redox Signal
Asunto de la revista:
METABOLISMO
Año:
2005
Tipo del documento:
Article
País de afiliación:
Canadá
Pais de publicación:
Estados Unidos