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Am J Physiol Endocrinol Metab ; 300(1): E103-10, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20978232

RESUMO

The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C(2)C(12) cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-ß-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectin-stimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNFα-stimulated p38 MAPK phosphorylation in C(2)C(12) myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Adiponectina/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem Celular , Ativação Enzimática , Humanos , Imunoprecipitação , MAP Quinase Quinase 3/genética , MAP Quinase Quinase 3/metabolismo , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Mutação , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno , Fatores de Tempo , Transfecção , Fator de Necrose Tumoral alfa/metabolismo
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