RESUMO
Defects in the insulin-signaling pathway may lead to the development of skeletal muscle insulin resistance, which is one of the earliest abnormalities detected in individuals with the metabolic syndrome and predisposes them to develop type 2 diabetes. Previous studies have shown that deletion of the mouse sequestosome 1/p62 gene results in mature-onset obesity that progresses to insulin and leptin resistance and, ultimately, type 2 diabetes. Sequestosome 1/p62 is involved in receptor-mediated signal transduction and functions as an intracellular signal modulator or adaptor protein. Insulin receptor substrate-1 (IRS-1) plays a central role in transducing the insulin signal via phosphorylation, protein-protein interactions, and protein modifications. Mapping studies demonstrated that the SH(2) domain at the amino terminus of sequestosome 1/p62 interacts with IRS-1 upon insulin stimulation. Further, IRS-1 interacts with p62 through its YMXM motifs at Tyr-608, Tyr-628, and/or Tyr-658 in a manner similar to its interaction with p85 of phosphoinositol 3-kinase. Overexpression of p62 increased phosphorylation of Akt, GLUT4 translocation, and glucose uptake, providing evidence that p62 participates in the insulin-signaling pathway through its interactions with IRS-1.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Insulina/metabolismo , Transdução de Sinais/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Motivos de Aminoácidos , Animais , Células CHO , Cricetinae , Cricetulus , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Choque Térmico/genética , Humanos , Insulina/genética , Proteínas Substratos do Receptor de Insulina/genética , Camundongos , Mapeamento de Peptídeos/métodos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/fisiologia , Transporte Proteico/fisiologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Sequestossoma-1 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Domínios de Homologia de srcRESUMO
Sequestosome 1/p62 is a signal modulator or adaptor protein involved in receptor-mediated signal transduction. Sequestosome 1/p62 is gaining attention as it is involved in several diseases including Parkinson disease, Alzheimer disease, liver and breast cancer, Paget's disease of bone, obesity and insulin resistance. In this review, we will focus on the most recent advances on the physiological function of p62 relevant to human diseases.