Abstract
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.
Highlights
Sequestosome 1/p62 is a scaffolding protein that plays a critical role in receptor-mediated signal transduction
We sought to investigate whether Insulin receptor substrate-1 (IRS-1) interacts with p62 upon insulin stimulation
The cells were lysed with Triton lysis buffer and immunoprecipitated with anti-insulin receptor substrate (IRS)-1 or anti-p62 antibody and Western blotted with anti-IRS-1 and anti-p62 antibody
Summary
Sequestosome 1/p62 is a scaffolding protein that plays a critical role in receptor-mediated signal transduction. Results: p62 interacts with IRS-1 to enhance the Akt phosphorylation, GLUT4 translocation, and glucose uptake upon insulin stimulation. 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 SH2 domain at the amino terminus of sequestosome 1/p62 interacts with IRS-1 upon insulin stimulation.
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