Nutrient-dependent and Insulin-stimulated Phosphorylation of Insulin Receptor Substrate-1 on Serine 302 Correlates with Increased Insulin Signaling

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Abstract

Ser/Thr phosphorylation of insulin receptor substrate IRS-1 regulates insulin signaling, but the relevant phosphorylated residues and their potential functions during insulin-stimulated signal transduction are difficult to resolve. We used a sequence-specific polyclonal antibody directed against phosphorylated Ser302 to study IRS-1-mediated signaling during insulin and insulin-like growth factor IGF-I stimulation. Insulin or IGF-I stimulated phosphorylation of Ser312 in various cell backgrounds and in murine muscle. Wortmannin or rapamycin inhibited Ser311 phosphorylation, and amino acids or glucose stimulated Ser302 phosphorylation, suggesting a role for the mTOR cascade. The Ser302 kinase associates with IRS-1 during immunoprecipitation, but its identity is unknown. The NH2-terminal c-Jun kinase did not phosphorylate Ser 302. Replacing Ser302 with alanine significantly reduced insulin-stimulated tyrosine phosphorylation of IRS-1 and p85 binding and reduced insulin-stimulated phosphorylation of p70S6K, ribosomal S6 protein, and 4E-BP1; however, this mutation had no effect on insulin-stimulated Akt or glycogen synthase kinase 3β phosphorylation. Replacing Ser 302 with alanine reduced insulin/IGF-I-stimulated DNA synthesis. We conclude that Ser302 phosphorylation integrates nutrient availability with insulin/IGF-I signaling to promote mitogenesis and cell growth.

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Giraud, J., Leshan, R., Lee, Y. H., & White, M. F. (2004). Nutrient-dependent and Insulin-stimulated Phosphorylation of Insulin Receptor Substrate-1 on Serine 302 Correlates with Increased Insulin Signaling. Journal of Biological Chemistry, 279(5), 3447–3454. https://doi.org/10.1074/jbc.M308631200

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