Phosphorylation of Ser307 in Insulin Receptor Substrate-1 Blocks Interactions with the Insulin Receptor and Inhibits Insulin Action*

By Vincent Aguirre, E. D. Werner, J. Giraud, Y. Lee, S. Shoelson, M. White. Journal of Biological Chemistry, 2002

1,017 citations recorded by the source corpus.

Serine phosphorylation of insulin receptor substrate-1 (IRS-1) inhibits insulin signal transduction in a variety of cell backgrounds, which might contribute to peripheral insulin resistance. However, because of the large number of potential phosphorylation sites, the mechanism of inhibition has been difficult to determine. One serine residue located near the phosphotyrosine-binding (PTB) domain in IRS-1 (Ser307in rat IRS-1 or Ser312 in human IRS-1) is phosphorylated via several mechanisms, including insulin-stimulated kinases or stress-activated kinases like JNK1. During a yeast tri-hybrid assay, phosphorylation of Ser307 by JNK1 disrupted the interaction between the catalytic domain of the insulin receptor and the PTB domain of IRS-1. In 32D myeloid progenitor cells, phosphorylation of Ser307 inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades. These results suggest that inhibition of PTB domain function in IRS-1 by phosphorylation of Ser307 (Ser312 in human IRS-1) might be a general mechanism to regulate insulin signaling.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/b83b9a105d64f9915b027772e101241fac63fc41

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Citations in the corpus

Inflammation and insulin resistance (2008, background): “When IRS1 is alternatively phosphorylated on serine 307, its downstream signaling ability is diminished [ 9 ].”
Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training (2013, neutral): “P A A uthor M anuscript binding domains (PTB) of IRS-1, Shc, and STAT5 (110, 246, 321, 573) (Fig.”
Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. (2005, neutral): “Evidence in support of this hypothesis stems from in vitro studies demonstrating that mutating IRS-1 Ser307 to Ala307 abrogates TNF-1 α –induced insulin resistance in 32D IR cells (21).”
Adipocytokines in Obesity and Metabolic Disease (2014, neutral): “JNK1 can directly inhibit insulin signaling by phosphorylating insulin receptor substrate 1 (IRS1) on serine residues (Aguirre et al. 2002) and can also potentiate fatty acid- induced cytokine production (Nguyen et al. 2005).”
Inflammation, stress, and diabetes. (2005, positive): “This phosphorylation reduces both tyrosine phosphorylation of IRS-1 in response to insulin and the ability of IRS-1 to associate with the insulin receptor and thereby inhibits downstream signal - ing and insulin action (35, 37, 38).”
Loss-of-Function Mutation in Toll-Like Receptor 4 Prevents Diet-Induced Obesity and Insulin Resistance (2007, background): “has become a molecular indicator of insulin resistance (3,4,43,44).”
An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. (2012, positive): “A recent study demonstrated that IRS-1pSer307 in mice is a positive regulatory site that sustains peripheral insulin signaling and moderates the severity of insulin resistance (65), in contrast to results obtained in previous cell-based experiments (26, 66, 67).”
Suppressor of Cytokine Signaling 1 (SOCS-1) and SOCS-3 Cause Insulin Resistance through Inhibition of Tyrosine Phosphorylation of Insulin Receptor Substrate Proteins by Discrete Mechanisms (2004, background): “TNF- stimulation increases serine phosphorylation of insulin receptor substrate 1 (IRS-1), decreasing its tyrosine phosphorylation by the insulin receptor (IR) kinase (2, 19).”
High-Fat Diet: Bacteria Interactions Promote Intestinal Inflammation Which Precedes and Correlates with Obesity and Insulin Resistance in Mouse (2010, background): “Numerous studies have demonstrated that TNF-a limits insulin receptor signaling and promotes insulin resistance [15,23].”