Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2

By K. Copps, M. White. Diabetologia, 2012

951 citations recorded by the source corpus.

The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/4a0d3c0cc28644ee74adb85f41814ca98b1b702b

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Citations in the corpus

Insulin resistance: Review of the underlying molecular mechanisms (2018, background): “This process creates a suitable binding site for IRS‐1 that is then activated via phosphorylation by different insulin‐induced kinases such as PKC, SIK2, AKT, S6K1, mTOR, extracellular signal‐regulated kinase 1/2 (ERK1/2), and ROCK1 (Copps & White, 2012; Kiselyov et al., 2009).”
Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives (2022, background): “A plethora of evidence suggests AGEs/RAGE signaling pathway, NFκB activation, inflammation, and ROS generation are directly related to the pathogenesis of insulin resistance by increased IRS-1serine phosphorylation and degradation, thus blocking the insulin signaling pathway [68,71,73,74].”
Molecular Mechanisms Linking Oxidative Stress and Diabetes Mellitus (2020, background): “Several types of insulin-dependent kinases such as ERK1/2 (extracellular signal-regulated kinase 1/2), atypical PKC (protein kinase C), S6K1 (ribosomal protein S6 kinase beta-1), SIK2 (serine/threonine-protein kinase 2), Akt (protein kinase B), mTOR (mammalian target of rapamycin), and ROCK1 (rho-as”