Cited by 1,017Metabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic DiseasesDiabetes, Cardiovascular Risks, and Lipoproteins

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

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Copps, K. D., White, M. F.·2012·Diabetologia

DOI 10.1007/s00125-012-2644-8PMC PMC4011499

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Abstract

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.

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Insulin Stimulates PKCζ-mediated Phosphorylation of Insulin Receptor Substrate-1 (IRS-1)
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Retracted
Common Inhibitory Serine Sites Phosphorylated by IRS-1 Kinases, Triggered by Insulin and Inducers of Insulin Resistance
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G Protein–Coupled Receptor Kinase 2 Plays a Relevant Role in Insulin Resistance and Obesity
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Background
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Background
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“Known kinases that phosphorylate IRS1 at these sites include mTOR (Ser302, positive regulation), ROCK1 (Ser636/639, positive regulation), and PKC (Ser612, negative regulation) (24 , 25 ).”
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“This is primarily mediated by serine phosphorylation of IRS proteins, which disrupts signal transduction (42, 43).”
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“…than a purely inhibitory one—mutating this residue paradoxically exacerbates insulin resistance under high-fat feeding—so the pathway is best understood as one node within a wider IRS-1/IRS-2 serine/threonine phosphorylation network rather than as the single defining biochemical endpoint [67].”
Surveying the relationship between Gly1057Asp polymorphism of IRS-2 gene and susceptibility to type 2 diabetes; a systematic review and meta-analysis study
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“Binding of the IRS to p85, as a regulatory subunit of PI-3-kinase, activate the PI-3-kinase-PKB/AKT pathway that is necessary for fulfillment of the insulin action on glucose transport and construction of glycogen in the liver (17).”
Background
there any association of metabolic disturbances with joint destruction and pain?
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Authors: Copps, K. D., & White, M. F.
Affiliations: Boston Children's Hospital (US)
Corresponding author: White, M. F.
ORCID: White, M. F.
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2012-08-08
Volume: 55
Issue: 10
Pages: 2565-2582
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-012-2644-8
PMC: PMC4011499
OpenAlex: W1982479748
Cited by: 1,017
References: 185
Citations by year: 2026: 72 · 2025: 56 · 2024: 76 · 2023: 83 · 2022: 103 · 2021: 113 · 2020: 83 · 2019: 76 · 2018: 75 · 2017: 70 · 2016: 59 · 2015: 63 · 2014: 51 · 2013: 31 · 2012: 5
FWCI: 4.40
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Diabetologia (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Institutes of Health (5r01dk098655-08)
National Institute of Diabetes and Digestive and Kidney Diseases (R01- DK098655, R01DK038712)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: insulin receptor substrate, IRS-1, insulin receptor substrate 2, serine/threonine phosphorylation, insulin sensitivity, insulin resistance, diabetes mellitus, insulin signaling, AMPK, glycogen synthase kinase-3, protein kinase C, Akt, mTOR, hyperinsulinemia, metabolic disorders
MeSH terms: Animals, Diabetes Mellitus, Humans, Insulin Resistance, Mice, Transgenic, Phosphorylation, Serine, Threonine, Signal Transduction, Mice, Knockout, Models, Animal, Mice, Insulin Receptor Substrate Proteins

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

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