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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3 retracted

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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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Background
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Background
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Background
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“First, Singh et al. (2023) found no differences in the pS312-IRS-1/pY-Insulin Receptor Substrate (IRS)-1 ratio — an index of insulin resistance (Copps and White, 2012) — in NDEVs in a sample of 21 drug-naïve acute inpatients with first-episode MDD.”
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“IRS1 and IRS2 promote propagation and amplification of insulin metabolic signals, whereas the SHC proteins promote and amplify insulin-activated mitogenic signals [40,41].”
Background
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Hoch, J., Burkhard, N., Zhang, S., Rieder, M., Marchini, T., Geest, V., Krauel, K., Zahn, T., Schommer, N., Hamad, M. A., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1184010 · Cited by 12
“This is shown by lower expression of the insulin-sensitive glucose transporter GLUT4 and lower expression of the insulin receptor substrate 2 (IRS2) which is an important component of insulindependent intracellular signal transduction (Figure 4K) (29, 30).”
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“Due to its proximity to the PTB of IRS1, phosphorylation of Ser307 results in inhibition of PTB binding to the IR leading to inhibition of signal transduction from the insulin receptor to its downstream effectors [24, 25].”
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“This negative feedback loop is thought to contribute to insulin resistance in the context of diabetes and other diseases [reviewed in (47)].”
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“Changes in IRS1 had been shown to affect PI3K/Akt signaling [28,29].”
Background
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“Module 1, describing the IR-IRS1 dynamics The new model is now described and compared with data for each of the three Modules 1–3, whereafter the combined model is analyzed.”
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“The complex formation between insulin receptor (IR) and IRS1/IRS2 is the rate determining step in the insulin signaling cascade.(75,76) The IRS1 (PDB ID: 1IRS) and IRS2 (PDB ID: 3BBU) are the key substrate proteins of IR.”
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“Although IRS2 mutations are unusual and have not been associated with human type 2 diabetes, enhanced phosphorylation on serine/threonine residues, many of which negatively regulate IRS2 function [30], may affect the proper IRS2 downstream signals, which in turn would affect NaW renal effects.”
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“Among them, it is well documented that the phosphorylation of IRS-1 at Ser-612 and Ser-632/635 residues is negatively correlated with insulin signaling [23,24].”
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“Additionally, the serine phosphorylation of IRS1 can inhibit the response to insulin receptor activation through reduced PI3K/AKT signaling [40].”
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“Unfortunately, we were not able to detect significant phosphorylation of IRS1 on both Ser636/639 and Ser307 using commercial antibodies (data not shown), although it is worth mentioning that the existence of this regulatory feedback loop and the exact IRS1 residue(s) involved are still a matter of debate, especially i…”
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“PKC-θ increases serine phosphorylation of IRS-1 but inhibits tyrosine phosphorylation, triggering insulin resistance [98] (Fig.”
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“The canonical lipid storage signaling pathway includes insulin binding its receptor, increasing the insulin receptor tyrosine kinase activity, which, in turn, phosphorylates insulin receptor substrate (IRS) proteins [45].”
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“It should be emphasized that phosphorylation of tyrosine residues in IRS1 activates insulin signal transduction, while phosphorylation of serine residues in IRS1 inhibits the activity of the insulin pathway [32].”
Background
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“As a consequence, the IRS–PI3K–Akt signaling pathway is specifically downregulated in insulin resistance (Figure 3) [65].”
Background
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“Phosphorylation on serine 312 of IRS1 decreases its activity while phosphorylation on tyrosine residues increases its activity [2].”
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“Moving further downstream, it activates the lipid kinase phosphatidylinositol-3 kinase (PI3-K) and the serine/threonine kinase Akt/PKB (protein kinase B) (Copps & White, 2012).”
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“In other studies, TRIM8 was reported to mediate the insulin signal transduction and involvement in insulin resistance [34,35].”
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“…interaction between its PTB domain and the phosphorylated receptor causing their dissociation and decreasing tyrosine phosphorylation (reviewed in Copps & White (2012)), although some studies have demonstrated that certain phosphorylations on serine residues have a positive effect on insulin…”
BackgroundResult
Identification of Three Significant Genes Associated with Immune Cells Infiltration in Dysfunctional Adipose Tissue-Induced Insulin-Resistance of Obese Patients via Comprehensive Bioinformatics Analysis
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“-e GSEA analysis results revealed that high expression ofCSF1R correlated with TNFR2 noncanonical NFκB pathway and Type 1 diabetic pathways activated, while the mTOR signaling pathway was inhibited, which participated in the insulin-sensitivity regulation [30].”
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“These results suggested that VN and its recep‐ tor integrin αvβ3 have a direct role in the insulin signal‐ ing pathway IRS-1, an intracellular protein that binds to other signaling molecules to regulate insulin signaling [25].”
Background

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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