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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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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Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
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Background

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Retracted
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“Besides, TNF‐α contributes to impair insulin signalling by increasing insulin receptor substrate‐1 phosphorylation [61].”
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Fucoidan from sea cucumber may improve hepatic inflammatory response and insulin resistance in mice
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“The phosphorylation of insulin receptor substrates (IRSs) and other downstream mediators of the insulin receptor by these kinases causes inflammation-induced insulin resistance in aging and metabolic diseases (see detailed review in [35]).”
Background
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Rapamycin reverses insulin resistance (IR) in high-glucose medium without causing IR in normoglycemic medium
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“Various kinases, such as S6K1, mTOR, Akt, PKC, Erk1/2, p90Rsk, each phosphorylate its numerous (more than 50 serine/ threonine residues) phosphorylation sites.(51) Not only kinases are redundant and overlapping, they are cell type- and condition-specific.”
Background
A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle
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“Phosphorylation of the inhibitory IRS1S612 site was detected at 30 and 60 min following IGF1 treatment (Fig.”
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“Also, ROS stimulate proinflammatory signaling via tumor necrosis factor a (TNFa) and interleukin 1b (IL1b) that can contribute to insulin resistance (Kim, Wei, and Sowers 2008; Copps and White 2012).”
Background
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“The protein stability of IRS1, insulin receptor substrate 1, is affected through serine phosphorylation by either S6K1 at Ser-307 or mTORC1 at Ser-636/639, and has been proposed to lead to insulin resistance (Copps and White, 2012; Um et al., 2006).”
Background
Development of Multimarker Diagnostic Models from Metabolomics Analysis for Gestational Diabetes Mellitus (GDM)
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“BCAAs are involved in several pathways of insulin resistance, including fatty acid oxidation, mTOR, JNK and IRS1 pathways (35, 36).”
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“Reduced tyrosine phosphorylation of IRS1 is a common feature in insulin-resistant human skeletal muscle, while either increased or decreased site-specific serine/threonine phosphorylation of IRS1 have been reported in insulin resistance and T2D (12).”
Background
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“Particularly, an increased serine phosphorylation of IRS1/IRS2 is implicated in the inhibition of insulin signaling (Copps and White 2012).”
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“JNK phosphorylates the serine residue in the IRS-2 phosphotyrosine-binding structural domain, leading to the dissociation of IRS-2 and the insulin receptor [35], which can block signal transduction over a short period.”
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“Insulin resistance is generally associated with suppressed PI3K pathway, with increased serine phosphorylation of IRS proteins and inhibited tyrosine phosphorylation [24]; IRS protein degradation also seems to occur in some conditions [25].”
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“Increased Ser/Thr phosphorylation of IRS proteins is one of the key features of IR (40).”
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“34).”
Hepatocyte DUSP14 maintains metabolic homeostasis and suppresses inflammation in the liver
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“As a well-known downstream effector of TAK1, JNK1 plays a critical role in regulating the patterns of IRS Ser/Tyr phosphorylation, which could profoundly influence insulin sensitivity.((33,34)) JNK1 potently promotes the phosphorylation of IRS1 at Ser307, and subsequently down-regulates Tyr608 phosphorylation, which r…”
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“Phospho-S6K can phosphorylate and degrade IRS1 (Copps & White, 2012), which is downstream of INSR/IGF1R but upstream of p-AKT.”
Background
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“CD36 overexpression caused a twofold increase in membrane-associated PKCe protein level (Fig.”
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“For example, several studies have shown that both mTORC1 and/or S6K1 phosphorylate specific serine residues on IRS proteins [6, 7].”
Background
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“Moreover, accumulated fatty acids activate PEPCK which produces hepatic glucose production thus, leading to hepatic glycemic burden [13,14].”
Background
In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles
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“…(pY) to serine 312 phosphorylated (pSer312) IRS1 (Y/S IRS1 ratio) was shown to decrease in response to insulin resistance in cell studies (Copps & White, 2012), and we have recently shown that it is significantly decreased in neuronal-enriched EVs of patients with Alzheimer’s disease…”
Background
Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium
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“The C-terminal part of IRS proteins contains a domain involved in specific interaction with various types of src-homology-2 (SH2)-domain-containing proteins responsible for the cell’s response to insulin [100].”
Background
Casein glycomacropeptide‐derived peptide IPPKKNQDKTE ameliorates high glucose‐induced insulin resistance in HepG2 cells via activation of AMPK signaling
Song, J., Wang, Q., Du, ‬., Li, T., Bin, C., & Mao, X. (2016) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201600301 · Cited by 56
“The impaired insulin signaling and the defect in downstream PI3K/Akt signal transduction are related to the phosphorylation of IRS on serine and threonine residues [34, 35].”
Background
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“In accord with these findings, prolonged insulin exposure has been shown to attenuate the insulinsignalling capacity by promoting inhibitory serine phosphorylation of IRS-1 through activation of serine/threonine kinases, such as JNK, IKK, S6K1, and mTOR [18,38,39].”
Background
An update on potential links between type 2 diabetes mellitus and Alzheimer’s disease
Sousa, R. A. L. D., Harmer, A. R., Freitas, D. A., Mendonça, V. A., Lacerda, A. C. R., & Leite, H. R. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-05693-z · Cited by 57
“Presence of low-grade systemic inflammation can impair IRS-1 and IRS-2 function and hence impair blood glucose regulation [35, 36].”
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Molecular basis of insulin resistance: the role of IRS and Foxo1 in the control of diabetes mellitus and its complications
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Exercise and Glycemic Control: Focus on Redox Homeostasis and Redox-Sensitive Protein Signaling
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“Signaling by ROS Sustained activation of redox-sensitive SAPK signaling pathways leads to impaired insulin signaling via increased phosphorylation of IRS-1 and IRS-2 on multiple serine and threonine residues, see the study by Copps and White (223) for a detailed review.”
Disruption of the Phosphate Transporter Pit1 in Hepatocytes Improves Glucose Metabolism and Insulin Signaling by Modulating the USP7/IRS1 Interaction
Forand, A., Koumakis, E., Rousseau, A., Sassier, Y., Journé, C., Merlin, J.-F., Leroy, C., Boitez, V., Codogno, P., Friedlander, G., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.08.012 · Cited by 57

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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