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Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.
Open accessAbstract
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 resistance in adipocytes is associated with impaired phosphorylation of insulin receptor substrate 1 (IRS-1) in obesity, which is further impaired in T2DM”
From Effect of Exercise Training on Fat Loss—Energetic Perspectives and the Role of Improved Adipose Tissue Function and Body Fat Distribution (2021) · cites this paper as Copps and White, 2012
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3 retracted
Insulin Stimulates PKCζ-mediated Phosphorylation of Insulin Receptor Substrate-1 (IRS-1)
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RetractedG Protein–Coupled Receptor Kinase 2 Plays a Relevant Role in Insulin Resistance and Obesity
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Increased Circulation and Adipose Tissue Levels of DNAJC27/RBJ in Obesity and Type 2-Diabetes
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“Tyrosine residues are autophosphorylated by insulin or IGF-1 when they bind to their receptors, which activates their intrinsic tyrosine activity and phosphorylates insulin receptor substrate (IRS) docking proteins at tyrosine residues (Duarte and Moreira 2012).”
InfluentialThe Role of Organelle Stresses in Diabetes Mellitus and Obesity: Implication for Treatment
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“Among the upregulated DEGs in IR pathway, Insulin receptor substrate proteins 1 (IRS1) is an important target of the insulin receptor tyrosine kinase (Copps and White, 2012).”
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“In addition, the InR pathway is known to be under homeostatic regulation (Copps and White, 2012; Boucher et al., 2014) and the adult behavioral phenotypes observed after developmental interference with InR signaling (Eddison et al., 2011; McClure et al., 2011) could therefore be due to a…”
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“IRS interacts with PI3K and generate phosphatidylinositol-3, 4, 5-triphosphate (PIP3) 3) AKT/protein kinase B (PKB) [8].”
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“…adipose tissue from female but not male mice (Figure 5B; p<0:05). mRNA abundance of IRS2, a molecular adaptor important in insulin receptor signaling (Copps and White 2012), was significantly higher in livers from female AhR+ =+ compared with male AhR+ =+ PCB-77-treated mice (Figure 6A; p< 0:05).”
BackgroundSevere Insulin Resistance Syndromes: Clinical Spectrum and Management
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“IRS-1 and IRS-2 tyrosine phosphorylation are responsible for the insulin signaling cascade, but the serine and threonine residues are phosphorylated before, during, and after insulin activation [130, 144].”
BackgroundInfluentialInsulin Resistance in Skeletal Muscle Selectively Protects the Heart in Response to Metabolic Stress
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“Subsequently, PIP3 (phosphatidylinositol 3,4,5-trisphosphate) is produced in the plasma membrane through the phosphorylation of PIP2 (phosphatidylinositol 4,5-bisphosphate) by PI3K and, in turn, recruits AKT, which is then activated through the phosphorylation of the T308 (threonine 308) site of protein kinase B and o…”
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“Moreover, this signaling pathway, together with elevated diacylglycerol and ceramides, increases serine phosphorylation of IRS-1, inhibiting proximal insulin signaling and eventually leading to IRS-1 degradation [8].”
BackgroundDiosgenin: An ingress towards solving puzzle for diabetes treatment
Arya, P., & Kumar, P. (2022) · Journal of Food Biochemistry · doi:10.1111/jfbc.14390 · Cited by 18
Ramadan, N. M., Elmasry, K., Elsayed, H. R. H., El‐Mesery, A., & Eraky, S. M. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.121145 · Cited by 18
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“The insulin receptor substrate undergoes phosphorylation at the serine residues under insulin-resistant conditions, modifying the signalling pathway [56].”
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“Increased phosphorylation of the serine residues of IRS-1 results in reduced downstream PI3K-Akt signaling and glucose uptake [62,63].”
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Review: Insulin resistance and mitochondrial dysfunction following severe burn injury
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“Among potential IRS1 serine kinases, JNK has been extensively studied in insulin resistant states.(36) Treatment with cytokines increased IRS1 serine 307 phosphorylation in 661W cells by 3.”
BackgroundDreher, S. I., Höckele, S., Huypens, P., Irmler, M., Hoffmann, C., Jeske, T., Hastreiter, M., Moller, A., Birkenfeld, A. L., Häring, H., et al. (2021) · Cells · doi:10.3390/cells10123443 · Cited by 17
“The insulin receptor substrate IRS1 is a key target of the insulin receptor tyrosine kinase and is required for insulin-associated control of metabolism [54,55].”
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Genetic and Epigenetic Factors in Gestational Diabetes Mellitus Pathology
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“Patients with diabetes and insulin resistance are differentiated by dysfunction of IRS-dependent signaling in their tissues [77].”
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“IRS1 and PKB phosphorylation in SNX5-depleted hRPTCs IRS1 is an adaptor protein, the phosphorylation of which initiates downstream insulin signaling pathways (29, 30).”
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“Deregulation of insulin signalling as a result of aberrant IRS1 and/or IRS2 function is a common mechanism of insulin resistance.(28)”
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“The available evidence have indicated that dysregulated expression of IRS was closely associated with insulin resistance and diabetes by regulating AKT/AMPK signaling pathway.(25,26) In this study, we found that IRS2 might be a target gene of miR‐141 by Targetscan.”
BackgroundCullin-RING E3 Ubiquitin Ligase 7 in Growth Control and Cancer
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“2011) and its downstream effector kinase S6K1 (s6 kinase 1), resulting in elevated ribosome biogenesis and cell growth (Copps and White 2012; Harrington et al. 2005; Shah and Hunter 2005).”
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“The latter is partly the result of a negative feedback mechanism, where the nutrient overload, followed by the prolonged activation of insulin/Rheb/mTORC1/S6K1 signaling, induces Ser/Thr phosphorylation of IRS-1, resulting in its degradation blocking the activity of this pathway [119,120].”
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Molecular mechanisms underlying hepatitis C virus infection-related diabetes
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Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila
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“In addition, various signaling pathways have been linked to glucose metabolism (Copps and White, 2012; Fullerton et al., 2013).”
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“IRS-1 is a key molecule for insulin signal transduction, and GLUT4 is an important carrier in glucose transport (67, 68).”
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“The hyperactivation of S6K1 could cause extensive serine site phosphorylation of IRS1, including at S270, S307, S312, S323, S527, S616, S636/639, and S1101 in human cells (S265, S302, S307, S318, S522, S612, S632/635, and S1097 in mice cells), which disrupts IRS1 activity and diminishes downstream signaling.(16,18,20,…”
Background
Metadata
- Authors
- Copps, K. D., & White, M. F.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- White, M. F.
- ORCID
- White, M. F.
- Venue
- Diabetologia
- Published
- 2012-08-08
- Volume
- 55
- Issue
- 10
- Pages
- 2565-2582
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- 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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