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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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“However, phosphorylation of residues adjacent to the PI3K binding sites by serine kinases displaces PI3K and thus interferes with its ability to activate IRS1.(90,94) The inhibitory effect of free FAs on IRS1 and insulin signaling was demonstrated in cell culture,(95,96) animal models, and human volunteers(100) and ma…”
BackgroundGalicia-García, U., Jebari‐Benslaiman, S., Larrea, A., Uribe, K. B., Siddiqi, H. F., Ostolaza, H., Benito‐Vicente, A., & Martín, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134725 · Cited by 165
“The downstream events that follow INSR activation include recruitment of several adaptor proteins, facilitating a suitable binding site for insulin receptor substrates (IRSs) [82] that once phosphorylated, trigger several downstream signals [83].”
BackgroundSin, T. K., Yung, B. Y., & Siu, P. M. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000369718 · Cited by 144
Antidiabetic potential of dietary polyphenols: A mechanistic review
Farias, D. D. P., de Araújo, F. F., Neri-Numa, I. A., & Pastore, G. M. (2021) · Food Research International · doi:10.1016/j.foodres.2021.110383 · Cited by 149
Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review
Berlanga‐Acosta, J., Guillén, G. E., Rodríguez-Rodríguez, N., Bringas-Vega, M. L., García-del-Barco-Herrera, D., Berlanga-Saez, J. O., Ojalvo, A. G., Valdés-Sosa, M. J., & Valdes-Sosa, P. A. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.560375 · Cited by 143
“A sort of feedback of serine/threonine phosphorylation of IRS underlies the magnitude of insulin stimulation (34).”
BackgroundInsulin receptor endocytosis in the pathophysiology of insulin resistance
Hall, C., Yu, H., & Choi, E. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-0456-3 · Cited by 149
Hong, C.-T., Chen, K.-Y., Wang, W., Chiu, J.-Y., Wu, D., Chao, T.-Y., Hu, C.-J., Chau, K.-Y., & Bamodu, O. (2020) · Cells · doi:10.3390/cells9030740 · Cited by 133
“Mechanistically, since increased p85α expression and IRS1 serine phosphorylation are essential for the induction of clinically-apparent IR [32], we demonstrated significant increase in the p-IRS1/IRS1 ratio (123%, p < 0.”
BackgroundMullins, R. J., Mustapić, M., Goetzl, E. J., & Kapogiannis, D. (2017) · Human Brain Mapping · doi:10.1002/hbm.23494 · Cited by 131
“Specific changes in the phosphorylation pattern of IRS-1 resulting in impaired insulin signaling have long been established as pathological markers of IR in peripheral tissues [Copps and White, 2012; Hoehn et al., 2008; Taniguchi et al., 2006].”
Nigi, L., Grieco, G. E., Ventriglia, G., Brusco, N., Mancarella, F., Formichi, C., Dotta, F., & Sebastiani, G. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123705 · Cited by 128
“Indeed pro-inflammatory cytokines can activate downstream kinases of insulin signaling pathway, including IκB kinase-β (IKKβ), JUN amino-terminal kinase 1 (JNK1) and p38 MAPK, which can contribute to increased serine phosphorylation that inactivates IRS protein and stimulate the production of suppressors of cytokine s…”
BackgroundThe Immune Landscape of Visceral Adipose Tissue During Obesity and Aging
Khan, S. M., Chan, Y. T., Revelo, X. S., & Winer, D. A. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00267 · Cited by 140
“In turn, proinflammatory cytokine release mediated by immune cells induces serine phosphorylation of insulin receptor substrate-1 (IRS-1) leading to local and systemic insulin resistance, which is thought to contribute toward whole body glucose and fatty acid metabolic dysregulation (24, 25) Furthermore, the obese adi…”
BackgroundWang, H., Li, Q.-M., Yu, N., Chen, W., Zha, X., Wu, D., Pan, L., Duan, J., & Luo, J. (2019) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2019.01.101 · Cited by 124
Benomar, Y., & Taouis, M. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00140 · Cited by 131
“JNK promotes the serine phosphorylation of IRS-1 that inhibits insulin-dependent IRS-1 tyrosine phosphorylation and downstream signaling (85, 86).”
BackgroundBabu, S., Krishnan, M., Rajagopal, P., Vijayalakshmi, P., Veeraraghavan, V., Govindan, R., & Jayaraman, S. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173004 · Cited by 127
Inflammation‐mediated metabolic regulation in adipose tissue
Xu, S., Lu, F., Gao, J., & Yuan, Y. (2024) · Obesity Reviews · doi:10.1111/obr.13724 · Cited by 137
“114,169 Mechanically, the TLR4-mediated activation of the IKK β and JNK pathways, likely via MYD88, is thought to directly mediate FA-induced insulin resistance 170 by inducing the serine/ threonine phosphorylation of IRSs and reducing their responsiveness to insulin.”
BackgroundInsulin Signaling in Type 2 Diabetes
Brännmark, C., Nyman, E., Fagerholm, S., Bergenholm, L., Ekstrand, E.-M., Cedersund, G., & Strålfors, P. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.432062 · Cited by 122
“The literature is replete with data implicating the phosphorylation of IRS1 at different serine/threonine residues in positive or negative control of insulin signaling and in positive or negative feedback loops of insulin signaling (16).”
BackgroundMarzia Perluigi, A., Domenico, F. D., Barone, E., & Butterfield, D. A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.04.025 · Cited by 126
The Role of Catechins in Regulating Diabetes: An Update Review
Wen, L., Wu, D., Tan, X., Zhong, M., Xing, J., Li, W., Li, D., & Cao, F. (2022) · Nutrients · doi:10.3390/nu14214681 · Cited by 132
“, PKC, AKT, mammalian target of rapamycin (mTOR), and extracellular regulated protein kinase (ERK)1/2) [38,39].”
BackgroundmTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes
Minard, A. Y., Tan, S., Yang, P., Fazakerley, D. J., Domanova, W., Parker, B. L., Humphrey, S. J., Jothi, R., Stöckli, J., & James, D. E. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.08.086 · Cited by 122
“(n = 3, mean ± SEM, one-sample t test, *p < 0.01). negative feedback loop that triggers insulin resistance and increased adiposity (Copps and White, 2012; Hsu et al., 2011; Um et al., 2004; Yu et al., 2011).”
BackgroundInfluentialInsulin resistance in Alzheimer's disease
Diehl, T. C., Mullins, R. J., & Kapogiannis, D. (2016) · Translational research · doi:10.1016/j.trsl.2016.12.005 · Cited by 124
Shared pathways for neuroprogression and somatoprogression in neuropsychiatric disorders
Morris, G., Puri, B. K., Walker, A. J., Maes, M. H. J., Carvalho, A. F., Bortolasci, C. C., Walder, K. R., & Berk, M. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.025 · Cited by 119
Kolnes, K. J., Petersen, M. H., Lien-Iversen, T., Højlund, K., & Jensen, J. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.737709 · Cited by 112
“Insulin resistance in adipocytes is associated with impaired phosphorylation of insulin receptor substrate 1 (IRS-1) in obesity, which is further impaired in T2DM (Copps and White, 2012).”
BackgroundInfluentialWong, C. Y. J., Al‐Salami, H., & Dass, C. R. (2020) · Journal of Pharmacy and Pharmacology · doi:10.1111/jphp.13359 · Cited by 112
“With respect to insulin-dependent signalling pathway, IRS-1 phosphorylation is altered in patients with diabetes.([16]) AMPK (cellular energy sensor) and its upstream kinase (LKB1) can be activated under ATP-depleted metabolic states, and these pathways are essential in promotion of glucose uptake and fat oxidation.”
BackgroundMechanistic Role of MicroRNAs in Coupling Lipid Metabolism and Atherosclerosis
Novák, J., Olejníčková, V., Tkáčová, N., & Santulli, G. (2015) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-22380-3_5 · Cited by 95
“Another putative target, insulin receptor substrate-2 (IRS2) , was confi rmed as miR-33 target by Fernandez-Hernando’s group [ 19 ]—IRS-2, together with IRS-1, are both important for transduction of insulin signaling over the cell membrane and their blockade thus interferes with insulin effects on the cells [ 71 ].”
BackgroundBatista, T. M., Jayavelu, A. K., Albrechtsen, N. J. W., Iovino, S., Lebastchi, J., Pan, H., Dreyfuss, J. M., Krook, A., Zierath, J. R., Mann, M., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.08.007 · Cited by 112
“Dysregulated serine phosphorylation of IRS-1 and IRS-2 represents a key mechanism to promote insulin resistance by interference of IRS-1/2 tyrosine phosphorylation and/or increased proteolytic degradation (Copps and White, 2012).”
BackgroundBlázquez, E., Hurtado-Carneiro, V., Ayuso, Y. L. B., Velázquez, E., García‐García, L., Gómez-Oliver, F., Ruiz‐Albusac, J. M., Ávila, J., & Pozo, M. A. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.873301 · Cited by 110
The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes
Hooper, P. L., Balogh, G. E., Rivas, E., Kavanagh, K., & Vígh, L. (2014) · Cell Stress and Chaperones · doi:10.1007/s12192-014-0493-8 · Cited by 110
“At baseline, obese subjects had increased phosphorylation and thus activation of JNK and pIKK-β with increased inhibitory serine phosphorylation of IRS-1 and reduced GLUT4 response to insulin.”
BackgroundInfluentialHançer, N. J., Qiu, W., Cherella, C. E., Li, Y., Copps, K. D., & White, M. F. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.554162 · Cited by 120
“Because a limited number of phospho-specific antibodies were generated in early studies, the phosphorylation of a few Ser/Thr residues (Ser302, Ser-307, Ser-318, Ser-612, and Ser-632) has been interrogated in many different contexts, whereas many others have never been examined (6).”
BackgroundInfluentialSelf-citationInsulin receptor substrate signaling controls cardiac energy metabolism and heart failure
Guo, C., & Guo, S. (2017) · Journal of Endocrinology · doi:10.1530/joe-16-0679 · Cited by 107
“Both metabolic and mechanic stresses activate intracellular protein kinases that trigger serine or threonine phosphorylation of IRS proteins, which couple with IRS ubiquitination and degradation (Copps & White 2012).”
BackgroundTeng, W., Zhao, L., Yang, S., Zhang, C., Liu, M., Luo, J., Jin, J., Zhang, M., Bao, C., Li, D., et al. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.06.023 · Cited by 107
Maternal Early Pregnancy Serum Metabolites and Risk of Gestational Diabetes Mellitus
Enquobahrie, D. A., Denis, M., Tadesse, M. G., Gelaye, B., Ressom, H. W., & Williams, M. A. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2862 · Cited by 107
IRS proteins and diabetic complications
Lavin, D. P., White, M. F., & Brazil, D. P. (2016) · Diabetologia · doi:10.1007/s00125-016-4072-7 · Cited by 113
“Retinal Müller cells: a primary site of IRS signalling in the retina IRS proteins are heavily phosphorylated on tyrosine, serine and threonine residues [37, 47, 48].”
BackgroundSelf-citationAn, S., Zhao, L., She, Z., Wang, S., Zhang, K., Yu, Q., Zheng, J., Zhang, X., Zhu, X., Bao, R., et al. (2017) · Hepatology · doi:10.1002/hep.29375 · Cited by 107
“(2) The insulin signal-transduction efficacy relies strongly on the phosphorylation of IRS1 at different sites (Ser/Tyr), which is correlated with the subcellular relocalization and proteasome-mediated degradation of IRS1.”
BackgroundTissue‐specific insulin signaling in the regulation of metabolism and aging
Zhang, J., & Liu, F. (2014) · IUBMB Life · doi:10.1002/iub.1293 · Cited by 105
“Insulin signaling is negatively regulated by a number of mechanisms, such as the binding of the adaptor protein Grb10 to the kinase domain of IR ((8), (9)), serine phosphorylation of IRS1 ((10), (11)), and dephosphorylation of IR and IRS1/2 by protein tyrosine phosphatase-1B (PTP-1B) (12).”
BackgroundRebollo‐Hernanz, M., Zhang, Q., Aguilera, Y., Martin-Cabrejas, M. A., & de Mejı́a, E. G. (2019) · Food and Chemical Toxicology · doi:10.1016/j.fct.2019.110672 · Cited by 108
Molecular mechanisms by which GLP-1 RA and DPP-4i induce insulin sensitivity
Yaribeygi, H., Sathyapalan, T., & Sahebkar, A. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116776 · Cited by 103
“IRS-1 can be also activated by other kinases including ERK1/25, atypical PKC6, S6K17, SIK28, AKT, mTOR9 and ROCK110 as well as other types of kinases such as AMPK11 and GSK312 [33, 34].”
BackgroundCarnagarin, R., Dharmarajan, A., & Dass, C. R. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.09.004 · Cited by 110
Cellular and Molecular Mechanisms of Insulin Resistance
Chandrasekaran, P., & Weiskirchen, R. (2024) · Current Tissue Microenvironment Reports · doi:10.1007/s43152-024-00056-3 · Cited by 137
Dierssen, M., Fructuoso, M., de Lagrán, M. M., Marzia Perluigi, A., & Barone, E. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00670 · Cited by 106
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“Indeed, once persistently stimulated, mTOR is able to phosphorylate IRS1 on Ser residues critical for BIR, including Ser307 [19,42] and previous studies from both our groups [43,44] and others [45–48] reported about the hyper-activation of mTOR in AD.”
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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