5′-AMP-activated Protein Kinase Phosphorylates IRS-1 on Ser-789 in Mouse C2C12 Myotubes in Response to 5-Aminoimidazole-4-carboxamide Riboside
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Exercise is known to increase insulin sensitivity and is an effective form of treatment for the hyperglycemia observed in type 2 diabetes. Activation of 5'-AMP-activated protein kinase (AMPK) by 5-aminoimidazole-4-carboxamide riboside (AICAR), exercise, or electrically stimulated contraction leads to increased glucose transport in skeletal muscle. Here we report the first evidence of a direct interaction between AMPK and the most upstream component of the insulin-signaling cascade, insulin receptor substrate-1 (IRS-1). We find that AMPK rapidly phosphorylates IRS-1 on Ser-789 in cell-free assays as well as in mouse C2C12 myotubes incubated with AICAR. In the C2C12 myotubes activation of AMPK by AICAR matched the phosphorylation of IRS-1 on Ser-789. This phosphorylation correlates with a 65% increase in insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity in C2C12 myotubes preincubated with AICAR. The binding of phosphatidylinositol 3-kinase to IRS-1 was not affected by AICAR. These results demonstrate the existence of an interaction between AMPK and early insulin signaling that could be of importance to our understanding of the potentiating effects of exercise on insulin signaling.
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AMPK rapidly phosphorylates IRS1 on S789 in vitro and treatment with AICAR increases IRS1 S789 phosphorylation in mouse C2C12 myotubes.
“It has been reported that AMPK rapidly phosphorylates IRS1 on S789 in vitro and treatment with AICAR increases IRS1 S789 phosphorylation in mouse C2C12 myotubes, suggesting a possible link between the potentiating effects of exercise on insulin signaling [145].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [145]
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“The molecular mechanisms by which AMPK activity augments insulin signaling have not yet been revealed, but a recent study has shown that AMPK can phosphorylate IRS-1 on Ser-789 in mouse C2C12 myotubes when these are exposed to AICAR, thereby establishing a link to the insulin-signaling cascade (14).”
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“Activation of AMPK phosphorylates IRS-1 at Ser 789 which enhances IGF/insulin signalling (Jakobsen et al. 2001), though this claim has been disputed (Qiao et al.”
BackgroundAdiponectin signaling in the liver
Combs, T. P., & Marliss, E. B. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9280-6 · Cited by 149 · see citing works
Commonalities Between Pain and Memory Mechanisms and Their Meaning for Understanding Chronic Pain
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“, 2012) and ERK signaling (Jakobsen et al., 2001; Shen et al., 2013) (Figure 3).”
BackgroundAMP‐activated protein kinase and muscle glucose uptake
Musi, N., & Goodyear, L. J. (2003) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2003.01168.x · Cited by 145 · see citing works
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AMPK exerts dual regulatory effects on the PI3K pathway
Tao, R., Gong, J., Luo, X., Zang, M., Guo, W., Wen, R., & Luo, Z. (2010) · Journal of Molecular Signaling · doi:10.1186/1750-2187-5-1 · Cited by 142 · see citing works
Weigert, C., Hennige, A. M., Lehmann, R., Brodbeck, K., Baumgärtner, F., Schaüble, M., Häring, H. U., & Schleicher, E. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m509782200 · Cited by 140 · see citing works
Lin, C., & Lin, J. (2008) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200700437 · Cited by 141 · see citing works
AMPK: A cellular metabolic and redox sensor. A minireview
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“, p300; hepatocyte nuclear factor-4α (HNF4-alpha); transducer of regulated CREB activity 2 (TORC2)] (16, 19, 45-52).”
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Tosca, L., Froment, P., Solnais, P., Ferré, P., Foufelle, F., & Dupont, J. (2005) · Endocrinology · doi:10.1210/en.2005-0301 · Cited by 133 · see citing works
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Physical inactivity and muscle weakness in the critically ill
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Molecular mechanisms of insulin receptor substrate protein‐mediated modulation of insulin signalling
Johnston, A., Pirola, L., & OBBERGHEN, E. V. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00438-1 · Cited by 123 · see citing works
Pu, P., Wang, X.-A., Salim, M., Zhu, L., Wang, L., Chen, K.-J., Xiao, J., Deng, W., Shi, H., Jiang, H., et al. (2012) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2012.06.002 · Cited by 122 · see citing works
AMPK in cardiovascular health and disease
Shirwany, N. A., & Zou, M. (2010) · Acta Pharmacologica Sinica · doi:10.1038/aps.2010.139 · Cited by 121 · see citing works
Chopra, I., Li, H. F., Wang, H., & Webster, K. A. (2012) · Diabetologia · doi:10.1007/s00125-011-2407-y · Cited by 116 · see citing works
“Whereas positive regulation by Ser789 has been suggested [20], such positive regulation has not been confirmed, and in light of more recent studies including the results described here, it seems likely that Ser789 exerts only negative regulation of IRS-1 [18, 19, 21, 22].”
Qiao, L.-Y., Zhande, R., Jetton, T. L., Zhou, G., & Sun, X. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201494200 · Cited by 104 · see citing works
Giraud, J., Leshan, R. L., Lee, Y.-H., & White, M. F. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m308631200 · Cited by 100 · see citing works
The Salt-Inducible Kinases: Emerging Metabolic Regulators
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Regulation of Carbohydrate Metabolism, Lipid Metabolism, and Protein Metabolism by AMPK
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Hepatic leptin signaling in obesity
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“(23) described positive effects of AMPK on IRS-1 phosphorylation, which may explain the interaction between the leptin and insulin signaling pathways at the molecular level.”
BackgroundHerschkovitz, A., Liu, Y., Ilan, E., Ronen, D., Boura‐Halfon, S., & Zick, Y. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610949200 · Cited by 97 · see citing works
RetractedAMPK: An emerging target for modification of injury-induced pain plasticity
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“AMPK also phosphorylates IRS1 [48] and AKT at negative regulatory sites [20].”
BackgroundNader, N., Ng, S. S. M., Lambrou, G. Ι., Pervanidou, P., Wang, Y., Chrousos, G. P., & Kino, T. (2010) · Molecular Endocrinology · doi:10.1210/me.2010-0192 · Cited by 96 · see citing works
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“Activation of AMPK improves the sensitivity of IGF-1 signaling through phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser789, which enhances IRS-1mediated signaling (Jakobsen et al., 2001).”
BackgroundBáez, A. M., Ayala, G., Pedroza-Saavedra, A., González-Sánchez, H. M., & Chihu-Amparán, L. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46010041 · Cited by 93 · see citing works
“However, it remains possible that IRS-1 phosphorylation and enhanced insulin signaling may be independent effects of AMPK activation, so more research is needed on this matter [53].”
BackgroundNovel immunomodulatory effects of adiponectin on dendritic cell functions
Tsang, J. Y. S., Li, D., Ho, D., Peng, J., Xu, A., Lamb, J. R., Chen, Y., & Tam, P. K. H. (2010) · International Immunopharmacology · doi:10.1016/j.intimp.2010.11.009 · Cited by 92 · see citing works
Curcumin stimulates glucose uptake through AMPK‐p38 MAPK pathways in L6 myotube cells
Kim, J. H., Park, J. M., Kim, E., Lee, J. O., Lee, S. K., Jung, J. H., You, G. Y., Park, S. H., Suh, P., & Kim, H. S. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22093 · Cited by 91 · see citing works
“These activations have been implicated as critical events in AMPK-mediated glucose uptake (Jakobsen et al., 2001; Lemieux et al., 2003; Musi and Goodyear, 2003).”
BackgroundKuznetsoff, J. N., Leclerc, G. J., Leclerc, G. M., & Barredo, J. C. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-10-0777 · Cited by 91 · see citing works
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Khatri, N., & Man, H. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00199 · Cited by 91 · see citing works
“Upon AICAR treatment, AMPK activation has been shown to phosphorylate IRS-1, the upstream component in the PI3K signaling pathway (45), suggesting IRS-1 as the intermediate factor linking AMPK to PI3K/Akt activation.”
MethodModulation of human insulin receptor substrate-1 tyrosine phosphorylation by protein kinase Cdelta
Greene, M. W., MORRICE, N. A., Garofalo, R. S., & Roth, R. A. (2004) · Biochemical Journal · doi:10.1042/bj20031493 · Cited by 89 · see citing works
Self-citationDissecting the role of AMP-activated protein kinase in human diseases
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PTEN and SHIP2 phosphoinositide phosphatases as negative regulators of insulin signalling
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“Indeed, several studies demonstrated that phosphorylation of IRS proteins on Ser/Thr residues by Akt/PKB, 50-AMP-activated protein kinase or other unknown candidates, promotes insulin signal transduction (Paz et al., 1999; Jakobsen et al., 2001; Greene & Garofalo, 2002; Giraud et al., 2004).”
BackgroundSalt-inducible kinase in steroidogenesis and adipogenesis
Okamoto, M., Takemori, H., & Katoh, Y. (2003) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2003.11.002 · Cited by 89 · see citing works
Ning, J., & Clemmons, D. R. (2010) · Molecular Endocrinology · doi:10.1210/me.2009-0474 · Cited by 89 · see citing works
Cheng, H., Huang, H.-K., Chang, C., Tsai, C.-P., & Chou, C. (2008) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf800801k · Cited by 88 · see citing works
Banerjee, S., Wang, D. W., Alzamora, R., Huang, X. N., Pastor‐Soler, N. M., Hallows, K. R., McGaffin, K. R., & Ahmad, F. (2010) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2010.06.003 · Cited by 85 · see citing works
“AMPK indirectly increases phosphatidylinositol 3-kinase (PI-3K) activity [51], and PI-3K activity in turn has been shown to regulate translocation of SGLT1 [52].”
Leclerc, G. M., Leclerc, G. J., Fu, G., & Barredo, J. C. (2010) · Journal of Molecular Signaling · doi:10.1186/1750-2187-5-15 · Cited by 84 · see citing works
Berasi, S. P., Huard, C., Li, D., Shih, H. H., Sun, Y. H., Zhong, W., Paulsen, J. E., Brown, E. L., Gimeno, R. E., & Martinez, R. V. P. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602416200 · Cited by 83 · see citing works
Timmers, S., Nabben, M., Bosma, M., van Bree, B., Lenaers, E., van Beurden, D., Schaart, G., Westerterp-Plantenga, M. S., Langhans, W., Hesselink, M. K. C., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206868109 · Cited by 80 · see citing works
“(30) reported a direct interaction between AMPK and the most upstream component of the insulin signaling cascade, IRS1, in mouse C2C12 myotubes preincubated with 5-amino-1-beta-D-ribofuranosyl-imidazole-4carboxamide (AICAR), which correlated with a 65% increase in insulin-stimulated IRS1-associated PI3 kinase activity.”
BackgroundSynergistic effect of curcumin and insulin on muscle cell glucose metabolism
Kang, C., & Kim, E. (2010) · Food and Chemical Toxicology · doi:10.1016/j.fct.2010.05.073 · Cited by 80 · see citing works
“Actually, AMPK has been reported to lead to the phosphorylation of insulin receptor substrate-1 on Ser 789 in C2C12 myotubes when exposed to AICAR, a known AMPK activator (Jakobsen et al., 2001).”
BackgroundDeconstructing feedback-signaling networks to improve anticancer therapy with mTORC1 inhibitors
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Hepatic amino acid‐dependent signaling is under the control of AMP‐dependent protein kinase
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“Among them are S302 (corresponding to S307 in human IRS1;Giraud et al. 2004), S307 (corresponding to S312 in human IRS1; Aguirre et al. 2000), S332 (corresponding to S337 in human IRS1; Liberman & Eldar-Finkelman 2005), S612 (corresponding to S616 in human IRS1;DeFea&Roth 1997), S632/635 (corresponding to S636/639 in…”
BackgroundInfluentialIRS‐1 Regulation in Health and Disease
Schmitz‐Peiffer, C., & Whitehead, J. P. (2003) · IUBMB Life · doi:10.1080/1521654031000138569 · Cited by 73 · see citing works
“Consistent with this, AMPK phosphorylated IRS-1 on Ser789 in vitro and in cells treated with the AMPK activator AICAR ( 35 ).”
BackgroundWang, D., Yan, J., Chen, J., Wu, W., Zhu, X., & Wang, Y. (2015) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0201-y · Cited by 73 · see citing works
- Authors
- Jakobsen, S. N., Hardie, D. G., Morrice, N., & Tornqvist, H. E.
- Affiliations
- Novo Nordisk (Denmark) (DK)
- Wellcome Trust (GB)
- University of Dundee (GB)
- Corresponding author
- Jakobsen, Søren N.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-12
- Volume
- 276
- Issue
- 50
- Pages
- 46912-46916
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2041502315
- Cited by
- 238
- References
- 36
- Citations by year
- 2025: 1 · 2024: 4 · 2023: 1 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 9 · 2017: 10 · 2016: 6 · 2015: 6 · 2014: 11 · 2013: 16 · 2012: 13
- FWCI
- 3.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- AMPK, IRS-1, AICAR, phosphatidylinositol 3-kinase, insulin signaling, skeletal muscle, C2C12 myotubes, physical activity, insulin sensitivity, type 2 diabetes, glucose transport
- MeSH terms
- Aminoimidazole Carboxamide, Animals, Binding Sites, Biological Transport, Cells, Cultured, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Enzyme Activation, Glucose, Humans, Insulin, Multienzyme Complexes, Myocardium, Peptides, Phosphoproteins, Phosphorylation, Protein Binding, Recombinant Proteins, Ribonucleosides, Serine, Subcellular Fractions, Time Factors, Blotting, Western, Signal Transduction, Protein Serine-Threonine Kinases, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Mice, AMP-Activated Protein Kinases, Insulin Receptor Substrate Proteins
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