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5′-AMP-activated Protein Kinase Phosphorylates IRS-1 on Ser-789 in Mouse C2C12 Myotubes in Response to 5-Aminoimidazole-4-carboxamide Riboside
Open accessAbstract
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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“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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“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].”
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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
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
“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 94
Pelletier, A., Joly, E. C., Prentki, M., & Coderre, L. (2005) · Endocrinology · doi:10.1210/en.2004-1565 · Cited by 89
Khatri, N., & Man, H. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00199 · Cited by 96
“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 91
Self-citationDissecting the role of AMP-activated protein kinase in human diseases
Li, J., Zhong, L., Wang, F., & Zhu, H. (2017) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2016.12.003 · Cited by 90
PTEN and SHIP2 phosphoinositide phosphatases as negative regulators of insulin signalling
Vinciguerra, M., & Foti, M. (2006) · Archives of Physiology and Biochemistry · doi:10.1080/13813450600711359 · Cited by 91
“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 88
Ning, J., & Clemmons, D. R. (2010) · Molecular Endocrinology · doi:10.1210/me.2009-0474 · Cited by 89
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
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
“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 87
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
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
“(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
“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
Carracedo, A., Baselga, J. M., & Pandolfi, P. P. (2008) · Cell Cycle · doi:10.4161/cc.7.24.7244 · Cited by 84
Hepatic amino acid‐dependent signaling is under the control of AMP‐dependent protein kinase
Dubbelhuis, P. F., & Meijer, A. J. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02815-6 · Cited by 76
Reiter, A. K., Bolster, D. R., Crozier, S. J., Kimball, S. R., & Jefferson, L. S. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00333.2004 · Cited by 76
Park, S., Hong, S. M., Sung, S. R., & Jung, H. K. (2008) · Endocrinology · doi:10.1210/en.2007-0754 · Cited by 73
Zheng, Y., Zhang, W., Pendleton, E., Leng, S.-H., Wu, J., Chen, R., & Sun, X. (2009) · Journal of Endocrinology · doi:10.1677/joe-09-0181 · Cited by 74
“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 78
“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 76
A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer
Khan, A., & Frigo, D. E. (2017) · Nature Reviews Urology · doi:10.1038/nrurol.2016.272 · Cited by 74
Metadata
- 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 (medical) › 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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