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First published online October 27, 2004
doi: 10.1242/10.1242/jcs.01540
Commentary |
Division of Molecular Physiology, Wellcome Trust Biocentre, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK
(e-mail: d.g.hardie{at}dundee.ac.uk)
The AMP-activated protein kinase (AMPK) cascade is a sensor of cellular energy status. Whenever the cellular ATP:ADP ratio falls, owing to a stress that inhibits ATP production or increases ATP consumption, this is amplified by adenylate kinase into a much larger increase in the AMP:ATP ratio. AMP activates the system by binding to two tandem domains on the 
subunits of AMPK, and this is antagonized by high concentrations of ATP. AMP binding causes activation by a sensitive mechanism involving phosphorylation of AMPK by the tumour suppressor LKB1. Once activated, AMPK switches on catabolic pathways that generate ATP while switching off ATP-consuming processes. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of hormones and cytokines such as leptin, adiponectin and ghrelin. A particularly interesting downstream target recently identified is TSC2 (tuberin). The LKB1
AMPKTSC2 pathway negatively regulates the target of rapamycin (TOR), and this appears to be responsible for limiting protein synthesis and cell growth, and protecting against apoptosis, during cellular stresses such as glucose starvation.
Key words: AMP-activated protein kinase, LKB1, TSC2
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S. P. Berasi, C. Huard, D. Li, H. H. Shih, Y. Sun, W. Zhong, J. E. Paulsen, E. L. Brown, R. E. Gimeno, and R. V. Martinez Inhibition of Gluconeogenesis through Transcriptional Activation of EGR1 and DUSP4 by AMP-activated Kinase J. Biol. Chem., September 15, 2006; 281(37): 27167 - 27177. [Abstract] [Full Text] [PDF]
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V. Bhalla, N. M. Oyster, A. C. Fitch, M. A. Wijngaarden, D. Neumann, U. Schlattner, D. Pearce, and K. R. Hallows AMP-activated Kinase Inhibits the Epithelial Na+ Channel through Functional Regulation of the Ubiquitin Ligase Nedd4-2 J. Biol. Chem., September 8, 2006; 281(36): 26159 - 26169. [Abstract] [Full Text] [PDF]
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K. Elbing, E. M. Rubenstein, R. R. McCartney, and M. C. Schmidt Subunits of the Snf1 Kinase Heterotrimer Show Interdependence for Association and Activity J. Biol. Chem., September 8, 2006; 281(36): 26170 - 26180. [Abstract] [Full Text] [PDF]
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S. Marshall Role of Insulin, Adipocyte Hormones, and Nutrient-Sensing Pathways in Regulating Fuel Metabolism and Energy Homeostasis: A Nutritional Perspective of Diabetes, Obesity, and Cancer Sci. Signal., August 1, 2006; 2006(346): re7 - re7. [Abstract] [Full Text] [PDF]
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 P. Tamas, S. A. Hawley, R. G. Clarke, K. J. Mustard, K. Green, D. G. Hardie, and D. A. Cantrell Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes J. Exp. Med., July 10, 2006; 203(7): 1665 - 1670. [Abstract] [Full Text] [PDF]
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D. L. Williamson, D. R. Bolster, S. R. Kimball, and L. S. Jefferson Time course changes in signaling pathways and protein synthesis in C2C12 myotubes following AMPK activation by AICAR. Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E80 - E89. [Abstract] [Full Text] [PDF]
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J. T. Treebak, S. Glund, A. Deshmukh, D. K. Klein, Y. C. Long, T. E. Jensen, S. B. Jorgensen, B. Viollet, L. Andersson, D. Neumann, et al. AMPK-Mediated AS160 Phosphorylation in Skeletal Muscle Is Dependent on AMPK Catalytic and Regulatory Subunits. Diabetes, July 1, 2006; 55(7): 2051 - 2058. [Abstract] [Full Text] [PDF]
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 H. Motoshima, B. J. Goldstein, M. Igata, and E. Araki AMPK and cell proliferation - AMPK as a therapeutic target for atherosclerosis and cancer J. Physiol., July 1, 2006; 574(1): 63 - 71. [Abstract] [Full Text] [PDF]
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B. Viollet, M. Foretz, B. Guigas, S. Horman, R. Dentin, L. Bertrand, L. Hue, and F. Andreelli Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders J. Physiol., July 1, 2006; 574(1): 41 - 53. [Abstract] [Full Text] [PDF]
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S. Ramamurthy and G. V. Ronnett Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain J. Physiol., July 1, 2006; 574(1): 85 - 93. [Abstract] [Full Text] [PDF]
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L. Bertrand, A. Ginion, C. Beauloye, A. D. Hebert, B. Guigas, L. Hue, and J.-L. Vanoverschelde AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H239 - H250. [Abstract] [Full Text] [PDF]
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R. J. McCrimmon, X. Fan, H. Cheng, E. McNay, O. Chan, M. Shaw, Y. Ding, W. Zhu, and R. S. Sherwin Activation of AMP-Activated Protein Kinase Within the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses in Rats With Defective Counterregulation Diabetes, June 1, 2006; 55(6): 1755 - 1760. [Abstract] [Full Text] [PDF]
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F. Andreelli, M. Foretz, C. Knauf, P. D. Cani, C. Perrin, M. A. Iglesias, B. Pillot, A. Bado, F. Tronche, G. Mithieux, et al. Liver Adenosine Monophosphate-Activated Kinase-{alpha}2 Catalytic Subunit Is a Key Target for the Control of Hepatic Glucose Production by Adiponectin and Leptin But Not Insulin Endocrinology, May 1, 2006; 147(5): 2432 - 2441. [Abstract] [Full Text] [PDF]
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K. Sakamoto, E. Zarrinpashneh, G. R. Budas, A.-C. Pouleur, A. Dutta, A. R. Prescott, J.-L. Vanoverschelde, A. Ashworth, A. Jovanovic, D. R. Alessi, et al. Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPK{alpha}2 but not AMPK{alpha}1 Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E780 - E788. [Abstract] [Full Text] [PDF]
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 L. Lin, M. Park, M. Hulver, and D. A. York Different metabolic responses to central and peripheral injection of enterostatin Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2006; 290(4): R909 - R915. [Abstract] [Full Text] [PDF]
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E. C. Nilsson, Y. C. Long, S. Martinsson, S. Glund, P. Garcia-Roves, L. T. Svensson, L. Andersson, J. R. Zierath, and M. Mahlapuu Opposite Transcriptional Regulation in Skeletal Muscle of AMP-activated Protein Kinase {gamma}3 R225Q Transgenic Versus Knock-out Mice J. Biol. Chem., March 17, 2006; 281(11): 7244 - 7252. [Abstract] [Full Text] [PDF]
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Z. Xie, Y. Dong, M. Zhang, M.-Z. Cui, R. A. Cohen, U. Riek, D. Neumann, U. Schlattner, and M.-H. Zou Activation of Protein Kinase C{zeta} by Peroxynitrite Regulates LKB1-dependent AMP-activated Protein Kinase in Cultured Endothelial Cells J. Biol. Chem., March 10, 2006; 281(10): 6366 - 6375. [Abstract] [Full Text] [PDF]
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D. S. Hutchinson and T. Bengtsson AMP-Activated Protein Kinase Activation by Adrenoceptors in L6 Skeletal Muscle Cells: Mediation by {alpha}1-Adrenoceptors Causing Glucose Uptake Diabetes, March 1, 2006; 55(3): 682 - 690. [Abstract] [Full Text] [PDF]
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K. R. Hallows, A. C. Fitch, C. A. Richardson, P. R. Reynolds, J. P. Clancy, P. C. Dagher, L. A. Witters, J. K. Kolls, and J. M. Pilewski Up-regulation of AMP-activated Kinase by Dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator in Cystic Fibrosis Airway Epithelial Cells Mitigates Excessive Inflammation J. Biol. Chem., February 17, 2006; 281(7): 4231 - 4241. [Abstract] [Full Text] [PDF]
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T. M. Wagner, J. E. Mullally, and F. A. Fitzpatrick Reactive Lipid Species from Cyclooxygenase-2 Inactivate Tumor Suppressor LKB1/STK11: CYCLOPENTENONE PROSTAGLANDINS AND 4-HYDROXY-2-NONENAL COVALENTLY MODIFY AND INHIBIT THE AMP-KINASE KINASE THAT MODULATES CELLULAR ENERGY HOMEOSTASIS AND PROTEIN TRANSLATION J. Biol. Chem., February 3, 2006; 281(5): 2598 - 2604. [Abstract] [Full Text] [PDF]
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 D. G. Hardie and K. Sakamoto AMPK: A Key Sensor of Fuel and Energy Status in Skeletal Muscle Physiology, February 1, 2006; 21(1): 48 - 60. [Abstract] [Full Text] [PDF]
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Y. Dagon, Y. Avraham, I. Magen, A. Gertler, T. Ben-Hur, and E. M. Berry Nutritional Status, Cognition, and Survival: A NEW ROLE FOR LEPTIN AND AMP KINASE J. Biol. Chem., December 23, 2005; 280(51): 42142 - 42148. [Abstract] [Full Text] [PDF]
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A. M. Evans, K. J. W. Mustard, C. N. Wyatt, C. Peers, M. Dipp, P. Kumar, N. P. Kinnear, and D. G. Hardie Does AMP-activated Protein Kinase Couple Inhibition of Mitochondrial Oxidative Phosphorylation by Hypoxia to Calcium Signaling in O2-sensing Cells? J. Biol. Chem., December 16, 2005; 280(50): 41504 - 41511. [Abstract] [Full Text] [PDF]
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 A. K. Al-Hakim, O. Goransson, M. Deak, R. Toth, D. G. Campbell, N. A. Morrice, A. R. Prescott, and D. R. Alessi 14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK J. Cell Sci., December 1, 2005; 118(23): 5661 - 5673. [Abstract] [Full Text] [PDF]
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S. Foroutan, J. Brillault, B. Forbush, and M. E. O'Donnell Moderate-to-severe ischemic conditions increase activity and phosphorylation of the cerebral microvascular endothelial cell Na+-K+-Cl- cotransporter Am J Physiol Cell Physiol, December 1, 2005; 289(6): C1492 - C1501. [Abstract] [Full Text] [PDF]
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N. Fujii, M. F. Hirshman, E. M. Kane, R. C. Ho, L. E. Peter, M. M. Seifert, and L. J. Goodyear AMP-activated Protein Kinase {alpha}2 Activity Is Not Essential for Contraction- and Hyperosmolarity-induced Glucose Transport in Skeletal Muscle J. Biol. Chem., November 25, 2005; 280(47): 39033 - 39041. [Abstract] [Full Text] [PDF]
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M. Widmer, M. Uldry, and B. Thorens GLUT8 Subcellular Localization and Absence of Translocation to the Plasma Membrane in PC12 Cells and Hippocampal Neurons Endocrinology, November 1, 2005; 146(11): 4727 - 4736. [Abstract] [Full Text] [PDF]
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A. Sofer, K. Lei, C. M. Johannessen, and L. W. Ellisen Regulation of mTOR and Cell Growth in Response to Energy Stress by REDD1 Mol. Cell. Biol., July 15, 2005; 25(14): 5834 - 5845. [Abstract] [Full Text] [PDF]
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B. Kola, E. Hubina, S. A. Tucci, T. C. Kirkham, E. A. Garcia, S. E. Mitchell, L. M. Williams, S. A. Hawley, D. G. Hardie, A. B. Grossman, et al. Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase J. Biol. Chem., July 1, 2005; 280(26): 25196 - 25201. [Abstract] [Full Text] [PDF]
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S.-P. Hong, M. Momcilovic, and M. Carlson Function of Mammalian LKB1 and Ca2+/Calmodulin-dependent Protein Kinase Kinase {alpha} as Snf1-activating Kinases in Yeast J. Biol. Chem., June 10, 2005; 280(23): 21804 - 21809. [Abstract] [Full Text] [PDF]
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E. B. Taylor, W. J. Ellingson, J. D. Lamb, D. G. Chesser, and W. W. Winder Long-chain acyl-CoA esters inhibit phosphorylation of AMP-activated protein kinase at threonine-172 by LKB1/STRAD/MO25 Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1055 - E1061. [Abstract] [Full Text] [PDF]
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