AMP-activated Protein Kinase

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William W. Winder - One of the best experts on this subject based on the ideXlab platform.

David Carling - One of the best experts on this subject based on the ideXlab platform.

  • Beyond energy homeostasis: the expanding role of AMP-activated Protein Kinase in regulating metabolism
    Cell Metabolism, 2015
    Co-Authors: David Carling, Benoit Viollet
    Abstract:

    The recent exciting advances in ourunderstanding of the regulation of the energy sensor AMP-activated Protein Kinase (AMPK), together with renewed appreciation of its importance in maintaining cellular function, brought together leading scientists at a recent FASEB-sponsored meeting inSeptember 2014. Here, we report some of the highlights of this conference.

  • Insulin Antagonizes Ischemia-induced Thr 172 Phosphorylation of AMP-activated Protein Kinase -Subunits
    2006
    Co-Authors: Sandrine Horman, Dietbert Neumann, Didier Vertommen, David Carling, Richard J. Heath, Angela Woods, Louis Hue, Mark H. Rider
    Abstract:

    Previous studies showed that insulin antagonizes AMP-activated Protein Kinase activation by ischemia and that Protein Kinase B might be implicated. Here we investigated whether the direct phosphorylation of AMP-activated Protein Kinase by Protein Kinase B might participate in this effect. Protein Kinase B phosphorylated recombinant bacterially expressed AMP-activated Protein Kinase heterotrimers at Ser 485 of the 1-subunits. In perfused rat hearts, phosphorylation of the 1/2 AMP-activated Protein Kinase subunits on Ser 485 /Ser 491 was increased by insulin and insulin pretreatment decreased the phosphorylation of the-subunits at Thr 172 in a subsequent ischemic episode. It is proposed that the effect of insulin to antagonize AMP-activated Protein Kinase activation involves a hierarchical mechanism whereby Ser 485 /Ser 491 phosphorylation by Protein Kinase B reduces subsequent phosphorylation of Thr 172 by

  • Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated Protein Kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491.
    The Journal of biological chemistry, 2005
    Co-Authors: Sandrine Horman, Dietbert Neumann, Didier Vertommen, David Carling, Richard J. Heath, Angela Woods, Uwe Schlattner, Véronique Mouton, Theo Wallimann, Louis Hue
    Abstract:

    Previous studies showed that insulin antagonizes AMP-activated Protein Kinase activation by ischemia and that Protein Kinase B might be implicated. Here we investigated whether the direct phosphorylation of AMP-activated Protein Kinase by Protein Kinase B might participate in this effect. Protein Kinase B phosphorylated recombinant bacterially expressed AMP-activated Protein Kinase heterotrimers at Ser(485) of the alpha1-subunits. In perfused rat hearts, phosphorylation of the alpha1/alpha2 AMP-activated Protein Kinase subunits on Ser(485)/Ser(491) was increased by insulin and insulin pretreatment decreased the phosphorylation of the alpha-subunits at Thr(172) in a subsequent ischemic episode. It is proposed that the effect of insulin to antagonize AMP-activated Protein Kinase activation involves a hierarchical mechanism whereby Ser(485)/Ser(491) phosphorylation by Protein Kinase B reduces subsequent phosphorylation of Thr(172) by LKB1 and the resulting activation of AMP-activated Protein Kinase.

  • activation of glut1 by metabolic and osmotic stress potential involvement of amp activated Protein Kinase ampk
    Journal of Cell Science, 2002
    Co-Authors: Kay Barnes, Grahame D Hardie, David Carling, Fabienne Foufelle, Jean C Ingram, Omar Porras, Felipe L Barros, Emma R Hudson, Lee G D Fryer, Stephen A Baldwin
    Abstract:

    In the rat liver epithelial cell line Clone 9, the V max for glucose uptake is actuely increased by inhibition of oxidative phosphorylation and by osmotic stress. By using a membrane-impermeant photoaffinity labelling reagent together with an isoform-specific antibody, we have, for the first time, provided direct evidence for the involvement of the GLUT1 glucose transporter isoform in this response. Transport stimulation was found to be associated with enhanced accessibility of GLUT1 to its substrate and with photolabelling of formerly `cryptic9 exofacial substrate binding sites in GLUT1 molecules. The total amount of cell surface GLUT1 remained constant. The precise mechanism for this binding site `unmasking9 is unclear but appears to involve AMP-activated Protein Kinase: in the current study, osmotic and metabolic stresses were found to result in activation of the α1 isoform of AMP-activated Protein Kinase, and transport stimulation could be mimicked both by 5-aminoimidazole-4-carboxamide ribonucleoside and by infection of cells with a recombinant adenovirus encoding constitutively active AMP-activated Protein Kinase. The effect of 5-aminoimidazole-4-carboxamide ribonucleoside, as for metabolic stress, was on the V max rather than on the K m for transport and did not affect the cell-surface concentration of GLUT1. The relevant downstream target(s) of AMP-activated Protein Kinase have not yet been identified, but stimulation of transport by inhibition of oxidative phosphorylation or by 5-aminoimidazole-4-carboxamide ribonucleoside was not prevented by either inhibitors of conventional and novel Protein Kinase C isoforms or inhibitors of nitric oxide synthase. These enzymes, which have been implicated in stress-regulated pathways in other cell types, are therefore unlikely to play a role in transport regulation by stress in Clone 9 cells.

  • the regulation of amp activated Protein Kinase by phosphorylation
    Biochemical Journal, 2000
    Co-Authors: Silvie C Stein, Matthew Davison, Angela Woods, Neil A Jones, David Carling
    Abstract:

    The AMP-activated Protein Kinase (AMPK) cascade is activated by an increase in the AMP/ATP ratio within the cell. AMPK is regulated allosterically by AMP and by reversible phosphorylation. Threonine-172 within the catalytic subunit (alpha) of AMPK (Thr(172)) was identified as the major site phosphorylated by the AMP-activated Protein Kinase Kinase (AMPKK) in vitro. We have used site-directed mutagenesis to study the role of phosphorylation of Thr(172) on AMPK activity. Mutation of Thr(172) to an aspartic acid residue (T172D) in either alpha1 or alpha2 resulted in a Kinase complex with approx. 50% the activity of the corresponding wild-type complex. The activity of wild-type AMPK decreased by greater than 90% following treatment with Protein phosphatases, whereas the activity of the T172D mutant complex fell by only 10-15%. Mutation of Thr(172) to an alanine residue (T172A) almost completely abolished Kinase activity. These results indicate that phosphorylation of Thr(172) accounts for most of the activation by AMPKK, but that other sites are involved. In support of this we have shown that AMPKK phosphorylates at least two other sites on the alpha subunit and one site on the beta subunit. Furthermore, we provide evidence that phosphorylation of Thr(172) may be involved in the sensitivity of the AMPK complex to AMP.

Bruce E Kemp - One of the best experts on this subject based on the ideXlab platform.

  • Structure and function of AMP-activated Protein Kinase.
    Acta physiologica (Oxford England), 2009
    Co-Authors: Jonathan S. Oakhill, John W. Scott, Bruce E Kemp
    Abstract:

    AMP-activated Protein Kinase (AMPK) regulates metabolism in response to energy demand and supply. AMPK is activated in response to rises in intracellular AMP or calcium-mediated signalling and is responsible for phosphorylating a wide variety of substrates. Recent structural studies have revealed the architecture of the abc subunit interactions as well as the AMP binding pockets on the c subunit. The a catalytic domain (1–280) is autoinhibited by a C-terminal tail (313–335), which is proposed to interact with the small lobe of the catalytic domain by homology modelling with the MARK2 Protein structure. Two direct activating drugs have been reported for AMPK, the thienopyridone compound A769662 and PTI, which may activate by distinct mechanisms.

  • Low salt concentrations activate AMP-activated Protein Kinase in mouse macula densa cells
    American journal of physiology. Renal physiology, 2009
    Co-Authors: Natasha Cook, Bruce E Kemp, Frosa Katsis, Scott A Fraser, Marina Katerelos, Kurt Gleich, Peter F Mount, Gregory R. Steinberg, Vicki Levidiotis, David A. Power
    Abstract:

    The energy-sensing Kinase AMP-activated Protein Kinase (AMPK) is associated with the sodium-potassium-chloride cotransporter NKCC2 in the kidney and phosphorylates it on a regulatory site in vitro....

  • AMP-activated Protein Kinase--the fat controller of the energy railroad.
    Canadian journal of physiology and pharmacology, 2006
    Co-Authors: Gregory R. Steinberg, S. Lance Macaulay, Mark A. Febbraio, Bruce E Kemp
    Abstract:

    AMP-activated Protein Kinase plays an important role in the regulation of lipid metabolism in response to metabolic stress and energy demand. It is also under endocrine control. AMPK acts at multiple steps and has a central role controlling fatty acid, triglyceride, and cholesterol synthesis, as well as the oxidation of fatty acids through direct phosphorylation effects and the control of gene transcription. As such, it can be considered to be the fat controller of the energy railroad. It is thought that AMPK may be a major mediator of the health benefits of exercise in mitigating the development of obesity and age-onset diseases.

  • Regulation of the energy sensor AMP-activated Protein Kinase in the kidney by dietary salt intake and osmolality.
    American journal of physiology. Renal physiology, 2004
    Co-Authors: Scott A Fraser, Bruce E Kemp, David Stapleton, Frosa Katsis, Peter F Mount, Vicki Levidiotis, Rebecca E Hill, David A. Power
    Abstract:

    The AMP-activated Protein Kinase (AMPK) is a key controller of cellular energy metabolism. We studied its expression and regulation by salt handling in the kidney. Immunoprecipitation and Western b...

  • regulation of 5 amp activated Protein Kinase activity and substrate utilization in exercising human skeletal muscle
    American Journal of Physiology-endocrinology and Metabolism, 2003
    Co-Authors: Jorgen F P Wojtaszewski, Christopher S Macdonald, Grahame D Hardie, Bente Kiens, Bruce E Kemp, Jakob Nielsen, Ylva Hellsten, Erik A Richter
    Abstract:

    The metabolic role of 5′AMP-activated Protein Kinase (AMPK) in regulation of skeletal muscle metabolism in humans is unresolved. We measured isoform-specific AMPK activity and β-acetyl-CoA carboxyl...

D. Grahame Hardie - One of the best experts on this subject based on the ideXlab platform.

  • AMP-activated Protein Kinase: Friend or Foe in Cancer?
    Annual Review of Cancer Biology, 2020
    Co-Authors: Diana Vara-ciruelos, Madhumita Dandapani, D. Grahame Hardie
    Abstract:

    The AMP-activated Protein Kinase (AMPK) is activated by energy stress and restores homeostasis by switching on catabolism, while switching off cell growth and proliferation. Findings that AMPK acts...

  • AMP-activated Protein Kinase in Metabolic Control and Insulin Signaling
    Circulation research, 2007
    Co-Authors: Mhairi C Towler, D. Grahame Hardie
    Abstract:

    The AMP-activated Protein Kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream Kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca2+-dependent and AMP-independent process involving phosphorylation by an alternate upstream Kinase, CaMKKβ. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the α subunit being catalytic, the β subunit containing a glycogen-sensing domain, and the γ subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome. This Review is part of a thematic series on AMP Kinase , which includes the following articles: AMP-activated Protein Kinase in Metabolic Control and Insulin Signaling Cardiac AMP-activated Protein Kinase in Health and Disease Bruce Kemp Guest Editor

  • AMP-activated Protein Kinase as a Drug Target
    Annual review of pharmacology and toxicology, 2007
    Co-Authors: D. Grahame Hardie
    Abstract:

    The AMP-activated Protein Kinase (AMPK) system is a regulator of energy balance at both the cellular and whole-body levels that, once activated by low energy status, effects a switch from ATP-consuming anabolic pathways to ATP-producing catabolic pathways. It now appears to be the major target for two existing classes of drug used to treat type 2 diabetes, i.e., the biguanides and thiazolidinediones. However, in both cases these activate AMPK indirectly, and an interesting question concerns whether a drug that directly activated AMPK would retain the therapeutic benefits of the existing drugs while eliminating unwanted side effects. AMPK activators also now have potential as anticancer drugs.

  • Does AMP-activated Protein Kinase couple inhibition of mitochondrial oxidative phosphorylation by hypoxia to calcium signaling in O2-sensing cells?
    The Journal of biological chemistry, 2005
    Co-Authors: A. Mark Evans, Kirsteen J. W. Mustard, Christopher N. Wyatt, Chris Peers, Michelle Dipp, Prem Kumar, Nicholas P. Kinnear, D. Grahame Hardie
    Abstract:

    Abstract Specialized O2-sensing cells exhibit a particularly low threshold to regulation by O2 supply and function to maintain arterial pO2 within physiological limits. For example, hypoxic pulmonary vasoconstriction optimizes ventilation-perfusion matching in the lung, whereas carotid body excitation elicits corrective cardio-respiratory reflexes. It is generally accepted that relatively mild hypoxia inhibits mitochondrial oxidative phosphorylation in O2-sensing cells, thereby mediating, in part, cell activation. However, the mechanism by which this process couples to Ca2+ signaling mechanisms remains elusive, and investigation of previous hypotheses has generated contrary data and failed to unite the field. We propose that a rise in the cellular AMP/ATP ratio activates AMP-activated Protein Kinase and thereby evokes Ca2+ signals in O2-sensing cells. Co-immunoprecipitation identified three possible AMP-activated Protein Kinase subunit isoform combinations in pulmonary arterial myocytes, with α1β2γ1 predominant. Furthermore, their tissue-specific distribution suggested that the AMP-activated Protein Kinase-α1 catalytic isoform may contribute, via amplification of the metabolic signal, to the pulmonary selectivity required for hypoxic pulmonary vasoconstriction. Immunocytochemistry showed AMP-activated Protein Kinase-α1 to be located throughout the cytoplasm of pulmonary arterial myocytes. In contrast, it was targeted to the plasma membrane in carotid body glomus cells. Consistent with these observations and the effects of hypoxia, stimulation of AMP-activated Protein Kinase by phenformin or 5-aminoimidazole-4-carboxamide-riboside elicited discrete Ca2+ signaling mechanisms in each cell type, namely cyclic ADP-ribose-dependent Ca2+ mobilization from the sarcoplasmic reticulum via ryanodine receptors in pulmonary arterial myocytes and transmembrane Ca2+ influx into carotid body glomus cells. Thus, metabolic sensing by AMP-activated Protein Kinase may mediate chemotransduction by hypoxia.

  • AMP-activated Protein Kinase: the guardian of cardiac energy status
    The Journal of clinical investigation, 2004
    Co-Authors: D. Grahame Hardie
    Abstract:

    Several years ago it was proposed that the AMP-activated Protein Kinase cascade might protect cells against stresses that deplete cellular ATP. Young et al. have now directly tested this by studying the effects of ischemia and reperfusion in perfused hearts from mice expressing a dominant-negative mutant that suppresses the Kinase activity in cardiac muscle. Compared with control hearts, the mutant hearts showed clear evidence for increased necrotic damage and increased apoptosis. These findings may have implications for the treatment of ischemic heart disease.

Laurie J. Goodyear - One of the best experts on this subject based on the ideXlab platform.

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