AMP Is a True Physiological Regulator of AMP-Activated Protein Kinase by Both Allosteric Activation and Enhancing Net Phosphorylation

Graeme J. Gowans, Simon A. Hawley, Fiona A. Ross, D. Grahame Hardie (Lead / Corresponding author)

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    Abstract

    While allosteric activation of AMPK is triggered only by AMP, binding of both ADP and AMP has been reported to promote phosphorylation and inhibit dephosphorylation at Thr172. Because cellular concentrations of ADP and ATP are higher than AMP, it has been proposed that ADP is the physiological signal that promotes phosphorylation and that allosteric activation is not significant in vivo. However, we report that: AMP is 10-fold more potent than ADP in inhibiting Thr172 dephosphorylation; only AMP enhances LKB1-induced Thr172 phosphorylation; and AMP can cause >10-fold allosteric activation even at concentrations 1-2 orders of magnitude lower than ATP. We also provide evidence that allosteric activation by AMP can cause increased phosphorylation of acetyl-CoA carboxylase in intact cells under conditions in which there is no change in Thr172 phosphorylation. Thus, AMP is a true physiological regulator of AMPK, and allosteric regulation is an important component of the overall activation mechanism.
    Original languageEnglish
    Pages (from-to)556-566
    Number of pages11
    JournalCell Metabolism
    Volume18
    Issue number4
    DOIs
    Publication statusPublished - 1 Oct 2013

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    AMP-Activated Protein Kinases
    Adenosine Monophosphate
    Phosphorylation
    Adenosine Diphosphate
    Adenosine Triphosphate
    Allosteric Regulation
    Acetyl-CoA Carboxylase

    Cite this

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    title = "AMP Is a True Physiological Regulator of AMP-Activated Protein Kinase by Both Allosteric Activation and Enhancing Net Phosphorylation",
    abstract = "While allosteric activation of AMPK is triggered only by AMP, binding of both ADP and AMP has been reported to promote phosphorylation and inhibit dephosphorylation at Thr172. Because cellular concentrations of ADP and ATP are higher than AMP, it has been proposed that ADP is the physiological signal that promotes phosphorylation and that allosteric activation is not significant in vivo. However, we report that: AMP is 10-fold more potent than ADP in inhibiting Thr172 dephosphorylation; only AMP enhances LKB1-induced Thr172 phosphorylation; and AMP can cause >10-fold allosteric activation even at concentrations 1-2 orders of magnitude lower than ATP. We also provide evidence that allosteric activation by AMP can cause increased phosphorylation of acetyl-CoA carboxylase in intact cells under conditions in which there is no change in Thr172 phosphorylation. Thus, AMP is a true physiological regulator of AMPK, and allosteric regulation is an important component of the overall activation mechanism.",
    author = "Gowans, {Graeme J.} and Hawley, {Simon A.} and Ross, {Fiona A.} and Hardie, {D. Grahame}",
    note = "Copyright {\circledC} 2013 The Authors. Published by Elsevier Inc. All rights reserved. G.J.G. was funded by a PhD studentship from AstraZeneca, and D.G.H., S.A.H., and F.A.R. were supported by a Senior Investigator Award (097726) from the Wellcome Trust. We are very grateful to Benoit Viollet for supplying AMPK knockout MEFs.",
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    AU - Gowans, Graeme J.

    AU - Hawley, Simon A.

    AU - Ross, Fiona A.

    AU - Hardie, D. Grahame

    N1 - Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved. G.J.G. was funded by a PhD studentship from AstraZeneca, and D.G.H., S.A.H., and F.A.R. were supported by a Senior Investigator Award (097726) from the Wellcome Trust. We are very grateful to Benoit Viollet for supplying AMPK knockout MEFs.

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    AB - While allosteric activation of AMPK is triggered only by AMP, binding of both ADP and AMP has been reported to promote phosphorylation and inhibit dephosphorylation at Thr172. Because cellular concentrations of ADP and ATP are higher than AMP, it has been proposed that ADP is the physiological signal that promotes phosphorylation and that allosteric activation is not significant in vivo. However, we report that: AMP is 10-fold more potent than ADP in inhibiting Thr172 dephosphorylation; only AMP enhances LKB1-induced Thr172 phosphorylation; and AMP can cause >10-fold allosteric activation even at concentrations 1-2 orders of magnitude lower than ATP. We also provide evidence that allosteric activation by AMP can cause increased phosphorylation of acetyl-CoA carboxylase in intact cells under conditions in which there is no change in Thr172 phosphorylation. Thus, AMP is a true physiological regulator of AMPK, and allosteric regulation is an important component of the overall activation mechanism.

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