The AMP-Activated Protein Kinase

Fuel Gauge of the Mammalian Cell?

Authors

  • D. Grahame Hardie,

    Corresponding author
    1. Biochemistry Department, The University, Dundee, UK
      D. G. Hardie, Biochemistry Department, The University, Dundee, DD1 4HN, UK
      Fax:+44 1382 201063.
      E-mail:d.g.hardie@dundee.ac.uk
      URL:http://www.dundee.ac.uk/biochemistry
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  • David Carling

    1. MRC Molecular Medicine Group, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK
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  • Note. This Review will be reprinted in EJB Reviews 1977 which will be available in April 1998.

D. G. Hardie, Biochemistry Department, The University, Dundee, DD1 4HN, UK
Fax:+44 1382 201063.
E-mail:d.g.hardie@dundee.ac.uk
URL:http://www.dundee.ac.uk/biochemistry

Abstract

A single entity, the AMP-activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutraryl-CoA reductase and acetyl-CoA carboxylase (key regulatory enzymes of sterol synthesis and fatty acid synthesis, respectively), and probably many additional targets. The kinase is activated by high AMP and low ATP via a complex mechanism, which involves allosteric regulation, promotion of phosphorylation by an upstream protein kinase (AMPK kinase), and inhibition of dephosphorylation. This protein-kinase cascade represents a sensitive system, which is activated by cellular stresses that deplete ATP, and thus acts like a cellular fuel gauge. Our central hypothesis is that, when it detects a ‘low-fuel’ situation, it protects the cell by switching off ATP-consuming pathways (e.g. fatty acid synthesis and sterol synthesis) and switching on alternative pathways for ATP generation (e.g. fatty acid oxidation). Native AMP-activated protein kinase is a heterotrimer consisting of a catalytic α subunit, and β and γ subunits, which are also essential for activity. All three subunits have homologues in budding yeast, which are components of the SNF1 protein-kinase complex. SNF1 is activated by glucose starvation (which in yeast leads to ATP depletion) and genetic studies have shown that it is involved in derepression of glucose-repressed genes. This raises the intriguing possibility that AMPK may regulate gene expression in mammals. AMPK/SNF1 homologues are found in higher plants, and this protein-kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress.

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