Role of the AMP-activated protein kinase in the cellular stress response.
BACKGROUND
AMP-activated protein kinase is the central component of a protein kinase cascade that phosphorylates and inactivates key regulatory enzymes of several biosynthetic pathways. Elevation of cellular AMP levels activates this kinase, both by allosteric activation, which causes more than 5-fold activation, and by phosphorylation by an upstream kinase kinase, leading to more than 20-fold activation; the result is a greater than 100-fold activation overall. As AMP is usually elevated when cellular ATP is depleted, we have assessed the possibility that the AMP-activated kinase is involved in the cellular response to stress, which is known to lead to ATP depletion.


RESULTS
We report that AMP is elevated, and ATP depleted, when isolated rat hepatocytes are subjected to treatments that activate the cellular stress response, namely heat shock or treatment with arsenite. Several events are correlated with these changes in nucleotide levels: first, a large activation of the AMP-activated protein kinase, which can be reversed by treatment with a protein phosphatase; second, phosphorylation and inactivation of one of the known substrates of the AMP-activated kinase, HMG-CoA reductase; and third, inhibition of two of the biosynthetic pathways known to be affected by the AMP-activated kinase, namely sterol and fatty-acid synthesis.


CONCLUSIONS
Our results suggest that a major function of the AMP-activated protein kinase is to act protectively, switching off biosynthetic pathways when the cell is subjected to stress that causes ATP depletion, the key signal being a rise in AMP level. By this mechanism, ATP is preserved for processes that may be more essential in the short term, such as the maintenance of ion gradients. This function of the kinase represents a novel role for protein phosphorylation.
Corton
J M
JM
Biochemistry Department, The University, Dundee, UK.
Gillespie
J G
JG
Hardie
D G
DG
D055372:AMP-Activated Protein Kinases; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000096:biosynthesis; D006358:Hot Temperature; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D051381:Rats; D013261:Sterols / Q000096:biosynthesis
D018053:Arsenites; D005227:Fatty Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009097:Multienzyme Complexes; D013261:Sterols; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C015001:arsenite