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 regula tory enzymes of several biosynthetic pathways. Elevation of cellular A MP levels activates this kinase, both by allosteric activation, which causes more than 5-fold activation, and by phosphorylation by an upstr eam kinase kinase, leading to more than 20-fold activation; the result is a greater than 100-fold activation overall. As AMP is usually elev ated when cellular ATP is depleted, we have assessed the possibility t hat the AMP-activated kinase is involved in the cellular response to s tress, which is known to lead to ATP depletion. Results: We report tha t AMP is elevated, and ATP depleted, when isolated rat hepatocytes are subjected to treatments that activate the cellular stress response, n amely heat shock or treatment with arsenite. Several events are correl ated with these changes in nucleotide levels: first, a large activatio n of the AMP-activated protein kinase, which can be reversed by treatm ent with a protein phosphatase; second, phosphorylation and inactivati on 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 fa tty-acid synthesis. Conclusions: Our results suggest that a major func tion of the AMP-activated protein kinase is to act protectively, switc hing off biosynthetic pathways when the cell is subjected to stress th at causes ATP depletion, the key signal being a rise in AMP level. By this mechanism, ATP is preserved for processes that may be more essent ial in the short term, such as the maintenance of ion gradients. This function of the kinase represents a novel role for protein phosphoryla tion.