Roles of the AMP-activated/SNF1 Protein Kinase Family in the Response to Cellular Stress

The AMP-activated protein kinase (AMPK) in mammals, and its homologue in Saccharomyces cerevisiae, are activated by cellular stresses associated with ATP depletion. AMPK is a heterotrimer comprising a catalytic alpha subunit with associated beta and gamma subunits, these being homologous with the products of the SNF1, SIP1/SIP2/GAL83 and SNF4 genes in S. cerevisiae. The alpha subunit has at least two isoforms (alpha 1 and alpha 2), which differ in their AMP-dependence and subcellular localization, with alpha 2 complexes being partly nuclear. AMPK is activated allosterically by 5'-AMP, which also promotes phosphorylation and activation by an upstream kinase, and inhibits dephosphorylation and inactivation. Elevation of AMP always accompanies depletion of ATP due to the action of adenylate kinase. Since high ATP antagonizes the activating effects of AMP, the system behaves like a cellular 'fuel gauge'. It is activated by various types of stress associated with ATP depletion, such as hypoxia, heat shock, metabolic poisoning and, in muscle, exercise. AMPK phosphorylates multiple targets which switch off anabolic pathways and switch on alternative catabolic pathways. The yeast SNF1 complex is switched on by glucose starvation, and its targets include transcription factors that repress transcription of genes required for catabolism of alternative carbon sources.