College of Life Sciences, University of Dundee, Dundee, Scotland, UK.
The AMP-activated protein kinase (AMPK) occurs as heterotrimeric complexes comprising a catalytic α subunit and regulatory β and γ subunits. It was discovered via its ability to phosphorylate and activate enzymes that catalyze regulatory steps in lipid synthesis, but it is now clear that it acts as a central sensor of cellular energy that has tens, if not hundreds, of downstream targets. AMPK is activated by falling cellular energy status via a complex mechanism involving allosteric activation by AMP, and modulation of the phosphorylation/dephosphorylation of Thr172 (within the α subunit) by upstream kinases and phosphatases. One activated, AMPK attempts to restore cellular energy homeostasis by activating catabolic pathways that generate ATP, while switching off biosynthetic pathways and other processes (including progress through the cell cycle) that consume ATP. The discovery that the major kinase phosphorylating Thr172 was a complex containing the tumour suppressor LKB1 provided a link between AMPK and cancer, and suggested that AMPK might exert the tumour suppressor functions of LKB1. Most rapidly proliferating cells, including tumour cells, utilize rapid glucose uptake and glycolysis to lactate to generate ATP, rather than the more energy-efficient mitochondrial oxidative metabolism. This phenomenon (the Warburg effect) may occur in part because the TCA cycle is being used not simply for catabolic purposes but also for provision of biosynthetic precursors, particularly citrate for lipid biosynthesis. Budding yeast display a related phenomenon, in that when incubated in high glucose they grow rapidly using fermentation (glycolysis to ethanol) to generate their ATP, whereas when glucose runs low their growth slows and they switch to use of oxidative metabolism instead. Intriguingly, the yeast orthologue of AMPK (the SNF1 complex) is required for this metabolic switch. By promoting oxidative metabolism, AMPK exerts a similar "anti-Warburg" effect in human cells. Thus, by inhibiting progress through the cell cycle and by promoting the metabolism utilized by quiescent cells, AMPK would be expected to exert anti-cancer effects. This idea is supported by findings that the AMPK-activating drug metformin reduces the risk of cancer in diabetics. Cells involved in inflammation, including dendritic cells and M1 macrophages, also tend to display rapid glycolysis even under normoxic conditions (aerobic glycolysis), whereas cells involved in the resolution of inflammation (e.g. M2 macrophages) tend to utilize oxidative metabolism instead. By promoting the latter, AMPK would exert anti-inflammatory effects, an idea supported by our findings that salicylate (the major breakdown product of the anti-inflammatory drug aspirin) activates AMPK by direct binding to the α subunit. Recent findings that may be discussed in the lecture include the detailed mechanism by which adenine nucleotides regulate AMPK, the identity of the upstream phosphatases that dephosphorylate Thr172, and the mechanism by which the insulin-activated kinase Akt/PKB (which is activated in many tumour cells) down-regulates AMPK by phosphorylating a site within the "ST loop" in the α subunit, which then sterically hinders Thr172 phosphorylation.