Position: Professor of Cellular Signalling
Division: Cell Signalling and Immunology
Address: College of Life Sciences, University of Dundee, Dundee
Telephone: +44 1382 384276, int ext. 84276
Fax: +44 1382 385507
The AMP-activated protein kinase (AMPK) cascade was first defined in our laboratory. All energy-consuming reactions in the cell are powered by the high ratio of ATP to ADP, and when metabolic stress causes this ratio to fall, the AMPK system is switched on [1,2]. We have established the mechanism by which this occurs, involving binding of AMP to the AMPK gamma subunit .
AMPK is only active after phosphorylation by the tumour suppressor kinase, LKB1 ; AMP binding inhibits dephosphorylation. We also discovered a second mode of regulation, involving CaMKK-beta and triggered by a rise in cytosolic calcium .
The beta subunit of AMPK contains a carbohydrate-binding module that causes it to bind to glycogen. We recently provided evidence that this allows AMPK to act as a “glycogen sensor”, modulating glycogen synthesis in response to the status of cellular reserves of this storage carbohydrate 
Once activated by a fall in cellular energy or rising calcium, the AMPK system has dramatic effects on cell function. It switches on ATP-producing catabolic pathways, while switching off ATP-consuming processes, including most biosynthetic pathways, as well as cell growth and proliferation 
AMPK activation limits cell growth in part by inhibiting mTOR complex-1 (TORC1), a growth-promoting pathway that is switched on by growth factors, and in many tumour cells by mutations in the Ras-Raf and PI-3-kinase-PKB/Akt pathways .
The AMPK system has been found to play a key role in modulating energy balance at the whole body level, by mediating effects of adipokines such as leptin and adiponectin and thus regulating food intake and energy expenditure . It is responsible for many acute metabolic changes induced by exercise in muscle, including increased glucose uptake, as well as longer term effects of endurance training, such as increased mitochondrial biogenesis . AMPK activation may explain in part the protective effects of exercise on the development of obesity and type 2 diabetes. The AMPK system is a target for the development of new drugs aimed at obesity, type 2 diabetes and cancer, and is the target for the existing anti-diabetic drug, metformin, prescribed to over 120 million people worldwide. AMPK is also now reaching centre stage in studies of cancer. The LKB1-AMPK pathway acts as a tumour suppressor by limiting cell growth and proliferation in response to metabolic stress. However, it appears that many tumours may have established mechanisms to prevent activation of the pathway .