The LKB1-AMPK signalling cascade

Research

The LKB1-AMPK cascade: a key regulator of energy balance and a target for drugs aimed at diabetes and cancer

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 [3].

AMPK is only active after phosphorylation by the tumour suppressor kinase, LKB1 [4]; AMP binding inhibits dephosphorylation. We also discovered a second mode of regulation, involving CaMKK-beta and triggered by a rise in cytosolic calcium [5].

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 [6]

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 [1]

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 [7].

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 [8]. 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 [9]. 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 [10].

Teaching

Publications

1. Hardie, D.G. (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat. Rev. Mol. Cell Biol. 8:774-785.
2. Hardie, D.G. (2008) Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Lett. 582:81-89.
3. Scott, J.W., Hawley, S.A., Green, K.A., Anis, M., Stewart, G., Scullion, G.A., Norman, D.G. and Hardie, D.G. (2004) CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by   disease mutations. J. Clin. Invest. 113:274-284.
4. Hawley, S.A., Boudeau, J., Reid, J.L., Mustard, K.J., Udd, L., Makela, T.P., Alessi, D.R. and Hardie, D.G. (2003) Complexes between the LKB1 tumor suppressor, STRADa/b and MO25a/b are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2:28.
5. Hawley, S.A., Pan, D.A., Mustard, K.J., Ross, L., Bain, J., Edelman, A.M., Frenguelli, B.G. and Hardie, D.G. (2005) Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2:9-19.
6. McBride, A., Ghilagaber, S., Nikolaev, A. and Hardie, D.G. (2009) The glycogen-binding domain on AMP-activated protein kinase is a regulatory domain that allows the kinase to act as a sensor of glycogen structure. Cell Metab. 9:23-34.
7. Hardie, D.G. (2007) AMPK and Raptor: matching cell growth to energy supply. Mol. Cell 30:263-265.
8. Kahn, B.B., Alquier, T., Carling, D. and Hardie, D.G. (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1:15-25.
9. Hardie, D.G. and Sakamoto, K. (2006) AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology (Bethesda) 21:48-60.
10. Hadad, S.M., Baker, L., Quinlan, P., Robertson, K.E., Bray, S.E., Thomson, G., Kellock, D., Jordan, L.B., Purdie, C.A., Hardie, D.G., Fleming, S. and Thompson, A.M. (2009) Histological evaluation of AMPK signalling in primary breast cancer. BMC Cancer 9:307.