“Our research is aimed at understanding the regulation of energy metabolism”
AMP-activated protein kinase (AMPK) is activated in response to a fall in the intracellular concentration of ATP, and has been dubbed the cell’s fuel gauge. AMPK phosphorylates a wide range of downstream targets involved in diverse pathways. Broadly speaking, activation of AMPK leads to an increase in catabolic pathways and a reduction in anabolic pathways, effects that are predicted to be beneficial in metabolic diseases. As a consequence, AMPK has attracted significant attention as a potential therapeutic target for drugs aimed at treating metabolic diseases, including obesity and type 2 diabetes.
Phosphorylation and activation of AMPK is catalysed by either LKB1 or Ca2+/calmodulin dependent protein kinase kinase 2 (CAMKK2). Inactivating mutations within LKB1 lead to a rare, dominantly inherited cancer predisposition in humans, termed Peutz-Jeghers Syndrome, whereas CAMKK2 expression is increased in human prostate cancers. These findings suggest that AMPK may play a role in human cancers. Our current focus is to understand the regulation of AMPK using structure/function analyses and to explore its physiological role using a recently developed transgenic mouse model expressing a gain-of-function AMPK mutant.
Structure of AMPK bound to a small molecule activator (A). H&E stained liver sections from mice fed a high fructose diet for 12 weeks. The fat accumulation that is clearly evident in liver from wild-type mice (white spots) is completely absent in liver from mice expressing the gain-of-function AMPK mutation (B).
Woods A, Williams JR, Muckett PJ, Mayer FV, Liljevald M, Bohlooly-Y M, Carling D. (2017). Liver-specific activation of AMPK prevents steatosis on a high-fructose diet. Cell Reports 18(13), 3043-3051.
Willows R, Sanders MJ, Xiao B, Patel BR, Martin SR, Read J, Wilson JR, Hubbard J, Gamblin SJ, Carling D. (2017). Phosphorylation of AMPK by upstream kinases is required for activity in mammalian cells. Biochemical Journal 474(17), 3059-3073.
Willows R, Navaratnam N, Lima A, Read J, Carling D. (2017). Effect of different γ-subunit isoforms on the regulation of AMPK. Biochemical Journal 474(10), 1741-1754.
Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S, Giordanetto F, Martin SR, Carling D, Gamblin SJ. (2013). Structural basis of AMPK regulation by small molecule activators. Nature Communications 4.