The tumor suppressor LKB1 controls glucose synthesis in the liver by regulating adenosine-monophosphate-activated protein kinase (AMPK).
Adenosine-monophosphate-activated protein kinase (AMPK) is an enzyme that senses cellular energy levels. It therefore has an important role in many metabolic processes in mammals. In the liver, AMPK controls gluconeogenesis and lipogenesis, although it has been unclear how the activity of AMPK is regulated. Now, a report in Science shows that the enzyme and tumour suppressor LKB1 — which is mutated in the human Peutz–Jeghers cancer syndrome — is the main upstream activating kinase for AMPK in the liver.
Previous work showing that LKB1 is a potential activator of AMPK in vivo prompted Shaw and colleagues to look at LKB1 as a potential central regulator of metabolism. The authors initially generated mice with an LKB1 deletion in the liver and found that AMPK was almost completely inactive. They also noted high levels of blood glucose in the mice, and an increase in the expression of the genes that encode enzymes involved in gluconeogenesis and lipogenesis. Importantly, Shaw et al. identified the CREB (cyclic-AMP-response-element-binding protein) coactivator TORC2 (transducer of regulated CREB activity-2) — an essential regulator of gluconeogenesis in mice — as being a crucial downstream target of LKB1–AMPK signalling in the control of gluconeogenesis. In addition, the authors showed that metformin, the most widely used drug for type-2 diabetes, requires LKB1 and AMPK activation to lower blood glucose levels.
The authors' work has uncovered a novel signalling pathway, involving a tumour suppressor, that controls the synthesis of glucose in the liver: LKB1 activation regulates downstream kinases, such as AMPK, that phosphorylate and inactivate the transcriptional coactivator TORC2, thereby turning off glucose production. These findings reinforce the link between cancer and the physiological control of metabolism, and could lead to new approaches for the treatment of some cancers, as well as diabetes.
Sharon Ahmad
References
Shaw R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science310, 1642–1646 (2005) | Article | PubMed |
