AMP-activated protein kinase - a journey from 1 to 100 downstream targets

A casual decision made one evening in 1976, in a bar near the Biochemistry Department at the University of Dundee, led me to start my personal research journey by following up a paper that suggested that acetyl-CoA carboxylase (ACC) (believed to be a key regulatory enzyme of fatty acid synthesis) was inactivated by phosphorylation by what appeared to be a novel, cyclic AMP-independent protein kinase. This led me to define and name the AMP-activated protein kinase (AMPK) signalling pathway, on which I am still working 46 years later. ACC was the first known downstream target for AMPK, but at least 100 others have now been identified. This article contains some personal reminiscences of that research journey, focussing on: (i) the early days when we were defining the kinase and developing the key tools required to study it; (ii) the late 1990s and early 2000s, an exciting time when we and others were identifying the upstream kinases; (iii) recent times when we have been studying the complex role of AMPK in cancer. The article is published in conjunction with the Sir Philip Randle Lecture of the Biochemical Society, which I gave in September 2022 at the European Workshop on AMPK and AMPK-related kinases in Clydebank, Scotland. During the early years of my research career, Sir Philip acted as a role model, due to his pioneering work on insulin signalling and the regulation of pyruvate dehydrogenase

Molecular pathways:is AMPK a friend or a foe in cancer?

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status expressed in essentially all eukaryotic cells. Once activated by energetic stress via a mechanism that detects increases in AMP:ATP and ADP:ATP ratios, AMPK acts to restore energy homeostasis by switching on catabolic pathways that generate ATP, while switching off ATP-consuming processes, including anabolic pathways required for cell growth and proliferation. AMPK activation promotes the glucose-sparing, oxidative metabolism utilized by most quiescent cells, rather than the rapid glucose uptake and glycolysis used by most proliferating cells. Numerous pharmacological activators of AMPK are known, including drugs in long use such as salicylate and metformin, and there is evidence that regular use of either of the latter provides protection against development of cancer. Tumor cells appear to be under selection pressure to down-regulate AMPK, thus limiting its restraining influence on cell growth and proliferation, and several interesting mechanisms by which this occurs are discussed. Paradoxically, however, a complete loss of AMPK function, which appears to be rare in human cancers, may be deleterious to survival of tumor cells. AMPK can therefore either be a friend and a foe in cancer, depending on the context

AMPK:a cellular energy sensor primarily regulated by AMP

AMPK (AMP-activated protein kinase) is a cellular energy sensor that monitors the ratio of AMP/ATP, and possibly also ADP/ATP, inside cells. Once activated by falling cellular energy levels, it acts to restore energy homoeostasis by switching on catabolic pathways that generate ATP, while switching off anabolic pathways and other processes consuming ATP. AMPK is switched on by increases in AMP via three mechanisms, all of which are antagonized by ATP: (i) promotion of phosphorylation of Thr172 by upstream activating kinases; (ii) inhibition of dephosphorylation of Thr172 by phosphatases; and (iii) allosteric activation of the phosphorylated kinase. Recently, it has been proposed that the first two mechanisms are also triggered by ADP, which might be the physiological signal rather than AMP, and that the third mechanism may not be physiologically significant. We have re-evaluated these questions, and found that only mechanism (ii) is mimicked by ADP, and that ADP is also less potent than AMP, which we still believe to be the primary signal. We have also provided evidence that mechanism (iii), i.e. allosteric activation by AMP, is a quantitatively significant mechanism in intact cells.</jats:p