AMPK Control of Metabolic Signaling

One of the central regulators of cellular and organismal metabolism in eukaryotes is AMP‐activated protein kinase (AMPK), which is activated when intracellular ATP production decreases. AMPK has critical roles in regulating growth and reprogramming metabolism, and has recently been connected to cellular processes such as autophagy and cell polarity. As AMPK is activated in response to a variety of stresses, in response to exercise, and by the widely used type 2 diabetes therapeutic metformin. Our laboratory has performed a three‐pronged screen to identify novel substrates of AMPK that may mediate its effects on metabolism and growth control. One of the first such novel substrates we reported was the mTOR‐binding subunit raptor. Phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and for cell cycle arrest following energy stress. More recently we have found additional connections between AMPK and the control of autophagy, discovering that AMPK directly phosphorylates and activates the ULK1/hATG1 kinase to initiate autophagy. We showed that the AMPK regulation of ULK1 is essential for mitochondrial homeostasis and cell survival under starvation conditions. Collectively, these studies have uncovered novel conserved effectors of LKB1 and AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status. We have also recently uncovered a number of new substrates of AMPK that play key roles in transcriptional control of metabolism, including the Class IIa family of HDACs and the Srebp1 transcription factor. Finally, we are examining whether biguanide compounds including phenformin and metformin, which activate the LKB1/AMPK pathway and are clinically used for treatment of type 2 diabetes, may show utility in the treatment of different mouse models of cancer. The connection between LKB1, AMPK, and mTOR signaling further illustrates molecular connections underlying the development of both cancer and metabolic syndrome.