AMPK Signaling

AMP-activated protein kinase (AMPK) plays a key role as a master regulator of cellular energy homeostasis. The kinase is activated in response to stresses that deplete cellular ATP supplies such as low glucose, hypoxia, ischemia, and heat shock. It exists as a heterotrimeric complex composed of a catalytic α subunit and regulatory β and γ subunits. Binding of AMP to the γ subunit allosterically activates the complex, making it a more attractive substrate for phosphorylation on Thr172 in the activation loop of the α subunit by its major upstream AMPK kinase, LKB1. AMPK can also be directly phosphorylated on Thr172 by CAMKK2 in response to changes in intracellular calcium as occurs following stimulation by metabolic hormones including adiponectin and leptin.

As a cellular energy sensor responding to low ATP levels, AMPK activation positively regulates signaling pathways that replenish cellular ATP supplies, including fatty acid oxidation and autophagy. AMPK negatively regulates ATP-consuming biosynthetic processes including gluconeogenesis, lipid and protein synthesis. AMPK accomplishes this through direct phosphorylation of a number of enzymes directly involved in these processes as well as through transcriptional control of metabolism by phosphorylating transcription factors, co-activators, and co-repressors.

Due to its role as a central regulator of both lipid and glucose metabolism, AMPK is considered to be a potential therapeutic target for the treatment of type II diabetes mellitus, obesity, and cancer. AMPK has also been implicated in a number of species as a critical modulator of aging through its interactions with mTOR and sirtuins.

Selected Reviews:

• Cantó C, Auwerx J (2010) AMP-activated protein kinase and its downstream transcriptional pathways. Cell. Mol. Life Sci. 67(20), 3407–23.
• Carling D, Mayer FV, Sanders MJ, Gamblin SJ (2011) AMP-activated protein kinase: nature's energy sensor. Nat. Chem. Biol. 7(8), 512–8.
• Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 25(18), 1895–908.
• Hardie DG, Ross FA, Hawley SA (2012) AMP-Activated Protein Kinase: A Target for Drugs both Ancient and Modern. Chem. Biol. 19(10), 1222–36.
• Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13(9), 1016–23.
• Steinberg GR, Kemp BE (2009) AMPK in Health and Disease. Physiol. Rev. 89(3), 1025–78.
• Zhang BB, Zhou G, Li C (2009) AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab. 9(5), 407–16.

We would like to thank Prof. Reuben Shaw, The Salk Institute for Biological Studies, La Jolla, CA, for reviewing this diagram.

created April 2006

revised February 2019