AMPK Signaling

• Description
• Reviews
• Pathway Key
• Download PDF

Pathway Description:

AMP-activated protein kinase (AMPK) exhibits 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 its major upstream AMPKK, LKB1. Several studies indicate that signaling through adiponectin, leptin and CAMKKβ may also be of importance to activating AMPK.

As a cellular energy sensor in response to low ATP levels, AMPK activation positively regulates signaling pathways that replenish cellular ATP supplies. For example, activation of AMPK enhances both the transcription and translocation of GLUT4, resulting in an increase in insulin-stimulated glucose uptake. In addition, it also stimulates catabolic processes such as fatty acid oxidation and glycolysis via inhibition of ACC and activation of PFK2. AMPK negatively regulates several proteins central to ATP consuming processes such as TORC2, glycogen synthase, SREBP-1 and TSC2, resulting in the downregulation or inhibition of gluconeogenesis, glycogen, lipid and protein synthesis. Due to its role as a central regulator of both lipid and glucose metabolism, AMPK is considered to be a key therapeutic target for the treatment of obesity, type II diabetes mellitus, and cancer.

Selected Reviews:

• Hardie DG (2008) Role of AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Lett. 582(1), 81–9.
• Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ. Res. 100(3), 328–41.
• Jorgensen SB, Rose AJ (2008) How is AMPK activity regulated in skeletal muscles during exercise? Front. Biosci. 13, 5589–604.
• Witters LA, Kemp BE, Means AR (2006) Chutes and Ladders: the search for protein kinases that act on AMPK. Trends Biochem. Sci. 31(1), 13–6.

CST would like to thank Dr. Lee Witters, Department of Biochemistry, Dartmouth Medical School, Hanover, NH, for reviewing this AMPK Signaling diagram.