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The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is expressed in essentially all eukaryotic cells, suggesting that it arose during early eukaryotic evolution. It occurs universally as heterotrimeric complexes containing catalytic α subunits and regulatory β and γ subunits. Although Drosophila melanogaster contains single genes encoding each subunit, in mammals each subunit exists as multiple isoforms encoded by distinct genes, giving rise to up to 12 heterotrimeric combinations. The multiple isoforms of each subunit are 2R-ohnologues generated by the two rounds of whole genome duplication that occurred at the evolutionary origin of the vertebrates. Although the differential roles of these isoform combinations remain only partly understood, there are indications that they may have different subcellular locations, different inputs and outputs, and different functions. The multiple isoforms are of particular interest with respect to the roles of AMPK in cancer, because genes encoding some isoforms, such as PRKAA1 and PRKAB2 (encoding α1 and β2) are quite frequently amplified in tumour cells, while genes encoding others, such as PRKAA2 (encoding α2) tend instead to be mutated, which may in some but not all cases cause a loss of function. Thus, although AMPK acts downstream of the tumour suppressor LKB1, and some of its isoform combinations may act as tumour suppressors that restrain growth and proliferation of tumour cells, other isoform combinations may paradoxically act as oncogenes, perhaps by aiding the survival of tumour cells that are undergoing environmental stresses such as hypoxia or nutrient deprivation. This article is protected by copyright. All rights reserved.