AMP‐activated protein kinase: a cellular energy sensor that comes in 12 flavours

Abstract

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 the genes encoding some isoforms, such as PRKAA1 and PRKAB2 (encoding α1 and β2), are quite frequently amplified in tumour cells, whereas the genes encoding others, such as PRKAA2 (encoding α2), tend to be mutated, which, in some but not all cases, may result in a loss of function. Thus, although AMPK acts downstream of the tumour suppressor liver kinase B1, and some of its isoform combinations may act as tumour suppressors that restrain the growth and proliferation of tumour cells, other isoform combinations may paradoxically act as oncogenes, perhaps by aiding the survival of tumour cells undergoing environmental stresses such as hypoxia or nutrient deprivation.

An Oncogenic Role for the Ubiquitin Ligase UBE2O by Targeting AMPK-α2 for Degradation

“…Taken together, these results suggest that while AMPK-α2 might indeed be a tumor suppressor, AMPK-α1 might be an oncoprotein that promotes the survival of tumor cells, possibly by protecting them under conditions of energy stress. Consistent with this, recent analyses of the human cancer genome databases revealed that while the PRKAA2 gene (encoding α2) is quite often mutated in human cancers, PRKAA1 tends to be amplified instead (Monteverde et al, 2015;Ross et al, 2016). Vila et al (2017) were interested in the role of UBE2O, a large ubiquitin ligase with both E2 and E3 activities.…”

“…AMP-activated protein kinase (AMPK) is a cellular energy sensor involved in matching the supply of ATP from catabolism to the demand created by anabolism and other ATP-consuming activities, including cell division (Ross et al, 2016). As soon as demand out-strips supply the ADP:ATP ratio will increase, and this is amplified by the adenylate kinase reaction (2ADP ↔ ATP + AMP) into even larger increases in AMP:ATP ratios.…”

“…However, this simple picture has recently become much more confused. The catalytic subunit of AMPK exists as two isoforms, α1 and α2 (Ross et al, 2016). While α2 knockout mouse embryo fibroblasts (MEFs) are sensitive to transformation by mutant H-Ras in vitro, and H-Ras-transformed α2-KO cells grow even more rapidly than wild type controls as tumors in vivo (correlating with reduced expression of p53), α1-KO MEFs are resistant to transformation in vitro and grow very poorly in vivo (Phoenix et al, 2012).…”

AMPK β1 reduces tumor progression and improves survival in p53 null mice

“…To the best of our knowledge, the in vivo importance of other AMPK subunits in combination with genetic loss of tumor‐suppressing pathways has not been studied. However, this is important given that the 12 different AMPK heterotrimer combinations have unique tissue‐specific expression, enzyme activities, and substrates (Ross et al ., 2016) and may have differential effects in distinct settings of oncogenesis (i.e., when interacting with distinct tumor‐promoting pathways).…”

Targeting an energy sensor to treat diabetes

“…Each occurs as multiple isoforms (α1/α2, β1/β2, γ1/γ2/γ3), generating up to twelve possible combinations (1). Repeated sequences in the γ subunits generate three binding sites for the regulatory nucleotides AMP, ADP and ATP, and some AMPK activators (e.g.…”