Mammalian AMPK is known to be activated by falling cellular energy status, signaled by rising AMP/ATP and ADP/ATP ratios. We review recent information about how this occurs but also discuss new studies suggesting that AMPK is able to sense glucose availability independently of changes in adenine nucleotides. The glycolytic intermediate fructose-1,6-bisphosphate (FBP) is sensed by aldolase, which binds to the v-ATPase on the lysosomal surface. In the absence of FBP, interactions between aldolase and the v-ATPase are altered, allowing formation of an AXIN-based AMPK-activation complex containing the v-ATPase, Ragulator, AXIN, LKB1, and AMPK, causing increased Thr172 phosphorylation and AMPK activation. This nutrient-sensing mechanism activates AMPK but also primes it for further activation if cellular energy status subsequently falls. Glucose sensing at the lysosome, in which AMPK and other components of the activation complex act antagonistically with another key nutrient sensor, mTORC1, may have been one of the ancestral roles of AMPK.

Mitogen-activated protein (MAP) kinase cascades represent one of the major signal systems used by eukaryotic cells to transduce extracellular signals into cellular responses. Four MAP kinase subgroups have been identified in humans: ERK, JNK (SAPK), ERK5 (BMK), and p38. Here we characterize a new MAP kinase, p38␤. p38␤ is a 372-amino acid protein most closely related to p38. It contains a TGY dual phosphorylation site, which is required for its kinase activity. Like p38, p38␤ is activated by proinflammatory cytokines and environmental stress. A comparison of events associated with the activation of p38␤ and p38 revealed differences, most notably in the preferred activation of p38␤ by MAP kinase kinase 6 (MKK6), whereas p38 was activated nearly equally by MKK3, MKK4, and MKK6. Moreover, in vitro and in vivo experiments showed a strong substrate preference by p38␤ for activating transcription factor 2 (ATF2). Enhancement of ATF2-dependent gene expression by p38␤ was ϳ20-fold greater than that of p38 and other MAP kinases tested. The data reported here suggest that while closely related, p38␤ and p38 may be regulated by differing mechanisms and may exert their actions on separate downstream targets.

The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK)1, but it has been unclear whether this occurs solely via changes in AMP or ADP, the classical activators of AMPK2–5. Here, we uncover a mechanism that triggers AMPK activation via an AMP/ADP-independent mechanism sensing absence of FBP, with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of lysosomal complexes containing the v-ATPase, Ragulator, AXIN, LKB1 and AMPK, previously shown to be required for AMPK activation6,7. Knockdown of aldolases activates AMPK even in cells with abundant glucose, while the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts association of AXIN/LKB1 with v-ATPase/Ragulator. Importantly, in some cell types AMP:ATP/ADP:ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

This is an unusual plant-specific b subunit that contains the C-terminal domain but lacks a CBM (carbohydrate-binding module).b By sequence, this appears to be an ortholog of mammalian g subunits, but it does not appear to form functional heterotrimers (Zhao, 2019).This is an unusual plant-specific g subunit that contains a CBM (carbohydrate-binding module) fused to the four CBS motifs found in other AMPK-g subunits.dThis is probably a non-functional protein (Moreau et al., 2012).