Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling

Abstract

O-linked N-acetylglucosamine, better known as O-GlcNAc, is a sugar post-translational modification participating in a diverse range of cell functions. Disruptions in the cycling of O-GlcNAc mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively, is a driving force for aberrant cell signaling in disease pathologies, such as diabetes, obesity, Alzheimer's disease, and cancer. Production of UDP-GlcNAc, the metabolic substrate for OGT, by the Hexosamine Biosynthetic Pathway (HBP) is controlled by the input of amino acids, fats, and nucleic acids, making O-GlcNAc a key nutrient-sensor for fluctuations in these macromolecules. The mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways also participate in nutrient-sensing as a means of controlling cell activity and are significant factors in a variety of pathologies. Research into the individual nutrient-sensitivities of the HBP, AMPK, and mTOR pathways has revealed a complex regulatory dynamic, where their unique responses to macromolecule levels coordinate cell behavior. Importantly, cross-talk between these pathways fine-tunes the cellular response to nutrients. Strong evidence demonstrates that AMPK negatively regulates the mTOR pathway, but O-GlcNAcylation of AMPK lowers enzymatic activity and promotes growth. On the other hand, AMPK can phosphorylate OGT leading to changes in OGT function. Complex sets of interactions between the HBP, AMPK, and mTOR pathways integrate nutritional signals to respond to changes in the environment. In particular, examining these relationships using systems biology approaches might prove a useful method of exploring the complex nature of cell signaling. Overall, understanding the complex interactions of these nutrient pathways will provide novel mechanistic information into how nutrients influence health and disease.

Energetic adaptations: Metabolic control of endocytic membrane traffic

“…As such, care must be taken when interpreting experiments involving perturbation of AMPK or mTORC1, as the effects may be because of alteration of the other kinase. Furthermore, a number of studies show crosstalk between the nutrient sensors AMPK, mTORC1 and HBP flux . For instance, AMPK activity mediates the substrate selectivity of OGT and O‐GlcNAc modification of AMPK modulates its activity, which could thus impact endocytic traffic.…”

Human and rodent temporal lobe epilepsy is characterized by changes in O-GlcNAc homeostasis that can be reversed to dampen epileptiform activity

“…The PD field provides insights as to how mTOR O-GlcNAcylation behaves in a neurodegenerative disorder which could provide further insights as to how it could be behaving in epilepsy. In addition, mTOR phosphorylation has been previously assoicated with epilepsy, which highlights the need for further study into the role of O-GlcNAcylated mTOR in epilepsy [96][97][98][99].…”

O -GlcNAcylation on LATS2 disrupts the Hippo pathway by inhibiting its activity

“…various cellular processes, such as cell growth, mobility, metabolism, and development, by regulating protein stability, localization, activity, and protein-protein interactions (30)(31)(32)(33)(34)(35)(36). In particular, it is well known that O-GlcNAcylation regulates phosphorylationmediated signaling pathways through interplay with phosphorylation (37,38).…”