Adenosine monophosphate-activated protein kinase-mechanistic target of rapamycin signaling pathway (AMPK-mTOR pathway)

The Adenosine monophosphate-activated protein kinase-mechanistic target of rapamycin (AMPK-mTOR) signaling pathway is a vital metabolic rheostat that coordinates cellular energy status with growth and proliferation [Saxton & Sabatini, 2017, Cell]. AMPK serves as an intracellular energy sensor, activated during metabolic stress when ATP levels are low, whereas mTOR functions as a master regulator that promotes protein synthesis and cell growth in response to nutrient sufficiency [Hardie, 2016, Nat Rev Drug Discov]. When energy is scarce, AMPK suppresses mTOR Complex 1 (mTORC1) activity through the dual phosphorylation of the TSC2 tumor suppressor and the mTORC1 component Raptor, effectively shifting the cell from an anabolic to a catabolic state [Inoki et al., 2012, Genes Dev]. This regulatory axis is frequently compromised in human diseases, often characterized by suppressed AMPK activity and hyperactive mTOR signaling in conditions such as type 2 diabetes and various oncological malignancies [Burkewitz et al., 2014, Cell Metab]. Therapeutic modulation of the pathway is a prominent area of clinical research, utilizing AMPK activators like metformin and mTOR inhibitors like rapamycin to restore metabolic balance or inhibit tumor progression [Liu et al., 2023, Signal Transduct Target Ther].

Other names

AMPK-mTOR axisAMP-activated protein kinase-mammalian target of rapamycin signaling pathwayAMPK-mTORC1 pathwayAMPK-mTOR signaling axis

AMPK acts as a negative regulator of mTORC1 by phosphorylating and activating the TSC2 complex and directly phosphorylating the Raptor subunit of mTORC1 to inhibit downstream anabolic signaling [Inoki et al., 2012, Genes Dev]. Pharmacological agents target this axis by either activating AMPK to promote its inhibitory effect on mTOR or by directly inhibiting the mTOR kinase complex to block growth signaling [Hardie, 2016, Nat Rev Drug Discov].