5'-AMP-activated protein kinase–mechanistic target of rapamycin signaling axis (AMPK–mTOR axis)

The 5'-AMP-activated protein kinase (AMPK)–mechanistic target of rapamycin (mTOR) signaling axis serves as the primary metabolic rheostat of the cell, balancing energy supply with demand (Hardie, 2011, PubMed: 21593404). AMPK is activated by an increased AMP:ATP ratio, signaling low energy status, whereas mTORC1 is a nutrient-sensitive kinase that promotes anabolic processes like protein and lipid synthesis (Saxton & Sabatini, 2017, PubMed: 28235197). AMPK antagonizes mTORC1 activity through the phosphorylation of the TSC2 tumor suppressor and the mTORC1 subunit Raptor, effectively halting cell growth under energy-stressed conditions (Inoki et al., 2003, PubMed: 14651849; Gwinn et al., 2008, PubMed: 18439901). This axis is frequently deregulated in human diseases; for instance, suppressed AMPK or overactive mTOR signaling is a hallmark of many cancers and metabolic syndromes (Shackelford & Shaw, 2009, PubMed: 19249085). Consequently, the axis is a high-priority therapeutic target, with drugs like metformin and rapamycin analogs being used to restore metabolic balance or inhibit proliferative signaling in oncology and gerontology (Laplante & Sabatini, 2012, PubMed: 22559948). Beyond metabolism, this signaling axis also plays a critical role in regulating autophagy, ensuring cellular survival during periods of nutrient deprivation (Kim et al., 2011, PubMed: 21258367). Therapeutic strategies targeting this axis often aim to either activate the energy-sensing capabilities of AMPK or selectively inhibit the growth-promoting functions of mTORC1.

Other names

AMPK/mTOR pathwayAMPK-mTORC1 signalingEnergy sensing pathwayAdenosine monophosphate-activated protein kinase–mammalian target of rapamycin signaling axisAMPK-mTOR signaling axis

AMPK activation leads to the inhibition of mTORC1 through the phosphorylation and activation of the TSC2 tumor suppressor and the direct inhibitory phosphorylation of the mTORC1 subunit Raptor, resulting in the suppression of protein synthesis and promotion of catabolic pathways (Gwinn et al., 2008, PubMed: 18439901; Inoki et al., 2003, PubMed: 14651849).