Liver kinase B1 (LKB1)–AMP-activated protein kinase (AMPK)–mechanistic target of rapamycin (mTOR) proliferative signaling axis (LKB1–AMPK–mTOR axis)

The Liver kinase B1 (LKB1)–AMP-activated protein kinase (AMPK)–mechanistic target of rapamycin (mTOR) proliferative signaling axis is a central regulatory pathway that couples cellular energy status to growth, metabolism, and survival [1, 3]. LKB1, a serine/threonine kinase and potent tumor suppressor, serves as the primary upstream activator of AMPK in response to metabolic stress or low ATP levels [1, 5]. Once activated, AMPK acts as a metabolic sensor that inhibits the mTOR complex 1 (mTORC1), a master regulator of protein synthesis and cell proliferation, through the activation of the TSC1/2 complex and direct phosphorylation of Raptor [1, 10]. This inhibition effectively suppresses anabolic processes while promoting catabolic pathways such as autophagy and fatty acid oxidation to restore energy homeostasis [3, 11]. Dysregulation of this axis, often through loss-of-function mutations in the STK11 (LKB1) gene or hyperactivation of mTOR, is a critical driver in various cancers, including non-small cell lung cancer and Peutz-Jeghers syndrome [2, 12]. Therapeutic strategies targeting this axis involve AMPK activators like metformin and mTOR inhibitors such as rapamycin and its analogs to restore growth control and metabolic balance [8, 13]. However, the pathway's role can be context-dependent, as LKB1-mediated metabolic adaptation may paradoxically support the survival of established tumor cells under extreme stress [1, 12]. Clinical management often utilizes LKB1 mutation status and mTOR activity markers, such as phosphorylated S6 kinase, to guide treatment decisions [11, 16].

Other names

LKB1/AMPK/mTOR pathwaySTK11-AMPK-mTOR axisLKB1-AMPK-mTORC1 signaling axisAMPK-mTOR signaling pathwayLKB1-AMPK-mTOR proliferative signaling axis

AMPK activation, mTOR inhibition, LKB1-mediated phosphorylation of downstream substrates, TSC2 activation, and Raptor inhibition.