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

The Liver kinase B1 (LKB1)–AMP-activated protein kinase (AMPK)–mechanistic target of rapamycin (mTOR) signaling pathway is a central metabolic checkpoint that integrates cellular energy status with growth and proliferation signals [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724988/]. LKB1 (STK11) acts as a master upstream kinase that phosphorylates and activates AMPK in response to energy stress, such as nutrient deprivation or hypoxia, which increases the intracellular AMP/ATP ratio [ResearchGate, https://www.researchgate.net/publication/388784444_The_LKB1-AMPK_signaling_pathway_A_master_regulator_of_cellular_energy_homeostasis_and_a_central_hub_in_stress_adaptation]. Activated AMPK then serves to restore energy homeostasis by inhibiting the mTORC1 complex—a key driver of protein synthesis and anabolic processes—through the phosphorylation of the TSC2 tumor suppressor and the mTORC1 subunit Raptor [Frontiers in Oncology, https://www.frontiersin.org/articles/10.3389/fonc.2021.657480/full]. This signaling axis is frequently disrupted in human pathologies; for example, loss-of-function mutations in LKB1 are the cause of Peutz-Jeghers syndrome and are prevalent in non-small cell lung cancer, leading to aberrant mTOR activation and tumorigenesis [EurekAlert, https://www.eurekalert.org/news-releases/1068954]. Therapeutic strategies targeting this pathway include the use of AMPK activators like metformin and mTOR inhibitors like rapamycin, which are being explored for their potential in treating cancer, metabolic disorders, and cardiovascular diseases. The pathway also plays a critical role in regulating cell polarity and autophagy, further emphasizing its importance in maintaining cellular integrity under metabolic stress.

Other names

LKB1-AMPK-mTOR axisSTK11-AMPK-mTOR pathwayLKB1-AMPK-mTORC1 signaling axisLKB1/AMPK/mTOR pathway

Activation of the LKB1–AMPK axis leads to the inhibition of the mTORC1 complex through the phosphorylation of TSC2 and Raptor, resulting in the suppression of protein synthesis, cell growth, and proliferation.