Protein kinase B-mechanistic target of rapamycin-ribosomal protein S6 kinase signaling pathway (Akt-mTOR-S6K pathway) (Akt-mTOR-S6K)

The Akt-mTOR-S6K pathway is a central intracellular signaling cascade that regulates critical cellular processes including growth, proliferation, survival, and metabolism [1, 14]. It is primarily activated by growth factors and nutrients, which trigger the activation of Akt (Protein Kinase B) [5, 8]. Akt then phosphorylates and inhibits the TSC1/2 complex, relieving the suppression of Rheb and leading to the activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) [7, 13]. Activated mTORC1 subsequently phosphorylates downstream effectors such as Ribosomal Protein S6 Kinase (S6K) and 4E-BP1 to promote protein synthesis and cell cycle progression [1, 11]. Dysregulation of this pathway, often through mutations in PI3K, Akt, or loss of the tumor suppressor PTEN, is a hallmark of many human cancers and contributes to metabolic and neurodegenerative disorders [2, 9]. Therapeutic strategies targeting this axis include mTOR inhibitors (rapalogs), Akt inhibitors, and dual PI3K/mTOR inhibitors, which aim to arrest tumor growth and overcome drug resistance [3, 11, 16].

Other names

PI3K/Akt/mTOR pathwayAkt/mTOR axisPAM pathwayAkt/mTOR/p70S6K signaling pathwayPI3K-Akt-mTOR signaling cascade

Inhibitors of this pathway typically bind to and inhibit the kinase activity of Akt or mTOR (specifically mTORC1), which prevents the phosphorylation of downstream substrates like S6K and 4E-BP1, leading to the suppression of protein synthesis, cell cycle arrest, and induction of apoptosis.