Structural and mechanistic basis of mTORC2 activation of protein kinase AKT/PKB

The PI3K/AKT/mTOR signaling pathway is crucial for regulating essential cellular processes such as growth, survival, metabolism, and protein synthesis. Dysregulation of this pathway is strongly associated with diseases like cancer, where it drives uncontrolled cell proliferation and survival. The mTOR kinase forms two multiprotein complexes, mTORC1 and mTORC2, which govern distinct signaling pathways. mTORC1, regulated by nutrients, controls protein synthesis, cell growth, and autophagy, while mTORC2 acts as a central node in phosphoinositide 3-kinase (PI3K) and Ras signaling, often disrupted in cancer and diabetes. AKT, recruited by PIP3 to the plasma membrane, is phosphorylated by PDK1 and mTORC2, enabling it to regulate various cellular functions. Notably, mTORC2 selectively phosphorylates AKT and PKC but no other closely related kinases targeted by mTORC1, reflecting a high degree of substrate specificity. This specificity is due to structural elements in AKT that interact with the mTORC2 subunit mSin1 as revealed by recent studies using semisynthetic probes, paving the way for the design of mTORC2-specific inhibitors. Given the pathway's significant role in disease progression, particularly cancer, targeting the AKT/mTOR axis holds considerable therapeutic promise. However, challenges remain due to the complex regulation and feedback mechanisms in this pathway. Emerging combination therapies show promise in overcoming these obstacles. This review highlights the intricate regulation of the AKT/mTOR pathway and its potential for developing targeted therapies.