PI3KAktmTOR

PI3K-AKT-mTOR signaling, also known as the PI3K/AKT/mTOR pathway, is a conserved network that transduces extracellular signals such as growth factors and insulin into cellular responses that regulate metabolism, growth, and survival. Activation begins at receptor tyrosine kinases or GPCRs, which stimulate class I PI3K to convert PIP2 to PIP3 at the inner plasma membrane. PIP3 recruits AKT and PDK1 via their PH domains; AKT is activated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2. PTEN acts as a counterbalance by dephosphorylating PIP3 to PIP2, thereby inhibiting signaling.

AKT activation leads to regulation of multiple downstream effectors including mTOR; mTOR functions in two complexes: mTORC1 and mTORC2. mTORC1 promotes protein synthesis and growth by phosphorylating S6K1 and 4E-BP1, and is inhibited by rapamycin. It is regulated by TSC1/2 via Rheb. AKT inhibits TSC2, thereby activating mTORC1. mTORC2 phosphorylates AKT at Ser473, completing activation, and also modulates cytoskeletal organization.

Physiological roles include control of cell growth, metabolism, autophagy, and survival. Dysregulation of PI3K-AKT-mTOR signaling is common in cancer, diabetes, and neurodegenerative diseases. Therapeutic approaches target different nodes: PI3K inhibitors, AKT inhibitors, and mTOR inhibitors (rapalogs such as everolimus, temsirolimus; and ATP-competitive mTOR inhibitors). Feedback mechanisms and cross-talk with other pathways can influence responses.