Phosphoinositide 3-kinase-AKT signaling pathway (PI3K-AKT pathway)

The Phosphoinositide 3-kinase-AKT (PI3K-AKT) signaling pathway is a primary intracellular transduction system that coordinates cell growth, proliferation, survival, and metabolic processes (StatPearls, 2023). It is typically activated by extracellular growth factors or cytokines that bind to receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs), stimulating PI3K to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 then recruits the serine/threonine kinase AKT to the plasma membrane for activation, which subsequently regulates multiple downstream effectors including mTOR and GSK3 (UniProt, P31749). Hyperactivation of this pathway is one of the most common occurrences in human malignancies, often driven by PIK3CA mutations, AKT mutations, or the loss of the tumor suppressor PTEN (PubMed, PMC4932314). Because of its central role in oncogenesis, multiple components of the pathway are therapeutic targets, with several PI3K and mTOR inhibitors currently approved for clinical use in oncology and immunology (NIH, 2023). However, targeting this pathway presents significant challenges, including the management of metabolic side effects like hyperglycemia and the emergence of resistance through feedback loops (PubMed, PMC6054738).

Other names

PI3K/AKT/mTOR pathwayPI3K signaling axisAKT signaling pathwayPhosphoinositide 3-kinase signaling pathway

Inhibition of phosphoinositide 3-kinase (PI3K) isoforms (alpha, beta, delta, or gamma), inhibition of the serine/threonine kinase AKT (Protein Kinase B), or inhibition of the downstream mechanistic target of rapamycin (mTOR) to block signal transduction through the PI3K-AKT axis.