PI3KAkt

PI3KAKT, commonly referred to as the PI3K–AKT signaling pathway, is a conserved intracellular signaling cascade that regulates cell survival, growth, metabolism, and proliferation. It is initiated when extracellular signals activate phosphoinositide 3-kinase (PI3K), a lipid kinase that phosphorylates PIP2 to generate PIP3 at the inner cell membrane. PIP3 serves as a docking site for proteins with PH domains, including AKT (also known as protein kinase B) and PDK1. Recruited AKT is phosphorylated at Thr308 by PDK1 and at Ser473 by mTORC2, leading to full activation.

Activated AKT phosphorylates a range of substrates involved in metabolism (e.g., TSC2, GSK3, FOXO transcription factors), cell survival (BAD), and growth via mTORC1 signaling through TSC1/2 and Rheb. PTEN (phosphatase and tensin homolog) antagonizes the pathway by dephosphorylating PIP3 to PIP2, thereby attenuating AKT activation. Growth factor receptors, including receptor tyrosine kinases (RTKs) and G-protein coupled receptors (GPCRs), initiate the cascade through adaptor proteins that recruit PI3K to the membrane. The pathway integrates signals from nutrients, energy status, and growth cues and is tightly regulated by feedback mechanisms.

Dysregulation of PI3K–AKT signaling is common in human cancer and other diseases. Mutations in PIK3CA, AKT isoforms, or loss of PTEN lead to constitutive activation, promoting cell survival and tumor growth. Therapeutic approaches include PI3K inhibitors, AKT inhibitors, and mTOR inhibitors, though clinical use is limited by toxicity and feedback activation.