PI3K/AKT pathway

The PI3K/AKT pathway is a central intracellular signalling axis activated by receptor tyrosine kinases (including the insulin and IGF-1 receptors), G-protein-coupled receptors, and other stimuli. Phosphoinositide 3-kinase (PI3K) phosphorylates PIP2 to generate PIP3 at the plasma membrane, recruiting AKT (also called protein kinase B) and its activating kinase PDK1; AKT is further activated by mTORC2-mediated phosphorylation at Ser473. Activated AKT phosphorylates a broad set of substrates — including FOXO transcription factors (promoting their nuclear exclusion), GSK-3β (suppressing glycogen synthesis inhibition), BAD (promoting survival), and TSC2 (activating mTORC1) — thereby coordinating cell survival, glucose metabolism, protein synthesis, and proliferation. The tumour suppressor PTEN counteracts PI3K by dephosphorylating PIP3. Reduced PI3K/AKT activity in C. elegans and other organisms extends lifespan through FOXO activation, but in humans the pathway is hyperactivated in many cancers and in insulin-resistant states, representing a complex, context-dependent role in ageing.