Fig. 1 |. The PI3K pathway in non-malignant cells and cancer.

a | Insulin and other growth factors stimulate receptor tyrosine kinases (RTKs), leading to transautophosphorylation at C-terminal domain tyrosine residues. These phosphotyrosines bind to SH2 domains in the regulatory p85α subunit of phosphatidylinositol 3-kinase-α (PI3Kα), activating the enzymatic p110α subunit and thus PI3Kα activity, catalysing the production of phosphatidylinositol 3,4,5-trisphosphate (PIP₃) from phosphatidylinositol 4,5-bisphosphate (PIP₂) in the inner layer of the cell membrane. The lipid phosphatase PTEN can reverse this process. PIP₃ recruits the serine/threonine kinases PDPK1 and AKT to the plasma membrane. Subsequently, PDPK1 and the mTOR complex 2 (mTORC2) phosphorylate AKT at T308 and S473, respectively. AKT then phosphorylates a host of cellular substrates, including tuberin (also known as TSC2), thus inactivating the TSC complex; suppression of the GTPase-activating protein activity of the TSC complex results in the activation of the GTPase RHEB, which in turn activates mTOR complex 1 (mTORC1), which drives numerous necessary processes in normal physiology and cancer. AKT also regulates cellular processes through various targets other than TSC2. b | Structural depiction of the oncogenic activating p110α E545K and H1047R mutations in the crystal structure of PI3Kα (PDB 4OVU)¹³. E545K is located at the p110α–p85α binding interface, and H1047R is located in the membrane-binding region. c | In cancer, PI3Kα is often activated through RTK phosphopeptide binding to p85α, p110α mutation or RAS stimulation of p110α. iSH2, inter Src homology 2 domain; niSH2, N-terminal and inter Src homology domains; nSH2, N-terminal Src homology 2 domain.