Fig. 1

Model of the PI3K/AKT/mTOR pathway, showing the targets of pathway inhibitors. Type I PI3Ks are activated by binding via their regulatory subunits, the tyrosine phosphorylation sites of activated tyrosine kinase and other receptors in the plasma membrane. Activated PI3K catalyzes the phosphorylation of PIP2 (PI-(4,5)-P2) in the D3 position of the inositol ring to form PIP3 (PI-(3,4,5)-P3). The three AKT isoforms (AKT1, AKT2, and AKT3) translocate to the membrane by binding PIP3, where they undergo phosphorylation in the activation loop by PDK1 and in the C-terminal hydrophobic motif by mTORC2. Following this, activated AKT isoforms regulate mTORC1 and its downstream targets by multiple mechanisms. The activation of the pathway is reversed by multiple mechanisms. Prominent among these mechanisms is the removal of the D3 phosphate from the inositol ring of PIP3 by the lipid phosphatase PTEN. The targets of inhibitors of the pathway are also shown