Fig. 1.

Biochemical mechanism of PI3K, PTEN and AKT regulation. A Mechanism of PI3K, PTEN and AKT regulation in normal cells. Induction of RTK or GPCR results in the activation of Ras-regulated PI3K, which interacts with PIP2, and produces PIP3 at the plasma membrane. Inactive AKT in the cytoplasmic matrix is recruited to cell membrane and binds PIP3 through a PH binding domain. This drives phosphorylation of T308 by PDK1, and phosphorylation of S473 by mTORC2, leading to complete activation of AKT (above). Signal termination is determined by loss of PI3K-PIP2 interaction, via inhibition by (PIP3) PTEN protein phosphatase, (AKT) PP2A protein phosphatase, and (AKT) PHLPP protein phosphatase, leading to AKT detaching from the cell membrane. Due to DNA damage response, p53 activates PTEN, whose function reduces PAM-induced cell proliferation (middle). AKT then shifts to off-mode in the cytoplasm (below). B Mechanism of PI3K, PTEN and AKT regulation in cancer cells. Mutations in RTK, Ras, PI3K, AKT (above), PTEN protein phosphatase, p53, (AKT) PP2A protein phosphatases and (AKT) PHLPP protein phosphatases may occur, resulting in AKT retention to cell membrane (middle). AKT then remains in on-mode in the cytoplasm (below), leading to dysregulation of PAM pathway signal transduction, and possibly cancer onset and/or progression (below). Activation (phosphorylation or non-phosphorylation) is shown with arrowhead lines, whereas dephosphorylation is indicated with roundhead lines. Red lightning symbol shows mutation for a particular gene in the PAM pathway. Red crosses emphasise signaling blockage. P: phosphoryl group