Figure 1. The PTEN-PI3K-AKT-mTOR pathway and therapeutic targets.

Activation of PI3K-AKT signaling can occur by binding of growth factors, hormones, or cytokines to receptor tyrosine kinases (RTK), leading to activation of phosphatidylinositol 3-phosphate kinase (PI3K). PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2), generating phosphatidylinositol 3,4,5-trisphosphate (PIP3), leading to the activation of AKT by phosphorylation at Thr³⁰⁸ (p-AKT). PTEN opposes the effect of PI3K by hydrolyzing PIP3 to PIP2. p-AKT deactivates glycogen synthase kinase-3 β (GSK3β), which is a negative regulator of β-catenin, and suppresses the tuberous sclerosis complex (TSC1/TSC2), a negative regulator of mTORC1. mTORC1 suppresses eukaryotic translation initiation factor 4E-binding protein (4EBP1) and activates p-S6, leading to increased protein translation. mTORC2 modulates cytoskeletal remodeling and ion channel activation and leads to phosphorylation of AKT at Ser⁴⁷³. Pharmacological treatment with LY294002 and BKM120 inhibits PI3K activity. AZD5363 inhibits AKT. Rapamycin inhibits mTORC1 activity. Abbreviations: AKT, protein kinase B; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; PTEN, phosphatase and tensin homolog; PKD1, polycystin 1; LKB1, liver kinase B1; SGK1, serum/glucocorticoid regulated kinase 1.