Editorial (Hot Topic: Inhibition of PI3K/Akt/mTOR Signaling by Natural Products)

Mammalian target of rapamycin (mTOR) lies downstream of the type I insulin-like growth factor receptor (IGFR), a transmembrane tyrosine kinase In response to ligand binding, IGFR is activated via autophosphorylation of multiple tyrosine residues. Activated IGFR in turn phosphorylates the insulin receptor substrates 1-4 (IRS1-4) and src-and collagen-homology (SHC) adaptor proteins, which can trigger multiple downstream signal transduction pathways including PI3K pathway Phosphorylated IRS recruits the p85 subunit of PI3K and signals to the p110 catalytic subunit of PI3K, resulting in activation of PI3K. Activated PI3K catalyzes the conversion of phosphatidylinositol (4,5)-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3) This pathway is negatively regulated by PTEN (phosphatase and tensin homolog on chromosome ten), a dualspecificity protein and lipid phosphatase. Increased PIP3 binds to the pleckstrin homology (PH) domain of Akt and, in combination with additional Ser/Thr phosphorylation of Akt by phosphoinositide-dependent kinase 1 (PDK1) and mTOR complex 2 (mTORC2), results in full activation of Akt Subsequently, activated PI3K or Akt may positively regulate mTOR, leading to increased phosphorylation of ribosomal p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), the two bestcharacterized downstream effector molecules of mTOR Studies have placed tuberous sclerosis complex (TSC) 1/2 as a modulator between PI3K/Akt and mTOR The TSC1/2 complex acts as a repressor of mTOR function TSC2 has GTPase-activating protein (GAP) activity towards the Ras family small GTPase Rheb (Ras homolog enriched in brain), and TSC1/2 antagonizes the mTOR signaling pathway via stimulation of GTP