Figure 1. The PI 3-K/Akt/mTOR signaling cascade.

Growth factors can activate mTOR signaling through phosphoinositide 3 kinase (PI 3-K) and Akt mediated pathways. Growth factors can stimulate PI 3-K activation and promote the production of phosphatidylinositide (3,4)-biphosphate (PI-3, 4-P₂) and phosphatidylinositide (3,4,5)-triphosphate (PI-3, 4, 5-P₃) resulting in the recruitment of Akt to the plasma membrane and subsequent activation by phosphoinositide dependent kinase 1 (PDK1) and PDK2. Akt activity can be inhibited by several entities that include the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) (specifically dephosphorylates PI-3, 4, 5-P₂ and PI-3, 4, 5-P₃ at the D3 position), SH2 domain-containing inositol phosphatase (SHIP), and carboxyl-terminal modulator protein (CTMP). In contrast, Akt can be activated by T cell leukemia/lymphoma 1(TCL1) and 90 kDa heat shock protein (Hsp90) which can inhibit protein phosphatase 2A (PP2A). Once active, Akt can result in the activation of mTORC1 through a series of signaling pathway. Akt functions as a key upstream kinase that mediates the phosphorylation of TSC2, resulting in the destabilization of TSC2 and disruption of its interaction with TSC1. Akt also may activate mTORC1 through I-kappaB kinase (IKK). IKKα regulates mTORC1 activity through associating with Raptor and IKKβ can physically interact with and phosphorylate TSC1 resulting in the suppression of TSC1 and the activation of mTORC1. In addition, Akt can directly phosphorylate proline rich Akt substrate 40 kDa (PRAS40) and reduce its binding to regulatory associated protein of mTOR (Raptor) and release mTORC1 from the suppression by PRAS40. Upon activation, mTORC1 phosphorylates its two major downstream targets p70 ribosome S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1) to promote protein synthesis, increase cell survival, and prevent autophagy. This can be reversed by rapamycin. mTORC2 activation also can occur through mTORC1. Activation of p70S6K results in the phosphorylation of Rictor and downregulation of mTORC2 activity. However, TSC1/TSC2 can activate mTORC2 but inhibit mTORC1. mTORC2 regulates actin skeleton organization, apoptosis, cell survival, and ion transport through Akt, protein kinase C alpha (PKCα), and serum- and glucocorticoid-induced protein kinase 1 (SGK1).