23.5: PI3K/mTOR/AKT Signaling Pathway
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a rapamycin-insensitive companion called Rictor, mammalian stress-activated protein map kinase-interacting protein 1 (mSin1 or MAPKAP1). Mammalian lethal with SEC13 protein 8 (mLST8) is a common protein of both complexes.
The binding of insulin to the insulin receptor, an RTK, initiates the mTOR pathway. The activated receptors auto-phosphorylate tyrosine 960 on its cytoplasmic domain. The phosphorylated tyrosine forms a docking site for the insulin receptor substrate (IRS) that binds the receptor via their phospho-tyrosine binding (PTB) domain. In addition, IRS contains a PH domain that helps them bind phosphoinositides on the plasma membrane. At least four types of IRS (IRS-1 to 4) assist in insulin receptor signaling. Once bound to the receptor, multiple tyrosines on the IRS are phosphorylated, which recruits the SH2 domain-containing phosphatidylinositol-3-kinase or PI-3K to the cytosolic surface of the plasma membrane. The PI-3K binds to the phosphatidylinositol (4,5)-bisphosphate (PIP2) and produces phosphatidylinositol (3,4,5)-trisphosphate or PIP3. Adjacent PIP3 functions as docking sites for protein kinase B (PKB) or AKT and 3-phosphoinositide-dependent kinase 1 or PDK1. As mTORC2 phosphorylates AKT at serine 473, it undergoes a conformational change and exposes a threonine 308 residue, which subsequently leads to phosphorylation of the AKT by PDK1.
Activated AKT dissociates from the membrane to phosphorylate a series of downstream targets to promote cell growth, proliferation, and other responses. For example, the forkhead transcription factor, FOXO3a, is a transcription factor that activates the transcription of pro-apoptotic proteins. Phosphorylation of FOXO3a by AKT induces its binding to 14-3-3 protein and its subsequent sequestration in the cytosol, thereby promoting cell survival. Activated Akt also inhibits tuberous sclerosis protein 2 or Tsc 2 and promotes Rheb activation. Activated Rheb (Rheb-GTP) further stimulates mTORC1 and induces cell growth.