PI3K/AKT1/MTOR Signaling

The phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (MTOR) cell signaling pathway functions in cell growth and proliferation, protein translation and synthesis, and the regulation of apoptosis. The PI3K pathway may be activated by the binding of extracellular growth factors (e.g., insulin-like growth factor 1, IGF1) to their corresponding receptor tyrosine kinases or by activating mutations in PIK3CA, AKT1, TSC1, or other genes. The pathway is inhibited by phosphatase and tensin homolog (PTEN), which dephosphorylates phosphoinositide phosphates.

PI3K_mTOR

Figure 1. Binding of a growth factor (e.g., EGF, HGF) to a receptor tyrosine kinase (RTK) activates the receptor. Insulin receptor substrate-1 (IRS-1) or an analogous adapter protein binds to the receptor tyrosine kinase. Phosphoinositide 3-kinase (PI3K) is composed of two subunits: p85 and p110. PI3K binds to IRS-1 and activates the enzymatic activity of the p110 subunit. Active PI3K binds to phosphatidylinositol 4, 5-bisphosphate (PIP2) in the cell membrane. PI3K initiates transphosphorylation from PIP2 to create PIP3. Phosphorylated PIP3 or PDK1 activate AKT1. The activation of AKT1 triggers downstream activation of protein complexes mTORC1 and mTORC2 complexes that activate gene transcription and promote cell growth and survival. Specific nodes in the pathway that are therapeutically actionable are noted. Click here to open a larger version of this image in a new window.

Upstream Pathways

Downstream Pathways

Diseases in Which Pathway is Aberrantly Activated

Therapies That Target This Pathway

  • Allosteric mTORC1 inhibitors
  • mTORC1/2 catalytic inhibitors

Genes Involved in the Pathway

Last Updated: November 28, 2016

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