PI3 K-Akt-mTOR Signaling

The PI3-K/AKT/mTOR signalling pathway plays an important role in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells. Alterations in phosphoinositide 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signaling are perhaps the most frequent events observed in solid tumors. The PI3-K/mTOR pathway can be activated by overproduction of growth factors or chemokines, loss of inositol polyphosphate 4-phosphatase type II (INPP4B) or PTEN expression, or by mutations in growth factor receptors, Ras, PTEN, or PI3-K itself. Activation of this pathway contributes to cell growth, cell cycle entry, cell survival, and cell motility, all important aspects of tumorigenesis. In this regard, rapamycin analogs have already been shown to have antitumor efficacy in some tumor types. New generation PI3-K, Akt, and mTOR inhibitors have shown significant promise preclinically and are now in clinical trials. Moreover, mTOR has been implicated in both Type 1 and Type 2 diabetes while PI3-Kinases are also key components in the insulin signaling pathway. The mTOR kinases, mTORC1 and mTORC2, have distinct functions but both are essential for viability. Briefly, PI3-K activation leads to the formation of PIP3 and the binding of both Akt and PDK1 to PIP3 (translocating them to the plasma membrane) where PDK1 partially activates Akt by phosphorylation on T308. Full activation of Akt requires its phosphorylation at S473 by the mTORC2 complex. The activated Akt disassociates the inhibitory tuberous sclerosis complex (TSC1/TSC2), allowing for Rheb (bound to GTP) activation which leads to the phosphorylation of 70S6K (S6K) and 4EBP and downstream phosphorylation of S6 and EIF-4B. The result is translational initiation, ribosome biogenesis and cell growth and proliferation. Both mTORC1 and mTORC2 respond to insulin and insulin like growth factors (IRS) via phosphorylated Akt, providing a link between mTORC1 and mTORC2 activities. Type 1 diabetes exhibits reduced insulin production due to the destruction of pancreatic -cells where mTOR affects protein translation and cell proliferation, while Type 2 diabetes arising initially from insulin resistance may be affected by phosphorylated S6-dependent inhibition of IRS1 & 2. In addition, mTOR expression is increased during adipogenesis and mTORC1 has been shown to regulate the sterol regulatory element binding protein (SREBP) which is a transcription factor that coordinates the expression of lipogenic genes. Hence, The PI3K pathway is implicated in a wide variety of human diseases including diabetes and cancer, and an understanding of the intricacies of this pathway may provide new avenues for therapeutic intervention.

PI3 K/Akt/mTOR Signaling Subcategories