Mammalian Target of Rapamycin mTOR

mTOR is a member of two distinct complexes, mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) [83, 117]. It is thought that the mTORC1 complex plays a more dominant role in tumor progression while the mTORC2 complex is more significant to mediating signals to the cytoskeleton [116] and now identified as the factor responsible for the phosphorylation of AKT at S473. This phosphorylation event maximizes the activity of AKT and opens its targets to include PRAS40 and FOXO [83]. Moreover, it is another mechanism through which to provide positive feedback on the PI3K pathway [86,113].

The mTORC1 pathway is a central point of signal integration for growth factor signalling, energy state (AMP levels), and, nutrient and oxygen availability [118] which are fundamental for regulating tumor cell growth. The particular interest for this pathway has been largely determined by the discovery of the specific inhibitor, rapamycin, which blocks mTORC1 activity through yet unknown mechanisms. mTORC1 is comprised of Regulatory Associated Protein of TOR (RAPTOR), LST8 and PRAS40 [83]. The complex itself has many substrates, which upon its activation phosphorylates and activates S6 kinases (S6K) 1 and 2 (activation of protein translation and ribosome biogenesis), as well as inactivates 4E binding protein (4EBP) 1, 4EBP2, 4EBP3, which releases the inhibition of eukaryotic intiation factor 4E (eIF4E). mTOR dependent protein synthesis affects 5' untranslated polypyrimidine tracts of complex secondary mRNA structures. Such mRNA structures require eIF4A helicase activity together with eukaryotic initiation factors eIF4E and eIF4G to from the EIF4F initation complex. Altogether, the main effect is to upregulated protein synthesis.

Although the PI3K/AKT pathway serves to activate the mTORC1 pathway, mTORC1 itself negatively regulated the PI3K pathway. Over the years, studies have shown that mTORC1 inhibition can lead to PI3K activation. Moreover, mTOR activity can be suppressed by PI3K inhibitors such as wortmannin and LY294002 [87]. However, it is unclear whether the mechanism of activation of mTOR by AKT can completely drive tumorigenesis. As rapamycin can inhibit AKT dependent cancers, it is presumed that in some part mTORC1 does have tumori-genic effects. Although there is correlation between increased translation and tumorigeneisis, whether this is sufficient for increased cancer susceptibility is yet to be determined.

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