mTOR Signaling

A principal pathway that signals through mTOR is the PI3K/AKT signal transduction pathway which is involved in cell survival and proliferation. The signal from activated receptors is transferred directly to the PI3K/AKT pathway or alternatively, through activated growth factor receptors that signal through oncogenic Ras, which is a pivotal activator of the MAPK pathway. PI3K/AKT pathway can also be activated by insulin via IRS1/2. The p85 regulatory subunit of PI3K binds phosphorylated IRS, which then activates the p110 catalytic subunit. PI3K activates PDK1 which in turn phosphorylates and activates AKT. AKT phosphorylates mTOR directly or indirectly through the action of TSC1/TSC2. The inhibitory effect of TSC1/TSC2 is mediated through TSC2 inactivation of RHEB. RHEB-GTP activates mTOR. PMA can also lead to mTOR phosphorylation independently of AKT through inhibition of the TSC1/2 complex as well as through activation of S6K1 by PKC.AMPK and phosphatidic acid modulate mTOR. Three different enzymes generate phosphatidic acid (PA): PLD, LPAAT and DGK. Serum stimulation leads to PLD activation, which correlates with increased mTOR signaling. Serum acts through GPCRs or RTKs. PLD and DGK may operate in parallel pathways but they may also act as diacylglycerol and PA-generating enzymes in a single pathway. PA is also produced by PLD action on phosphatidylcholine. Two stress-induced proteins, Redd1 and Redd2, potently inhibit signaling through mTOR. Another inhibitor of mTOR is rapamycin. When complexed with its cellular receptor, FKBP12, rapamycin binds directly to mTOR to inhibit downstream signaling.mTOR activation results in phosphorylation of several downstream targets. For mTOR to activate its signaling cascade, it must form one of 2 ternary complexes, mTOR complex-1 (mTORC1) or mTOR complex-2 (mTORC2). mTORC1 contains mTOR, RAPTOR and G-βL, while the mTORC2 complex consists of mTOR, G-βL and Rictor. Activated mTOR mediates the phosphorylation of eIF4EBP1 and the ribosomal protein p70S6K or S6K1. 4EBP1 can repress the activity of the eIF4F complex. In its unphosphorylated state, 4EBP1/PHAS1 binds tightly to eIF4E, the mRNA cap binding subunit of the eIF4F complex, which inhibits the activity of eIF4E in the initiation of protein synthesis. Phosphorylation of 4EBP1 by mTOR reduces its affinity for eIF4E and the 2 proteins dissociate. eIF4E is then able to associate with the other components of eIF4F, which include the large scaffolding protein eIF4G, the RNA helicase eIF4A, and eIF4B. This complex facilitates cap-dependent protein translation. Inhibition of mTOR results in the dephosphorylation of 4EBP1, followed by its reassociation with eIF4E and a subsequent reduction in cap-specific translation. mTOR may indirectly influence the phosphorylation state of 4EBP1 by modulating the activity of PP2A. mTOR also activates S6K1, which phosphorylates and activates the 40S ribosomal S6 protein, facilitating the recruitment of the 40S ribosomal subunit into actively translating polysomes. mTORC1 also regulates VEGF by phosphorylating HIF1α. mTORC2 controls the formation of activated, GTP-bound Rac1 and activation of PKC-α. As a central modulator of proliferative signal transduction, mTOR is an ideal therapeutic target against cancer.