mTOR Pathway
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mTOR Pathway

Most organisms have evolved mechanisms for efficiently transitioning between anabolic and catabolic states, allowing them to survive and grow in environments in which nutrient availability is variable. In mammals, an example of such a mechanism is the signaling network anchored by the protein kinase mTOR (originally mammalian TOR , but now officially mechanistic TOR ). mTOR nucleates at least two distinct multi-protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 has five components: mTOR, which is the catalytic subunit of the complex; regulatory-associated protein of mTOR (Raptor); mammalian lethal with Sec13 protein 8 (mLST8, also known as GbetaL); proline-rich AKT substrate 40 kDa (PRAS40); and DEP-domain-containing mTOR-interacting protein (Deptor). mTORC2 comprises six different proteins, several of which are common to mTORC1 and mTORC2: mTOR; rapamycin-insensitive companion of mTOR (Rictor); mammalian stress-activated protein kinase interacting protein (mSIN1); protein observed with Rictor-1 (Protor-1); mLST8; and Deptor (Ref.1 and 2).

A principal pathway that signals through mTOR is the PI3K/Akt signal transduction pathway, which is critically involved in the mediation of cell survival and proliferation.PI3K/Akt pathway can also be activated by Insulin via IRS1/2. PI3K binds phosphorylated IRS to get activated. PI3K then catalyzes the conversion of membrane-bound PIP2 to PIP3. PIP3 then binds and phosphorylate Akt. Akt phosphorylates mTOR directly. Akt may also work indirectly on mTOR through the actions of the TSC1/TSC2. AMPK can also modulate mTOR (Ref.3, 4 and 6).

PA (Phosphatidic Acid) can also activate mTOR. Three different enzymes generate PA: PLD (Phospholipase-D), LPAAT (Lysophosphatidic Acid Acyltransferase), and DGK (Diacylglycerol Kinase). Serum stimulation leads to PLD activation, which correlates with increased mTOR signaling. Lipids such as DAG (Diacylglycerol) and PA are generated in membrane domains, where an intimate connection between distinct lipid metabolic pathways is maintained, to produce appropriate spatio-temporal responses. This PA can serve either as a messenger, promoting vesicle fission, or as a substrate for Phosphatases that transform PA to DAG. Two stress-induced proteins, RTP801/Redd1 and RTP801L /Redd2, potently inhibit signaling through mTOR. RTP801 and RTP801L work downstream of AKT and upstream of TSC2 to inhibit mTOR functions. Another inhibitor of mTOR is Rapamycin. When complexed with its cellular receptor, FKBP12 (FK506 Binding Protein-12), Rapamycin binds directly to TOR to inhibit downstream signaling (Ref. 5, 7 and 8).

Activated mTOR mediates the phosphorylation of the eIF4EBP1and the ribosomal protein p70S6K or S6K1. 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 adenosine triphosphate dependent RNA helicase eIF4A, and eIF4B, to form an active complex. This complex facilitates cap-dependent protein translation. Such mRNAs include those that code for c-Myc, CcnD1 (Cyclin-D1), and Ornithine Decarboxylase. Cyclin-D1 binds with CDK4 to form a complex required for the phosphorylation of Rb protein, which subsequently contributes to progression of the cell cycle and DNA replication. mTOR may also indirectly influence the phosphorylation state of 4EBP1 by modulating the activity of PP2A. The second principal effector downstream of mTOR is the S6K1 serine/threonine kinase. After receiving a proliferative upstream signal mediated by the PI3K/Akt pathway, mTOR phosphorylates and activates S6K1. In turn, S6K1 phosphorylates and activates the 40S ribosomal S6 protein, facilitating the recruitment of the 40S ribosomal subunit into actively translating polysomes (Ref.9, 10 and 11). mTOR also modulates protein synthesis through regulation of RNA Polymerase I and RNA Polymerase III , which are responsible for the transcription of ribosomal and transfer RNAs. mTORC2 may signal to the actin cytoskeleton through a small Rho-type GTPase and PKC. Furthermore, mTORC2 also controls the phosphorylation and activation of PKC-Alpha. mTOR acts as a central modulator of proliferative signal transduction is an ideal therapeutic target against cancer(Ref.10 and 12).