TOR kinase

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Review

The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. The Tor kinases play a role in nutrient sensing in yeast and mammalian cells. MTOR is a highly conserved protein kinase that is found in 2 structurally and functionally distinct protein complexes: TOR complex-1 (TORC1) and TORC2. TORC1 is a key regulator of cell growth and proliferation and mRNA translation, whereas TORC2 promotes actin cytoskeletal rearrangement, cell survival, and cell cycle progression.

TORs are high molecular-weight proteins that contain several distinct and conserved structural domains. The N terminus possesses 20 tandem HEAT (for Huntignton, EF3, A subunit of PP2A, TOR1) repeats. Each HEAT repeat consists of two α helices of ∼40 amino acids, each with a specific pattern of hydrophobic and hydrophilic residues. Tandem HEAT repeats are present in many proteins and are implicated in protein–protein interactions. The C-terminal half of mTOR contains the kinase domain, which has sequence similarity with the catalytic domain of phosphatidylinositol 3-kinase (PI3K). In addition, mTOR contains a relatively large FAT (for FRAP, ATM, TRAP) domain, which is also present in other PIKK proteins. The C-terminal end contains another FAT domain, designated FATC. The FATC domain is absolutely necessary for mTOR activity. mTOR also contains a putative negative regulatory domain (NRD) between the catalytic and FATC domains.

mTORC1 senses the energy status of a cell through AMP-activated protein kinase (AMPK). AMPK is activated in response to low cellular energy (high AMP/ATP ratio). Activated AMPK downregulates energetically demanding processes like protein synthesis and stimulates ATP-generating processes such as fatty acid oxidation. Activation of AMPK by AICAR, an AMP analog, inhibits mTORC1-dependent phosphorylation of S6K1 and 4E-BP1. Activated AMPK directly phosphorylates TSC2 and thereby enhances its GAP activity, leading to the inhibition of mTORC1 signaling. mTORC1 regulates translation via S6K1 and 4E-BP. S6K1 belongs to the AGC family of protein kinases and requires phosphorylation at two sites for its full activation, a site in a C-terminal hydrophobic motif and a site in the T loop of the kinase domain. mTORC1 mediates phosphorylation of Thr389 within the hydrophobic motif, whereas PDK1 is responsible for phosphorylation of the T loop. Activated S6K1 phosphorylates the 40S ribosomal protein S6, and this was commonly thought to lead to increased translation of a subset of mRNAs that contain a 5′ tract of oligopyrimidine (TOP). The 5′TOP mRNAs encode components of the translation apparatus, such as ribosomal proteins and elongation factors, and are predicted to account for 15%–20% of total cellular mRNA.

Partial inhibition of TOR function in yeast, worms, and flies results in a significant increase in the life span of these organisms, possibly by mimicking calorie restriction. Although links between mTOR signaling and mammalian longevity have not yet been reported, it appears that TOR signaling plays different roles in development and adulthood in metazoans. During development, TOR primarily controls growth, whereas in the adult, where there is relatively little growth, TOR controls aging and other aspects of nutrient-related physiology.