![]() We will refer to this catalytic core as the FAT plus KINase domain (FATKIN). PIKKs share a catalytic core consisting of a kinase domain flanked by a helical FAT domain (named after FKBP12 Rapamycin Associated Protein (FRAP)–ATM–TRRAP) at the N-terminus and a short FAT-C domain at its C-terminus 36. MTOR is a member of the phosphoinositide 3-kinase related kinases (PIKKs), which also include Ataxia telangiectasia mutated (ATM), ATR (ATM related), Suppressor of morphogenesis in genitalia-1 (SMG-1), Transformation/Transcription Domain-Associated Protein (TRRAP) and DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) 35. Tor signalling motifs are present in these substrates and are recognized by the RAPTOR subunit 34. Through these substrates, mTORC1 controls cap-dependent translation initiation and elongation 33. The best-characterized substrates of mTORC1 are eIF4E-binding protein (4E-BP1) and ribosomal S6 kinase (S6K) 32. ![]() The prominent role of mTORC1 in the PI3K pathway has led to widespread efforts to develop mTOR inhibitors that could act as anti-cancer therapeutics 31. The activity of TORC1 is regulated by direct interaction with small GTPases, such as Gtr1/Gtr2 (Rag heterodimers in mammals) that regulate Tor localization and activity 26, 27, 28, 29, 30. Lst8 is a requisite component for both TORC1 and TORC2 (refs 15, 22, 25). The core subunits of the TORC2 complex are Tor2 (mTOR in mammals), Lst8 (mLST8 in mammals), Avo1 (mSin1 in mammals) and Avo3 (RICTOR in mammals) 12, 13, 21, 23, 24. The TORC1 complex consists of three core subunits: the catalytic subunit, Tor1 or Tor2 in yeast (mTOR in mammals), Lst8 (mLST8) and Kog1 (RAPTOR in mammals) 11, 14, 15, 21, 22. TORC2 regulates lipid metabolism, actin cytoskeleton and the survival of DNA damage 4, 16, 19, 20. The TORC1 complex is activated by amino acids 18 and in mammalian cells also by growth factors, insulin, energy levels and oxidative stress 2. ![]() TORC1 controls cell size/volume by regulating protein translation, ribosome biogenesis and autophagy 2, 16, 17. Both Tor and mTOR occur in two complexes known as TORC1 and TORC2 (refs 11, 12, 13, 14, 15). While some yeast species such as Saccharomyces cerevisiae have two genes that encode Tor1 and Tor2 proteins 5, 6, 7, 8, mammalian cells have a single gene encoding mTOR 9, 10. The Ser/Thr protein kinase Tor is a hub for cellular homeostatic regulation 1, 2, 3, 4. ![]()
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