Mammalian target of rapamycin

The mammalian target of rapamycin, commonly known as mTOR, is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription.^[1][2]

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Function

  Current research indicates that mTOR integrates the input from multiple upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and mitogens.^[1] mTOR also functions as a sensor of cellular nutrient and energy levels and redox status.^[3] The dysregulation of the mTOR pathway is implicated as a contributing factor to various human disease processes, especially various types of cancer.^[2] Rapamycin is a bacterial natural product that can inhibit mTOR through association with its intracellular receptor FKBP12.^[4][5] The FKBP12-rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR.^[5]

mTOR has been shown to function as the catalytic subunit of two distinct molecular complexes in cells.^[6]

Complexes

mTORC1

mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory associated protein of mTOR (Raptor), and mammalian LST8/G-protein β-subunit like protein (mLST8/GβL).^[7][8] This complex possesses the classic features of mTOR by functioning as a nutrient/energy/redox sensor and controlling protein synthesis.^[7][1] The activity of this complex is stimulated by insulin, growth factors, serum, phosphatidic acid, amino acids (particularly leucine), and oxidative stress.^[7][9]

mTORC1 is inhibited by low nutrient levels, growth factor deprivation, reductive stress, caffeine, rapamycin, farnesylthiosalicylic acid (FTS) and curcumin.^[7][10][2] The two best characterized targets of mTORC1 are p70-S6 Kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1).^[1]

mTORC1 phosphorylates S6K1 on at least two residues, with the most critical modification occurring on threonine389.^[11][12] This event stimulates the subsequent phosphorylation of S6K1 by PDK1.^[12][13] Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the ribosome) and other components of the translational machinery.^[14] S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at threonine2446 and serine2448; events which appear to be stimulatory in regards to mTOR activity.^[15][16]

mTORC1 has been shown to phosphorylate at least four residues of 4E-BP1 in a hierarchical manner.^[17][4][18] Non-phosphorylated 4E-BP1 binds tightly to the translation initiation factor eIF4E, preventing it from binding to 5'-capped mRNAs and recruiting them to the ribosomal initiation complex.^[19] Upon phosphorylation by mTORC1, 4E-BP1 releases eIF4E, allowing it to perform its function.^[19] The activity of mTORC1 appears to be regulated through a dynamic interaction between mTOR and Raptor, one which is mediated by GβL.^[7][8] Raptor and mTOR share a strong N-terminal interaction and a weaker C-terminal interaction near mTOR's kinase domain.^[7] When stimulatory signals are sensed, such as high nutrient/energy levels, the mTOR-Raptor C-terminal interaction is weakened and possibly completely lost, allowing mTOR kinase activity to be turned on. When stimulatory signals are withdrawn, such as low nutrient levels, the mTOR-Raptor C-terminal interaction is strengthened, essentially shutting off kinase function of mTOR .^[7]

mTORC2

mTOR Complex 2 (mTORC2) is composed of mTOR, rapamycin-insensitive companion of mTOR (Rictor), GβL, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1).^[20][21] mTORC2 has been shown to function as an important regulator of the cytoskeleton through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C α (PKCα).^[21] However, unexpectedly mTORC2 also functions as the elusive "PDK2." mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at serine473, an event which stimulates Akt phosphorylation at threonine308 by PDK1 and leads to full Akt activation.^[22][23]

mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels.^[20] Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation.^[22] It has also been shown that curcumin can inhibit the mTORC2-mediated phosphorylation of Akt/PKB at serine473, with subsequent loss of PDK1-mediated phosphorylation at threonine308.^[2]

mTOR inhibitors as therapies

mTOR inhibitors are already used in the treatment of transplant rejection . They are also beginning to be used in the treatment of cancer.^[24]

References

Further reading