mammalian target of rapamycin
FRAP, RAFT1
ラパマイシンの細胞内標的タンパク質で分子量29万の巨大なセリントレオニンキナーゼである。
進化的に高度に保存されている。リボソームタンパク質のリン酸化によりタンパク質合成の制御に係わり、細胞サイズの調節をおこなっている。
ラパマイシン
rapamycin
放線菌が産生する化合物。免疫抑制作用をもつ。
Serine/threonine-protein kinase mTOR
EC=2.7.11.1
Alternative name(s):
FK506-binding protein 12-rapamycin complex-associated protein 1
FKBP12-rapamycin complex-associated protein
Mammalian target of rapamycin
Short name=mTOR
Mechanistic target of rapamycin
Rapamycin and FKBP12 target 1
Rapamycin target protein 1
Function
セリントレオニンキナーゼ活性をもつ。ホルモンや増殖因子、栄養、エネルギー、ストレスなどに反応し、細胞の代謝、成長、生存を調節する中心的な役割をもつ。
少なくとも800のタンパク質を直接、または間接的にリン酸化する。
mTOR1はmRNAの翻訳とリボソームの合成を促進することでタンパク質の合成を増加させる。
mTOR2複合体はPKCを介して細胞骨格の調節をおこなう。。
Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4. Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1.
- Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton.
- Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1.
- mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'. Ref.10 Ref.11 Ref.12 Ref.13 Ref.16 Ref.17 Ref.18 Ref.19 Ref.21 Ref.23 Ref.26 Ref.27 Ref.30 Ref.37 Ref.41 Ref.46 Ref.49 Ref.50
Catalytic activity
ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation
増殖因子、インスリンなどによるAKTを介する経路で活性化される。ラパマイシン（放線菌が産生する免疫抑制剤）によりmTORのリン酸化による経路は阻害される。
Activation of mTORC1 by growth factors such as insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase a potent activator of the protein kinase activity of mTORC1. Insulin-stimulated and amino acid-dependent phosphorylation at Ser-1261 promotes autophosphorylation and the activation of mTORC1. Activation by amino acids requires relocalization of the mTORC1 complex to lysosomes that is mediated by the Ragulator complex and the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD. On the other hand, low cellular energy levels can inhibit mTORC1 through activation of PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent mechanism which may also require PRKAA1. The kinase activity of MTOR within the mTORC1 complex is positively regulated by MLST8 and negatively regulated by DEPTOR and AKT1S1. MTOR phosphorylates RPTOR which in turn inhibits mTORC1. MTOR is the target of the immunosuppressive and anti-cancer drug rapamycin which acts in complex with FKBP1A/FKBP12, and specifically inhibits its kinase activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. It may be regulated by RHEB but in an indirect manner through the PI3K signaling pathway. Ref.16 Ref.19 Ref.25 Ref.30 Ref.31
Subunit structure
Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. The mTORC1 complex is a 1 Md obligate dimer of two stoichiometric heterotetramers with overall dimensions of 290 A x 210 A x 135 A. It has a rhomboid shape and a central cavity, the dimeric interfaces are formed by interlocking interactions between the two MTOR and the two RPTOR subunits. the MLST8 subunits forms distal foot-like protuberances, and contacts only one MTOR within the complex, while the small PRAS40 localizes to the midsection of the central core, in close proximity to RPTOR. Part of the mammalian target of rapamycin COmplex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Interacts with PPAPDC3 and PML. Interacts with PRR5 and RICTOR; the interaction is direct within the mTORC2 complex. Interacts with UBQLN1. Interacts with TTI1 and TELO2. Interacts with CLIP1; phosphorylates and regulates CLIP1. Interacts with NBN. Ref.9 Ref.10 Ref.11 Ref.12 Ref.14 Ref.17 Ref.18 Ref.21 Ref.24 Ref.25 Ref.26 Ref.31 Ref.38 Ref.39 Ref.40 Ref.48 Ref.54 Ref.55
Subcellular location
Endoplasmic reticulum membrane; Peripheral membrane protein; Cytoplasmic side. Golgi apparatus membrane; Peripheral membrane protein; Cytoplasmic side. Mitochondrion outer membrane; Peripheral membrane protein; Cytoplasmic side. Lysosome. Cytoplasm By similarity. Nucleus › PML body By similarity. Note: Shuttles between cytoplasm and nucleus. Accumulates in the nucleus in response to hypoxia By similarity. Targeting to lysosomes depends on amino acid availability and RRAGA and RRAGB. Ref.8 Ref.15 Ref.20 Ref.30 Ref.36
Tissue specificity
Expressed in numerous tissues, with highest levels in testis. Ref.7 Ref.14
Domain
The kinase domain (PI3K/PI4K) is intrinsically active but has a highly restricted catalytic center (Ref.55). Ref.55
The FAT domain forms three discontinuous subdomains of alpha-helical TPR repeats plus a single subdomain of HEAT repeats. The four domains pack sequentially to form a C-shaped a-solenoid that clamps onto the kinase domain (Ref.55). Ref.55
Post-translational modification
Autophosphorylates when part of mTORC1 or mTORC2. Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation. Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and PRAS40 and leads to increased intrinsic mTORC1 kinase activity.
