Affinage

MTOR

Serine/threonine-protein kinase mTOR · UniProt P42345

Round 2 corrected
Length
2549 aa
Mass
288.9 kDa
Annotated
2026-04-29
130 papers in source corpus 31 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

mTOR is a conserved serine/threonine kinase that serves as a central integrator of nutrient, energy, and growth factor signals to coordinate cell growth, proliferation, metabolism, and autophagy. It nucleates two structurally and functionally distinct complexes: mTORC1 (with raptor and mLST8), which is recruited to the lysosomal surface by the Rag GTPase–Ragulator machinery in response to amino acids and activated by Rheb-GTP downstream of the Akt–TSC1/TSC2 axis, phosphorylating S6K1, 4E-BP1, ULK1, TFEB, and SREBP to promote protein and lipid synthesis while suppressing autophagy and lysosomal biogenesis (PMID:12150925, PMID:18497260, PMID:20381137, PMID:19211835, PMID:22343943, PMID:18762023); and mTORC2 (with rictor, SIN1, and mLST8), which phosphorylates Akt on Ser473 and PKCα to regulate cell survival and actin cytoskeleton organization (PMID:15718470, PMID:16962653, PMID:15268862). Crystal and cryo-EM structures reveal that the FRB domain acts as a gatekeeper restricting substrate access to a deeply recessed active site, which rapamycin–FKBP12 further occludes; activating cancer-associated MTOR mutations increase intrinsic kinase activity and confer resistance to active-site inhibitors, overcome by bivalent third-generation inhibitors (PMID:23636326, PMID:26678875, PMID:27279227). mTOR is essential for embryonic development, as homozygous loss of function in mice is lethal (PMID:11707573).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Identification of FRAP/mTOR as the direct intracellular target of the FKBP12–rapamycin complex resolved the molecular basis of rapamycin's antiproliferative activity and connected a mammalian kinase to yeast TOR biology.

    Evidence Biochemical purification of FKBP12-rapamycin-associated protein from mammalian cells, peptide sequencing, cDNA cloning

    PMID:8008069

    Open questions at the time
    • No endogenous substrates identified
    • Mechanism of kinase regulation unknown
    • Whether mTOR acts alone or in complex undefined
  2. 2001 High

    Mouse knockout demonstrated that mTOR is essential for embryonic viability and patterning, establishing that rapamycin-sensitive mTOR signaling is required for organismal development, not just cultured-cell proliferation.

    Evidence Loss-of-function mutation in mice phenocopied by rapamycin treatment of embryos

    PMID:11707573

    Open questions at the time
    • Tissue-specific requirements undefined
    • Which mTOR effectors mediate developmental phenotypes unknown
  3. 2002 High

    Discovery of raptor as a stoichiometric mTOR partner (defining mTORC1) and identification of TSC1/TSC2 as upstream negative regulators downstream of Akt established the core signaling architecture linking growth factor input to mTOR-dependent protein synthesis via S6K1 and 4E-BP1.

    Evidence Affinity purification/mass spectrometry of raptor–mTOR complex; in vitro Akt phosphorylation of TSC2 with epistasis analysis; yeast TORC1/TORC2 genetic characterization

    PMID:12150925 PMID:12150926 PMID:12172553 PMID:12408816

    Open questions at the time
    • Second mTOR complex in mammals not yet biochemically defined
    • How amino acids feed into this pathway unknown
    • Structural basis of raptor–mTOR interaction unresolved
  4. 2004 High

    Biochemical isolation of the rictor–mTOR complex (mTORC2) in mammalian cells demonstrated that a single kinase nucleates two functionally distinct complexes: rapamycin-sensitive mTORC1 controlling translation and rapamycin-insensitive mTORC2 controlling the actin cytoskeleton, resolving the long-standing question of how TOR mediates rapamycin-insensitive functions.

    Evidence Co-immunoprecipitation and mass spectrometry identifying rictor–mTOR; RNAi and actin staining showing cytoskeletal phenotype; rapamycin sensitivity assays

    PMID:15268862 PMID:15467718

    Open questions at the time
    • Direct kinase substrate of mTORC2 not yet identified
    • SIN1 role not established
    • How rictor confers substrate specificity unknown
  5. 2005 High

    Demonstration that mTORC2 directly phosphorylates Akt on Ser473 identified mTORC2 as the long-sought PDK2, closing a major gap in PI3K–Akt signaling and establishing Rheb-GTP as a direct activator of mTOR kinase activity.

    Evidence Reconstituted in vitro kinase assay of mTORC2 on Akt-Ser473; RNAi in Drosophila and human cells; Rheb GTPase mutant binding and kinase activation assays

    PMID:15718470 PMID:15854902

    Open questions at the time
    • How Rheb specifically activates mTORC1 vs mTORC2 unclear
    • Site of Rheb–mTOR interaction on the endomembrane system not defined
  6. 2006 High

    Genetic ablation of SIN1 completed the mTORC2 subunit inventory and showed that loss of Akt-Ser473 phosphorylation selectively impairs FoxO1/3a but not TSC2 or GSK3 signaling, revealing substrate-specific output channels downstream of Akt; prolonged rapamycin was shown to disrupt mTORC2 assembly indirectly.

    Evidence sin1−/− cells with phospho-Akt substrate analysis; co-immunoprecipitation of mTORC2 assembly under chronic rapamycin

    PMID:16603397 PMID:16962653

    Open questions at the time
    • Structural basis for SIN1 requirement unresolved
    • How prolonged rapamycin disrupts mTORC2 mechanistically unclear
  7. 2008 High

    Discovery that Rag GTPases interact with raptor to relay amino acid sufficiency and that mTORC1 promotes lipid biosynthesis via SREBP1/2 expanded the model from a translation controller to a metabolic master regulator responsive to intracellular amino acid levels.

    Evidence Co-immunoprecipitation with Rag GTPase mutants; cell fractionation showing mTOR translocation; rapamycin/RNAi with lipid synthesis and SREBP assays including Drosophila genetics

    PMID:18497260 PMID:18762023

    Open questions at the time
    • Lysosomal localization machinery not identified
    • How amino acids regulate Rag nucleotide state unknown
  8. 2009 High

    Identification of ULK1–Atg13–FIP200 as a direct mTORC1 substrate complex and of SLC7A5/SLC3A2-mediated leucine import as an upstream amino acid signal linked mTOR to autophagy suppression and defined the amino acid sensing input at the transporter level.

    Evidence In vitro kinase assays of mTOR on ULK1/Atg13; rapamycin-induced dephosphorylation; SLC1A5/SLC7A5 knockdown with mTOR activity readouts

    PMID:19203585 PMID:19211835 PMID:19225151

    Open questions at the time
    • Full complement of mTOR phosphorylation sites on ULK1 unknown
    • Whether other autophagy regulators are direct mTOR substrates untested
  9. 2010 High

    Identification of the Ragulator complex as the lysosomal anchor for Rag GTPases and the demonstration that mTOR reactivation during prolonged starvation drives lysosome reformation from autolysosomes established the lysosome as the spatiotemporal platform for mTORC1 activation and placed mTOR at the center of a lysosome–autophagy feedback cycle.

    Evidence Subcellular fractionation and live-cell imaging of mTOR lysosomal translocation; constitutive targeting constructs; autolysosome-to-lysosome reformation imaging; metabolomic/genomic analysis of mTORC1-driven glycolysis and lipogenesis via HIF1α/SREBP

    PMID:20381137 PMID:20526321 PMID:20670887

    Open questions at the time
    • How amino acids are sensed inside the lysosomal lumen unknown
    • Ragulator GEF activity toward Rags not yet demonstrated
  10. 2011 High

    Mechanistic dissection of the mTOR–AMPK toggle on ULK1 showed that mTOR phosphorylation of Ser757 disrupts AMPK–ULK1 interaction, establishing a binary nutrient-sensing switch that gates autophagy initiation.

    Evidence In vitro kinase assays with phospho-specific antibodies; co-immunoprecipitation under fed/starved conditions; AMPK/mTOR knockdown

    PMID:21258367

    Open questions at the time
    • Whether additional kinases contribute to ULK1 Ser757 phosphorylation in vivo unclear
    • Integration with mTORC2 signaling during starvation unresolved
  11. 2012 High

    Demonstration that mTORC1 phosphorylates TFEB on the lysosomal membrane to prevent its nuclear translocation established a direct mechanism by which mTOR coordinates lysosomal biogenesis and autophagy gene transcription with nutrient status.

    Evidence TFEB-GFP live imaging; phospho-TFEB assays; Rag GTPase mutant epistasis; starvation and lysosomal disruption experiments

    PMID:22343943

    Open questions at the time
    • Whether mTORC1 directly phosphorylates all TFEB regulatory sites or requires co-kinases
    • How TFEB escapes mTOR on the lysosome upon starvation kinetically undefined
  12. 2013 High

    Crystal structures of the mTOR kinase domain bound to mLST8 and inhibitors revealed an intrinsically active kinase whose recessed active site is gated by the FRB domain; this explained both how rapamycin–FKBP12 inhibits substrate access and how cancer-associated activating mutations destabilize the inhibitory framework.

    Evidence X-ray crystallography at atomic resolution with ATP-site inhibitors and transition-state mimics; mutagenesis of FRB and active-site residues

    PMID:23636326

    Open questions at the time
    • Full-length mTORC1/mTORC2 holoenzyme structures lacking
    • Structural basis for substrate discrimination between complexes unknown
  13. 2015 High

    Cryo-EM structure of intact human mTORC1 (mTOR–raptor–mLST8) bound to FKBP12–rapamycin showed how raptor's N-terminal domain is positioned near the active site to deliver substrates, providing the first view of the holoenzyme architecture.

    Evidence 5.9 Å cryo-EM structure of mTORC1; 4.3 Å crystal structure of raptor

    PMID:26678875

    Open questions at the time
    • Substrate-bound structures not available
    • mTORC2 holoenzyme structure still unresolved at this time
  14. 2016 High

    Mapping of resistance mutations to mTOR active-site inhibitors showed they increase intrinsic kinase activity rather than block drug binding, and design of the bivalent inhibitor RapaLink-1 that bridges two drug-binding sites overcame this resistance, providing both mechanistic insight into activation and a therapeutic strategy.

    Evidence Resistance mutation mapping; in vitro kinase assays with mutant mTOR; cell-based screens; glioblastoma xenograft models

    PMID:27279227

    Open questions at the time
    • Long-term resistance mechanisms to RapaLink-1 not explored
    • Whether all clinical activating mutations are captured by this model unclear
  15. 2018 High

    Discovery that galectin-8 associates with the Ragulator–Rag machinery on damaged lysosomes to inhibit mTOR (GALTOR pathway) revealed a damage-sensing input to mTOR regulation that connects lysosomal integrity surveillance to autophagy and anti-mycobacterial defense.

    Evidence Co-immunoprecipitation of galectin-8 with mTOR apparatus; lysosomal damage induction (LLOMe); galectin-knockout cells; bacterial killing assays

    PMID:29625033

    Open questions at the time
    • Whether GALTOR operates in all cell types or is myeloid-specific unclear
    • Structural basis for galectin-8–Ragulator interaction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of mTORC2 holoenzyme architecture, how lysosomal lumenal amino acids are sensed and transmitted to the Rag GTPase cycle, how mTORC1 and mTORC2 substrate specificity is enforced at the structural level, and whether additional non-canonical mTOR inputs (such as galectin-mediated damage sensing) operate in diverse tissues.
  • mTORC2 high-resolution structure with substrates not reported in this timeline
  • Lumenal amino acid sensor identity unresolved
  • Tissue-specific mTOR complex stoichiometries and functions poorly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016740 transferase activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005764 lysosome 5 GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-392499 Metabolism of proteins 4 R-HSA-9612973 Autophagy 4 R-HSA-1430728 Metabolism 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
MAPKSP1MLST8RHEBRICTORRPTORRRAGASIN1ULK1
Complex memberships
mTORC1 (mTOR-raptor-mLST8)mTORC2 (mTOR-rictor-SIN1-mLST8)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 FRAP (mTOR) was identified as a mammalian protein that directly binds the FKBP12-rapamycin complex; binding correlates with rapamycin's ability to inhibit G1 cell-cycle progression. FRAP is related to yeast TOR1/TOR2. Biochemical purification of FKBP12-rapamycin-associated protein, peptide sequencing, cDNA cloning Nature High 8008069
1999 mTOR (RAFT1) interacts with gephyrin; mTOR mutants unable to bind gephyrin fail to signal to downstream effectors p70 S6K and 4E-BP1, placing gephyrin as a required scaffold for rapamycin-sensitive mTOR signaling. Co-immunoprecipitation, yeast two-hybrid, functional signaling assays with mTOR mutants Science Medium 10325225
2001 FRAP/mTOR is required for embryonic proliferation and patterning in the mouse; loss-of-function mutation is lethal and phenocopied by rapamycin treatment, demonstrating an essential in vivo developmental role. Mouse knockout/loss-of-function mutation; rapamycin treatment of early embryos Proceedings of the National Academy of Sciences of the United States of America High 11707573
2002 TSC2 is directly phosphorylated by Akt, which destabilizes TSC2 and disrupts its interaction with TSC1; the TSC1-TSC2 complex inhibits mTOR signaling to S6K1 and 4E-BP1, placing TSC1/TSC2 as an upstream negative regulator of mTOR in the insulin/Akt pathway. In vitro kinase assay (Akt phosphorylates TSC2), co-immunoprecipitation, epistasis by overexpression/knockdown Nature cell biology High 12172553
2002 mTOR forms a stoichiometric complex with raptor (regulatory associated protein of mTOR); raptor positively regulates nutrient-stimulated signaling to S6K1 and cell size, while its association with mTOR under nutrient-deprived conditions negatively regulates mTOR kinase activity. Affinity purification, mass spectrometry, co-immunoprecipitation, RNAi knockdown, in vitro kinase assay Cell High 12150925 12150926
2002 Two functionally distinct TOR complexes (TORC1 and TORC2) exist in yeast: TORC1 (containing TOR1 or TOR2, KOG1/raptor, LST8) is rapamycin-sensitive; TORC2 (containing TOR2, AVO1/2/3, LST8) is rapamycin-insensitive and mediates actin cytoskeleton organization. This dichotomy is conserved in mammals. Genetic and biochemical complex characterization in yeast, FKBP-rapamycin binding assays, actin phenotype analysis Molecular cell High 12408816
2004 mTOR forms a second, distinct complex with rictor (rapamycin-insensitive companion of mTOR) and GβL but not raptor; the rictor-mTOR complex is not bound by FKBP12-rapamycin, does not regulate S6K1, but modulates PKCα phosphorylation and actin cytoskeleton organization. Co-immunoprecipitation, mass spectrometry, RNAi, in vitro kinase assay, actin staining Current biology : CB High 15268862
2004 Mammalian TORC2 (mTORC2) controls the actin cytoskeleton and is rapamycin-insensitive; it contains mTOR, mLST8, and mAVO3 but not raptor, functionally conserving yeast TORC2 in mammals. Co-immunoprecipitation, RNAi knockdown, rapamycin sensitivity assays, actin cytoskeleton phenotyping Nature cell biology High 15467718
2005 The rictor-mTOR complex (mTORC2) directly phosphorylates Akt/PKB on Ser473 in vitro and in cells; reduction of rictor or mTOR expression inhibits Akt-Ser473 phosphorylation and downstream Akt effector activity, identifying mTORC2 as the long-sought PDK2. In vitro kinase assay (mTORC2 phosphorylates Akt-Ser473), RNAi knockdown in Drosophila and human cells, epistasis Science High 15718470
2005 Rheb directly binds the mTOR complex through interactions with the mTOR catalytic domain and with LST8; Rheb-GTP binding is required for mTOR kinase activation—mTOR polypeptides bound to GTP-locked Rheb(Gln64Leu) show substantially higher kinase activity in vitro. Co-immunoprecipitation, in vitro binding, in vitro kinase assay with Rheb mutants Current biology : CB High 15854902
2006 SIN1/MIP1 is an essential subunit of the rictor-mTOR (mTORC2) complex; genetic ablation of sin1 abolishes Akt-Ser473 phosphorylation and disrupts rictor-mTOR interaction, while leaving Thr308 phosphorylation intact. Defective Ser473 phosphorylation specifically affects FoxO1/3a but not TSC2, GSK3, S6K, or 4E-BP1 substrates. Genetic knockout (sin1-/- cells), co-immunoprecipitation, phospho-specific antibody assays, substrate-specificity analysis Cell High 16962653
2006 Prolonged rapamycin treatment inhibits mTORC2 assembly and reduces Akt/PKB Ser473 phosphorylation in many cell types; cells expressing a rapamycin-resistant Akt/PKB mutant are protected from rapamycin's pro-apoptotic effects, revealing an mTORC2-dependent survival pathway. Co-immunoprecipitation to assess complex assembly, phospho-Akt assays, rescue with rapamycin-resistant Akt mutant Molecular cell High 16603397
2008 The Rag GTPases (RagA/B/C/D) interact with mTORC1 via raptor in an amino acid-sensitive manner; constitutively GTP-bound Rag renders mTORC1 amino acid-insensitive, while GDP-bound Rag blocks amino acid activation. Rags do not directly stimulate mTOR kinase activity but promote mTOR translocation to a Rheb-containing compartment. Co-immunoprecipitation, GTPase mutant analysis, cell fractionation, epistasis with constitutively active/dominant-negative Rags Science High 18497260
2008 mTORC1 regulates SREBP1/2 transcription factors to promote lipid biosynthesis; mTORC1-activated S6K1 mediates SREBP nuclear accumulation; SREBP silencing blocks Akt-dependent lipogenesis and cell size increase. Rapamycin treatment, RNAi knockdown of SREBP, lipid synthesis assays, cell size measurement, Drosophila genetic experiments Cell metabolism High 18762023
2009 mTORC1 is incorporated into the ULK1-Atg13-FIP200 complex through ULK1 in a nutrient-dependent manner; mTOR directly phosphorylates ULK1 and Atg13; rapamycin treatment or starvation leads to dephosphorylation of ULK1 and Atg13, triggering autophagy. Co-immunoprecipitation of mTORC1 with ULK1-Atg13-FIP200 complex, in vitro kinase assay, rapamycin treatment, RNAi Molecular biology of the cell High 19211835 19225151 19258318
2009 Amino acid activation of mTORC1 requires bidirectional amino acid transport: SLC1A5 mediates glutamine uptake, and SLC7A5/SLC3A2 mediates simultaneous glutamine efflux and essential amino acid (leucine) import; this flux activates mTOR signaling. SLC1A5/SLC7A5 knockdown, mTOR activity assays, cell growth and autophagy readouts Cell High 19203585
2010 Ragulator (a complex encoded by MAPKSP1, ROBLD3, and c11orf59) interacts with Rag GTPases and is required to recruit them to lysosomal membranes; amino acids induce mTORC1 translocation to the lysosomal surface where Rheb resides; constitutive lysosomal targeting of mTORC1 bypasses Rag/Ragulator but not Rheb requirement. Subcellular fractionation, live-cell imaging, co-immunoprecipitation, RNAi knockdown, constitutive lysosome-targeting constructs Cell High 20381137
2010 mTOR signaling is inhibited during autophagy initiation by starvation but reactivated by prolonged starvation in an autophagy-dependent manner requiring degradation of autolysosomal products; reactivated mTOR generates proto-lysosomal tubules from autolysosomes, terminating autophagy and reforming functional lysosomes. Live-cell imaging, pharmacological mTOR inhibition/activation, electron microscopy, lysosome reformation assays in multiple species Nature High 20526321
2010 mTORC1 activation is sufficient to stimulate glycolysis, the oxidative pentose phosphate pathway, and de novo lipid biosynthesis through activation of HIF1α and SREBP1/2 transcriptional programs; SREBP activation is mediated by S6K1. Unbiased genomic, metabolomic, and bioinformatic approaches; constitutively active mTORC1 (TSC1/2 knockdown); rapamycin; RNAi of SREBP Molecular cell High 20670887
2011 Under nutrient sufficiency, mTOR phosphorylates Ulk1 at Ser757 and disrupts the interaction between Ulk1 and AMPK, preventing autophagy induction. Under glucose starvation, AMPK promotes autophagy by activating Ulk1 via phosphorylation of Ser317 and Ser777. In vitro kinase assays, phospho-specific antibodies, AMPK/mTOR knockdown, co-immunoprecipitation, autophagy induction assays Nature cell biology High 21258367
2012 mTORC1 phosphorylates TFEB on the lysosomal membrane, inhibiting TFEB nuclear translocation and lysosomal biogenesis gene expression; starvation, lysosomal disruption, or pharmacological mTORC1 inhibition promotes TFEB nuclear translocation; Rag GTPases are necessary and sufficient to regulate TFEB localization. Subcellular fractionation, live-cell imaging of TFEB-GFP, phospho-TFEB assays, TFEB-/- cells, Rag GTPase mutants The EMBO journal High 22343943
2013 Crystal structures of truncated mTOR-mLST8 complex with ATP transition-state mimics and ATP-site inhibitors reveal an intrinsically active kinase conformation; the FRB domain acts as a gatekeeper by interacting with substrates to grant access to the recessed active site; rapamycin-FKBP12 inhibits mTOR by directly blocking substrate recruitment and further restricting active-site access; mTOR-activating mutations map to the structural framework holding these elements in place. X-ray crystallography, in vitro biochemistry, mutagenesis of active-site and FRB domain residues Nature High 23636326
2014 mTOR is activated through a dectin-1-Akt-HIF-1α pathway during β-glucan training of monocytes; mTOR-dependent aerobic glycolysis (shift to glycolysis with high glucose consumption and lactate production) is the metabolic basis for trained immunity; inhibition of Akt, mTOR, or HIF-1α blocks trained immunity induction. Pharmacological inhibition (rapamycin, Akt inhibitor, HIF-1α inhibitor), metabolic flux measurements, myeloid-specific HIF-1α knockout mice Science High 25258083
2015 Cryo-EM structure of human mTORC1 (mTOR-Raptor-mLST8) bound to FKBP-rapamycin at 5.9 Å resolution, combined with 4.3 Å crystal structure of Raptor, reveals that FKBP-rapamycin and architectural elements of mTORC1 limit access to the recessed active site; the conserved N-terminal domain of Raptor is juxtaposed to the kinase active site, consistent with a role in substrate recognition and delivery. Cryo-electron microscopy, X-ray crystallography, structural analysis Science High 26678875
2016 Resistance to mTOR kinase inhibitors (TORKi) arises from activating MTOR mutations that increase intrinsic kinase activity rather than blocking drug binding; a third-generation bivalent inhibitor (RapaLink-1) exploiting two drug-binding pockets overcomes resistance to first- and second-generation mTOR inhibitors including resistant activating mutants. Resistance mutation mapping, in vitro kinase assays with MTOR mutants, cell-based drug resistance screens, xenograft tumor models Nature High 27279227
2018 Lysosomal damage is recognized by galectin-8 (Gal8), which associates with the mTOR apparatus on the lysosome and inhibits mTOR activity through the Ragulator-Rag signaling machinery (termed GALTOR); galectin-9 concurrently activates AMPK; both systems converge on autophagy induction and defense against Mycobacterium tuberculosis. Co-immunoprecipitation, in vitro mTOR activity assays, lysosomal damage induction (LLOMe), galectin knockout cells, autophagy and bacterial killing assays Molecular cell High 29625033
2022 Comprehensive review with structural context establishes that mTORC1 and mTORC2, despite sharing the mTOR catalytic subunit, phosphorylate distinct substrates by recruiting different substrate-binding partners to phosphorylate a common minimal motif; all reported direct substrates of mTOR are catalogued. Systematic literature review with structural analysis of substrate-binding mechanisms Cell Medium 35580586
2022 Brain-restricted mTOR inhibition can be achieved by combining the brain-permeable bivalent inhibitor RapaLink-1 with the brain-impermeable FKBP12 ligand RapaBlock; RapaBlock deactivates RapaLink-1 outside the brain while retaining efficacy in glioblastoma xenografts, demonstrating a pharmacological strategy for tissue-selective mTOR inhibition. Brain permeability assays, pharmacokinetic studies, glioblastoma xenograft models, biochemical FKBP12-dependent inhibitor design Nature High 36104566

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 mTOR signaling in growth control and disease. Cell 6875 22500797
2011 AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature cell biology 5883 21258367
2005 Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science (New York, N.Y.) 5534 15718470
2017 mTOR Signaling in Growth, Metabolism, and Disease. Cell 4891 28283069
2004 Upstream and downstream of mTOR. Genes & development 3417 15314020
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2002 TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature cell biology 2509 12172553
2002 mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2446 12150925
1997 Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Current biology : CB 2434 9094314
2006 Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular cell 2221 16603397
2008 The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science (New York, N.Y.) 2220 18497260
2004 Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Current biology : CB 2201 15268862
2010 Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 1984 20381137
2014 mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science (New York, N.Y.) 1742 25258083
2004 Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature cell biology 1726 15467718
2015 mTOR: a pharmacologic target for autophagy regulation. The Journal of clinical investigation 1725 25654547
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
1994 A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1696 8008069
2009 Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Molecular biology of the cell 1651 19211835
2010 Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Molecular cell 1647 20670887
2009 ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Molecular biology of the cell 1625 19225151
2012 A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. The EMBO journal 1597 22343943
2002 Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Molecular cell 1547 12408816
2017 YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell research 1488 28106072
2002 Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 1482 12150926
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 1435 19203585
2011 The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends in biochemical sciences 1426 21531565
2013 mTOR is a key modulator of ageing and age-related disease. Nature 1308 23325216
2005 Growing roles for the mTOR pathway. Current opinion in cell biology 1288 16226444
2010 Network organization of the human autophagy system. Nature 1286 20562859
2010 Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 1224 20526321
2009 ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. The Journal of biological chemistry 1222 19258318
2008 Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. The Journal of clinical investigation 1218 18725988
2006 SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 1161 16962653
2008 SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell metabolism 1141 18762023
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2013 mTOR kinase structure, mechanism and regulation. Nature 841 23636326
2005 Rheb binds and regulates the mTOR kinase. Current biology : CB 793 15854902
2009 Immunoregulatory functions of mTOR inhibition. Nature reviews. Immunology 716 19390566
2013 Amino acid signalling upstream of mTOR. Nature reviews. Molecular cell biology 708 23361334
2019 Targeting mTOR for cancer therapy. Journal of hematology & oncology 703 31277692
2011 Regulation of immune responses by mTOR. Annual review of immunology 687 22136167
2014 The neurology of mTOR. Neuron 579 25374355
2006 mTOR, translation initiation and cancer. Oncogene 522 17041626
2019 mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy. International journal of molecular sciences 458 30754640
2010 Dysregulation of mTOR signaling in fragile X syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience 453 20071534
2013 Where is mTOR and what is it doing there? The Journal of cell biology 430 24385483
2005 An expanding role for mTOR in cancer. Trends in molecular medicine 424 16002336
2013 mTOR in aging, metabolism, and cancer. Current opinion in genetics & development 385 23317514
2016 Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature 377 27279227
2009 Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochimica et biophysica acta 376 20005306
2008 Rapamycin and mTOR kinase inhibitors. Journal of chemical biology 335 19568796
2022 mTOR substrate phosphorylation in growth control. Cell 327 35580586
2016 Molecular neurobiology of mTOR. Neuroscience 322 27889578
2013 Nutrient signaling to mTOR and cell growth. Trends in biochemical sciences 309 23465396
2019 Regulation of Autophagy by mTOR Signaling Pathway. Advances in experimental medicine and biology 287 31776980
2015 mTOR in Brain Physiology and Pathologies. Physiological reviews 287 26269525
2015 Architecture of human mTOR complex 1. Science (New York, N.Y.) 273 26678875
2003 Tuberous sclerosis: from tubers to mTOR. Annals of human genetics 269 12556239
2004 mTOR, translational control and human disease. Seminars in cell & developmental biology 260 15659337
2018 mTOR Pathways in Cancer and Autophagy. Cancers 245 29329237
2015 The Roles of mTOR Complexes in Lipid Metabolism. Annual review of nutrition 243 26185979
2014 mTOR signaling in cellular and organismal energetics. Current opinion in cell biology 237 25554914
2018 Galectins Control mTOR in Response to Endomembrane Damage. Molecular cell 236 29625033
2010 PTEN/mTOR and axon regeneration. Experimental neurology 236 20079353
2017 The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling. Nutrients 231 29077002
2009 Activation of the mammalian target of rapamycin (mTOR) is essential for oligodendrocyte differentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience 225 19439614
2009 The multiple facets of mTOR in immunity. Trends in immunology 224 19362054
2021 Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Molecular neurodegeneration 219 34215308
2004 mTOR signaling to translation. Current topics in microbiology and immunology 211 14560958
2015 Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders. British journal of clinical pharmacology 168 26469771
2012 Adverse events associated with mTOR inhibitors. Expert opinion on drug safety 164 23252795
2020 Research progress of mTOR inhibitors. European journal of medicinal chemistry 163 32966896
1999 Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling. Science (New York, N.Y.) 161 10325225
2010 Updates of mTOR inhibitors. Anti-cancer agents in medicinal chemistry 158 20812900
2018 The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis. International journal of molecular sciences 148 29518028
2007 The biology behind mTOR inhibition in sarcoma. The oncologist 148 17766661
2007 Regulation of mTOR by phosphatidic acid? Cancer research 145 17210675
2001 FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse. Proceedings of the National Academy of Sciences of the United States of America 145 11707573
2011 Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug discovery today 144 21333749
2021 mTORC2: The other mTOR in autophagy regulation. Aging cell 143 34250734
2004 Targeting the molecular target of rapamycin (mTOR). Current opinion in oncology 142 15627018
2013 Mammalian target of rapamycin (mTOR) pathways in neurological diseases. Biomedical journal 140 23644232
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