Human Gene MTOR (uc001asd.3) Description and Page Index
Description: Homo sapiens mechanistic target of rapamycin (serine/threonine kinase) (MTOR), mRNA. RefSeq Summary (NM_004958): The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. The ANGPTL7 gene is located in an intron of this gene. [provided by RefSeq, Sep 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##Evidence-Data-START## Transcript exon combination :: AB209995.1, U88966.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support SAMEA1965299, SAMEA1966682 [ECO:0000350] ##Evidence-Data-END## Transcript (Including UTRs) Position: hg19 chr1:11,166,588-11,322,608 Size: 156,021 Total Exon Count: 58 Strand: - Coding Region Position: hg19 chr1:11,167,542-11,319,466 Size: 151,925 Coding Exon Count: 57
ID:MTOR_HUMAN DESCRIPTION: RecName: Full=Serine/threonine-protein kinase mTOR; EC=2.7.11.1; AltName: Full=FK506-binding protein 12-rapamycin complex-associated protein 1; AltName: Full=FKBP12-rapamycin complex-associated protein; AltName: Full=Mammalian target of rapamycin; Short=mTOR; AltName: Full=Mechanistic target of rapamycin; AltName: Full=Rapamycin and FKBP12 target 1; AltName: Full=Rapamycin target protein 1; FUNCTION: 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'. Regulates osteoclastogensis by adjusting the expression of CEBPB isoforms (By similarity). CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: 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, SLC38A9, and the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD (PubMed:18497260, PubMed:20381137, PubMed:25561175, PubMed:25567906). 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. SUBUNIT: 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 PLPP7 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. Interacts with HTR6 (PubMed:23027611). Interacts with BRAT1. INTERACTION: P31749:AKT1; NbExp=2; IntAct=EBI-359260, EBI-296087; Q8TB45:DEPTOR; NbExp=5; IntAct=EBI-359260, EBI-2359040; Q13541:EIF4EBP1; NbExp=2; IntAct=EBI-359260, EBI-74090; P62942:FKBP1A; NbExp=2; IntAct=EBI-359260, EBI-1027571; Q9BVC4:MLST8; NbExp=4; IntAct=EBI-359260, EBI-1387471; Q8TCU6:PREX1; NbExp=11; IntAct=EBI-359260, EBI-1046542; P62820:RAB1A; NbExp=4; IntAct=EBI-359260, EBI-716845; Q6R327:RICTOR; NbExp=27; IntAct=EBI-359260, EBI-1387196; Q8N122:RPTOR; NbExp=32; IntAct=EBI-359260, EBI-1567928; Q96EB6:SIRT1; NbExp=2; IntAct=EBI-359260, EBI-1802965; Q8NHX9:TPCN2; NbExp=2; IntAct=EBI-359260, EBI-5239949; SUBCELLULAR LOCATION: Endoplasmic reticulum membrane ; Peripheral membrane protein ; Cytoplasmic side Golgi apparatus membrane ; Peripheral membrane protein ; Cytoplasmic side Mitochondrion outer membrane ; Peripheral membrane protein ytoplasmic side Lysosome toplasm Nucleus, PML body Microsome membrane 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 (PubMed:18497260, PubMed:20381137). TISSUE SPECIFICITY: Expressed in numerous tissues, with highest levels in testis. DOMAIN: The kinase domain (PI3K/PI4K) is intrinsically active but has a highly restricted catalytic center. DOMAIN: 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 (PubMed:23636326). PTM: 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. Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity. DISEASE: Smith-Kingsmore syndrome (SKS) [MIM:616638]: An autosomal dominant syndrome characterized by intellectual disability, macrocephaly, seizures, umbilical hernia, and facial dysmorphic features. te=The disease is caused by mutations affecting the gene represented in this entry. SIMILARITY: Belongs to the PI3/PI4-kinase family. SIMILARITY: Contains 1 FAT domain. SIMILARITY: Contains 1 FATC domain. SIMILARITY: Contains 32 HEAT repeats. SIMILARITY: Contains 1 PI3K/PI4K domain. SIMILARITY: Contains 16 TPR repeats. SEQUENCE CAUTION: Sequence=AAC39933.1; Type=Frameshift; Positions=956, 999; Evidence=; Sequence=BAE06077.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence=; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/FRAP1ID40639ch1p36.html"; WEB RESOURCE: Name=Wikipedia; Note=Mammalian target of rapamycin entry; URL="https://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin"; WEB RESOURCE: Name=Target mTOR; Note=mTOR signaling pathway and mTOR inhibition resource; URL="http://www.targetmtor.com/index.jsp";
Genetic Association Studies of Complex Diseases and Disorders
Genetic Association Database (archive): MTOR CDC HuGE Published Literature: MTOR Positive Disease Associations: Corneal Topography Related Studies:
Corneal Topography Siyu Han et al. Human molecular genetics 2011, Association of variants in FRAP1 and PDGFRA with corneal curvature in Asian populations from Singapore., Human molecular genetics.
[PubMed 21665993]
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P42345
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000166 nucleotide binding GO:0001030 RNA polymerase III type 1 promoter DNA binding GO:0001031 RNA polymerase III type 2 promoter DNA binding GO:0001032 RNA polymerase III type 3 promoter DNA binding GO:0001156 TFIIIC-class transcription factor binding GO:0004674 protein serine/threonine kinase activity GO:0005515 protein binding GO:0005524 ATP binding GO:0008144 drug binding GO:0016301 kinase activity GO:0016740 transferase activity GO:0016772 transferase activity, transferring phosphorus-containing groups GO:0016773 phosphotransferase activity, alcohol group as acceptor GO:0019904 protein domain specific binding GO:0043022 ribosome binding GO:0046983 protein dimerization activity GO:0051219 phosphoprotein binding
Biological Process: GO:0000724 double-strand break repair via homologous recombination GO:0001934 positive regulation of protein phosphorylation GO:0001938 positive regulation of endothelial cell proliferation GO:0005979 regulation of glycogen biosynthetic process GO:0006109 regulation of carbohydrate metabolic process GO:0006468 protein phosphorylation GO:0006950 response to stress GO:0007165 signal transduction GO:0007173 epidermal growth factor receptor signaling pathway GO:0007281 germ cell development GO:0007584 response to nutrient GO:0008286 insulin receptor signaling pathway GO:0008543 fibroblast growth factor receptor signaling pathway GO:0010507 negative regulation of autophagy GO:0010592 positive regulation of lamellipodium assembly GO:0010628 positive regulation of gene expression GO:0010831 positive regulation of myotube differentiation GO:0016049 cell growth GO:0016242 negative regulation of macroautophagy GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0018107 peptidyl-threonine phosphorylation GO:0030030 cell projection organization GO:0030163 protein catabolic process GO:0030838 positive regulation of actin filament polymerization GO:0031295 T cell costimulation GO:0031529 ruffle organization GO:0031641 regulation of myelination GO:0031669 cellular response to nutrient levels GO:0031929 TOR signaling GO:0031998 regulation of fatty acid beta-oxidation GO:0032095 regulation of response to food GO:0032314 regulation of Rac GTPase activity GO:0032868 response to insulin GO:0032956 regulation of actin cytoskeleton organization GO:0034605 cellular response to heat GO:0038095 Fc-epsilon receptor signaling pathway GO:0040007 growth GO:0043200 response to amino acid GO:0043610 regulation of carbohydrate utilization GO:0045087 innate immune response GO:0045727 positive regulation of translation GO:0045792 negative regulation of cell size GO:0045859 regulation of protein kinase activity GO:0045945 positive regulation of transcription from RNA polymerase III promoter GO:0046777 protein autophosphorylation GO:0046889 positive regulation of lipid biosynthetic process GO:0048010 vascular endothelial growth factor receptor signaling pathway GO:0048011 neurotrophin TRK receptor signaling pathway GO:0048015 phosphatidylinositol-mediated signaling GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation GO:0051496 positive regulation of stress fiber assembly GO:0051534 negative regulation of NFAT protein import into nucleus GO:0051897 positive regulation of protein kinase B signaling GO:0071456 cellular response to hypoxia GO:1900034 regulation of cellular response to heat
U88966 - Human protein rapamycin associated protein (FRAP2) gene, complete cds. AB209995 - Homo sapiens mRNA for FRAP1 variant protein, clone: ef01094. AK302863 - Homo sapiens cDNA FLJ60991 complete cds, highly similar to FKBP12-rapamycin complex-associated protein. AK304273 - Homo sapiens cDNA FLJ56559 complete cds, highly similar to FKBP12-rapamycin complex-associated protein. BC117166 - Homo sapiens FK506 binding protein 12-rapamycin associated protein 1, mRNA (cDNA clone MGC:150775 IMAGE:40125717), complete cds. L34075 - Human FKBP-rapamycin associated protein (FRAP) mRNA, complete cds. AB384693 - Synthetic construct DNA, clone: pF1KB1123, Homo sapiens FRAP1 gene for FKBP12-rapamycin complex-associated protein, complete cds, without stop codon, in Flexi system. AK126762 - Homo sapiens cDNA FLJ44809 fis, clone BRACE3044172, highly similar to FKBP12-rapamycin complex-associated protein. JD506378 - Sequence 487402 from Patent EP1572962. JD159533 - Sequence 140557 from Patent EP1572962. JD089021 - Sequence 70045 from Patent EP1572962. JD105180 - Sequence 86204 from Patent EP1572962. JD193187 - Sequence 174211 from Patent EP1572962. JD551053 - Sequence 532077 from Patent EP1572962. JD368094 - Sequence 349118 from Patent EP1572962. JD171795 - Sequence 152819 from Patent EP1572962. JD435342 - Sequence 416366 from Patent EP1572962. JD249010 - Sequence 230034 from Patent EP1572962. JD060421 - Sequence 41445 from Patent EP1572962. HZ473918 - WO 2016002844-A/32: ANTI-INVASIVE/ANTI-METASTATIC DRUG FOR PANCREATIC CANCER CELL. AK024393 - Homo sapiens cDNA FLJ14331 fis, clone PLACE4000320. L35478 - Homo sapiens RAPT1 (RAPT1) mRNA, partial cds. HZ473916 - WO 2016002844-A/30: ANTI-INVASIVE/ANTI-METASTATIC DRUG FOR PANCREATIC CANCER CELL. BC127611 - Homo sapiens cDNA clone IMAGE:40031732, partial cds. HZ473917 - WO 2016002844-A/31: ANTI-INVASIVE/ANTI-METASTATIC DRUG FOR PANCREATIC CANCER CELL. HW795841 - JP 2014527827-A/1: Novel use of leucyl tRNA synthetase. LP057243 - Sequence 2 from Patent EP2758775. HZ473915 - WO 2016002844-A/29: ANTI-INVASIVE/ANTI-METASTATIC DRUG FOR PANCREATIC CANCER CELL. JD458424 - Sequence 439448 from Patent EP1572962.
Biochemical and Signaling Pathways
KEGG - Kyoto Encyclopedia of Genes and Genomes hsa04012 - ErbB signaling pathway hsa04150 - mTOR signaling pathway hsa04910 - Insulin signaling pathway hsa04920 - Adipocytokine signaling pathway hsa04930 - Type II diabetes mellitus hsa05200 - Pathways in cancer hsa05214 - Glioma hsa05215 - Prostate cancer hsa05221 - Acute myeloid leukemia
US Server
