MTOR - Serine/threonine-protein kinase mTOR - human protein (Function)
 
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MTOR »  Serine/threonine-protein kinase mTOR   [ EC 2.7.11.1 ]
 
Protein also known as:  FK506-binding protein 12-rapamycin complex-associated protein 1.
Gene name:  MTOR
Family name: PI3/PI4-kinase
Entry whose protein(s) existence is based on evidence at protein level
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1 951 1
GENE REF ISO

Function

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Overview 
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'.  
18
  • CuratedUniProtKB
GO molecular function 
ATP bindingdefinition[GO:0005524]  
  • IEAUniProtKB KW
Drug bindingdefinition[GO:0008144] silver  
  • IEAInterPro 2 GO
Kinase activitydefinition[GO:0016301]  
2
  • IDAMGI
  • TASUniProtKB
Phosphoprotein bindingdefinition[GO:0051219]  
1
  • IPIUniProtKB
Protein bindingdefinition[GO:0005515]  
23
  • IPIIntAct
  • IPIUniProtKB
Protein domain specific bindingdefinition[GO:0019904] silver  
  • IEAOrtholog Compara
Protein serine/threonine kinase activitydefinition[GO:0004674]  
1
  • IDAUniProtKB
Ribosome bindingdefinition[GO:0043022] silver  
  • IEAOrtholog Compara
RNA polymerase III type 1 promoter DNA bindingdefinition[GO:0001030]  
1
  • IDAUniProtKB
RNA polymerase III type 2 promoter DNA bindingdefinition[GO:0001031]  
1
  • IDAUniProtKB
RNA polymerase III type 3 promoter DNA bindingdefinition[GO:0001032]  
1
  • IDAUniProtKB
TFIIIC-class transcription factor bindingdefinition[GO:0001156]  
1
  • IDAUniProtKB
GO biological process 
Cell growthdefinition[GO:0016049]  
2
  • IDAUniProtKB
Cellular response to hypoxiadefinition[GO:0071456]  
  • ISSOrtholog Curator
Cellular response to nutrient levelsdefinition[GO:0031669]  
  • ISSOrtholog Curator
Germ cell developmentdefinition[GO:0007281] silver  
  • IEAOrtholog Compara
Growthdefinition[GO:0040007]  
1
  • NASUniProtKB
Negative regulation of autophagydefinition[GO:0010507]  
  • ISSOrtholog Curator
Negative regulation of cell sizedefinition[GO:0045792] silver  
  • IEAOrtholog Compara
Negative regulation of macroautophagydefinition[GO:0016242] silver  
  • IEAOrtholog Compara
Negative regulation of NFAT protein import into nucleusdefinition[GO:0051534] silver  
  • IEAOrtholog Compara
Peptidyl-serine phosphorylationdefinition[GO:0018105]  
1
  • IMPUniProtKB
Peptidyl-threonine phosphorylationdefinition[GO:0018107] silver  
  • IEAOrtholog Compara
Phosphorylationdefinition[GO:0016310]  
1
  • IDAUniProtKB
Positive regulation of actin filament polymerizationdefinition[GO:0030838] silver  
  • IEAOrtholog Compara
Positive regulation of endothelial cell proliferationdefinition[GO:0001938] silver  
  • IEAOrtholog Compara
Positive regulation of gene expressiondefinition[GO:0010628]  
1
  • IMPUniProtKB
Positive regulation of lamellipodium assemblydefinition[GO:0010592] silver  
  • IEAOrtholog Compara
Positive regulation of lipid biosynthetic processdefinition[GO:0046889]  
1
  • IMPUniProtKB
Positive regulation of myotube differentiationdefinition[GO:0010831] silver  
  • IEAOrtholog Compara
Positive regulation of peptidyl-tyrosine phosphorylationdefinition[GO:0050731] silver  
  • IEAOrtholog Compara
Positive regulation of protein kinase B signalingdefinition[GO:0051897] silver  
  • IEAOrtholog Compara
Positive regulation of protein phosphorylationdefinition[GO:0001934]  
1
  • IDAUniProtKB
Positive regulation of stress fiber assemblydefinition[GO:0051496] silver  
  • IEAOrtholog Compara
Positive regulation of transcription from RNA polymerase III promoterdefinition[GO:0045945]  
1
  • IMPUniProtKB
Positive regulation of translationdefinition[GO:0045727]  
1
  • IDAUniProtKB
Protein autophosphorylationdefinition[GO:0046777]  
1
  • IDAMGI
Protein catabolic processdefinition[GO:0030163]  
1
  • TASUniProtKB
Protein phosphorylationdefinition[GO:0006468]  
3
  • IDAUniProtKB
  • IDAMGI
Regulation of actin cytoskeleton organizationdefinition[GO:0032956]  
1
  • IMPUniProtKB
Regulation of carbohydrate utilizationdefinition[GO:0043610] silver  
  • IEAOrtholog Compara
Regulation of fatty acid beta-oxidationdefinition[GO:0031998] silver  
  • IEAOrtholog Compara
Regulation of glycogen biosynthetic processdefinition[GO:0005979] silver  
  • IEAOrtholog Compara
Regulation of protein kinase activitydefinition[GO:0045859] silver  
  • IEAOrtholog Compara
Regulation of Rac GTPase activitydefinition[GO:0032314] silver  
  • IEAOrtholog Compara
Regulation of response to fooddefinition[GO:0032095] silver  
  • IEAOrtholog Compara
Response to amino aciddefinition[GO:0043200]  
1
  • IDAUniProtKB
Response to nutrientdefinition[GO:0007584]  
1
  • NASUniProtKB
Response to stressdefinition[GO:0006950]  
1
  • IMPUniProtKB
Ruffle organizationdefinition[GO:0031529] silver  
  • IEAOrtholog Compara
Signal transductiondefinition[GO:0007165]  
1
  • NASUniProtKB
TOR signalingdefinition[GO:0031929]  
3
  • IMPUniProtKB
Enzymatic activity 
This protein acts as an enzyme. It is known to catalyze the following reaction
EC 2.7.11.1: ATP + a protein ADP + a phosphoprotein.  
  • CuratedUniProtKB
It is regulated in the following manner
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.  
5
  • CuratedUniProtKB
Pathways 
According to KEGG, this protein belongs to the following pathways:
Acute myeloid leukemia  hsa05221+2475  
Adipocytokine signaling pathway  hsa04920+2475  
ErbB signaling pathway  hsa04012+2475  
Glioma  hsa05214+2475  
Insulin signaling pathway  hsa04910+2475  
mTOR signaling pathway  hsa04150+2475  
Pathways in cancer  hsa05200+2475  
Prostate cancer  hsa05215+2475  
Type II diabetes mellitus  hsa04930+2475  
According to Reactome, this protein belongs to the following pathways:
CD28 dependent PI3K/Akt signaling  REACT_19358  
Constitutive PI3K/AKT Signaling in Cancer  REACT_147727  
HSF1-dependent transactivation  REACT_200775  
mTOR signalling  REACT_6838  
PIP3 activates AKT signaling  REACT_75829  
Release of eIF4E  REACT_6836  
S6K1-mediated signalling  REACT_6754  
 

Keywords

Molecular function 
Kinase  definition   [KW-0418]
Serine/threonine-protein kinase  definition   [KW-0723]
Transferase  definition   [KW-0808]
Technical term 
Reference proteome  definition   [KW-1185]
 

Further external links

Other
GeneWiki: Mammalian_target_of_rapamycin
GenomeRNAi: 2475
PRO: PR:P42345
Chemistry
GuidetoPHARMACOLOGY: 2109