Serine/threonine-protein kinase mTOR (MTOR)
The protein contains 2549 amino acids for an estimated molecular weight of 288892 Da.
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 (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). 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) (PubMed:15268862, PubMed:15467718, PubMed:18925875, PubMed:18497260, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (By similarity). Moreover, phosphorylat (updated: May 8, 2019)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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Biological Process
'de novo' pyrimidine nucleobase biosynthetic process
Activation of protein kinase B activity
Anoikis
Brain development
Cardiac muscle cell development
Cardiac muscle contraction
Cell aging
Cell cycle arrest
Cell growth
Cellular response to amino acid starvation
Cellular response to amino acid stimulus
Cellular response to heat
Cellular response to hypoxia
Cellular response to leucine
Cellular response to leucine starvation
Cellular response to nutrient levels
Cellular response to starvation
DNA repair
Double-strand break repair via homologous recombination
Energy reserve metabolic process
Epidermal growth factor receptor signaling pathway
Fc-epsilon receptor signaling pathway
Fibroblast growth factor receptor signaling pathway
Germ cell development
Growth
Heart morphogenesis
Heart valve morphogenesis
Innate immune response
Insulin receptor signaling pathway
Long-term memory
Lysosome organization
Maternal process involved in female pregnancy
MRNA stabilization
Multicellular organism growth
Negative regulation of autophagy
Negative regulation of autophagy of mitochondrion
Negative regulation of calcineurin-NFAT signaling cascade
Negative regulation of cell size
Negative regulation of cholangiocyte apoptotic process
Negative regulation of iodide transmembrane transport
Negative regulation of macroautophagy
Negative regulation of muscle atrophy
Negative regulation of NFAT protein import into nucleus
Negative regulation of protein phosphorylation
Negative regulation of protein ubiquitination
Neurotrophin TRK receptor signaling pathway
Nucleus localization
Peptidyl-serine phosphorylation
Peptidyl-threonine phosphorylation
Phosphatidylinositol-mediated signaling
Phosphorylation
Positive regulation of actin filament polymerization
Positive regulation of cell growth involved in cardiac muscle cell development
Positive regulation of cholangiocyte proliferation
Positive regulation of cytoplasmic translational initiation
Positive regulation of dendritic spine development
Positive regulation of eating behavior
Positive regulation of endothelial cell proliferation
Positive regulation of epithelial to mesenchymal transition
Positive regulation of gene expression
Positive regulation of glial cell proliferation
Positive regulation of granulosa cell proliferation
Positive regulation of keratinocyte migration
Positive regulation of lamellipodium assembly
Positive regulation of lipid biosynthetic process
Positive regulation of myotube differentiation
Positive regulation of neuron death
Positive regulation of neuron maturation
Positive regulation of neuron projection development
Positive regulation of nitric oxide biosynthetic process
Positive regulation of oligodendrocyte differentiation
Positive regulation of peptidyl-tyrosine phosphorylation
Positive regulation of phosphoprotein phosphatase activity
Positive regulation of protein kinase B signaling
Positive regulation of protein phosphorylation
Positive regulation of sensory perception of pain
Positive regulation of skeletal muscle hypertrophy
Positive regulation of smooth muscle cell proliferation
Positive regulation of stress fiber assembly
Positive regulation of transcription by RNA polymerase III
Positive regulation of transcription of nucleolar large rRNA by RNA polymerase I
Positive regulation of translation
Positive regulation of wound healing, spreading of epidermal cells
Post-embryonic development
Protein autophosphorylation
Protein catabolic process
Protein phosphorylation
Regulation of actin cytoskeleton organization
Regulation of brown fat cell differentiation
Regulation of carbohydrate utilization
Regulation of cell growth
Regulation of cell size
Regulation of cellular response to heat
Regulation of circadian rhythm
Regulation of fatty acid beta-oxidation
Regulation of glycogen biosynthetic process
Regulation of GTPase activity
Regulation of locomotor rhythm
Regulation of macroautophagy
Regulation of membrane permeability
Regulation of myelination
Regulation of osteoclast differentiation
Regulation of protein kinase activity
Regulation of response to food
Regulation of signal transduction by p53 class mediator
Regulation of translation at synapse, modulating synaptic transmission
Response to activity
Response to amino acid
Response to cocaine
Response to insulin
Response to morphine
Response to nutrient
Response to nutrient levels
Response to stress
Rhythmic process
Ruffle organization
Signal transduction
Social behavior
Spinal cord development
T cell costimulation
T-helper 1 cell lineage commitment
TOR signaling
TORC1 signaling
Vascular endothelial growth factor receptor signaling pathway
Visual learning
Voluntary musculoskeletal movement
Wound healing
Cellular Component
Cytoplasm
Cytosol
Dendrite
Endomembrane system
Endoplasmic reticulum membrane
Glutamatergic synapse
Golgi membrane
Lysosomal membrane
Lysosome
Membrane
Mitochondrial outer membrane
Neuronal cell body
Nuclear envelope
Nucleoplasm
Nucleus
Phagocytic vesicle
Phosphatidylinositol 3-kinase complex
PML body
Postsynaptic cytosol
TORC1 complex
TORC2 complex
Molecular Function
ATP binding
Drug binding
Identical protein binding
Kinase activity
Phosphoprotein binding
Protein dimerization activity
Protein domain specific binding
Protein kinase activity
Protein kinase binding
Protein serine kinase activity
Protein serine/threonine kinase activity
Protein threonine kinase activity
Ribosome binding
RNA polymerase III type 1 promoter DNA binding
RNA polymerase III type 1 promoter sequence-specific DNA binding
RNA polymerase III type 2 promoter DNA binding
RNA polymerase III type 2 promoter sequence-specific DNA binding
RNA polymerase III type 3 promoter DNA binding
RNA polymerase III type 3 promoter sequence-specific DNA binding
TFIIIC-class transcription factor complex binding
Translation regulator activity
The reference OMIM entry for this protein is 601231
Mechanistic target of rapamycin; mtor
Mammalian target of rapamycin
Fkbp12-rapamycin complex-associated protein 1; frap1
Fk506-binding protein 12-rapamycin complex-associated protein 1
Frap
Frap2
Raft1 mtor complex, included; mtorc, inclu
DESCRIPTION
MTOR is a highly conserved protein kinase that is found in 2 structurally and functionally distinct protein complexes: TOR complex-1 (TORC1) and TORC2. TORC1 is a key regulator of cell growth and proliferation and mRNA translation, whereas TORC2 promotes actin cytoskeletal rearrangement, cell survival, and cell cycle progression (summary by Jacinto et al. (2004) and Thoreen et al. (2012)).CLONING
To identify the target for the FKBP12-rapamycin complex in human, Brown et al. (1994) used a FKBP12/glutathione-S-transferase fusion protein and glutathione affinity chromatography to purify a 220-kD bovine brain protein which bound the FKBP12-rapamycin complex. They designed oligonucleotide probes based on the bovine protein sequence and screened a human Jurkat T-cell cDNA library. Their complete human cDNA for FRAP encoded a predicted 2,549-amino acid protein with a calculated molecular mass of approximately 300 kD. Brown et al. (1994) showed by Northern blot analysis that the 7.6-kb gene transcript was present in a variety of human tissues. They noted that, while the precise functions of FRAP and its yeast homologs TOR1/TOR2 are unknown, the C-terminal regions of these proteins share amino acid homology (approximately 21% identity on average) with several phosphatidylinositol kinases; see 171834. In a review, Hay and Sonenberg (2004) described the domain structure of MTOR. The N-terminal half of the protein contains 20 tandem HEAT repeats, which are implicated in protein-protein interactions. Each HEAT repeat consists of 2 alpha helices of about 40 amino acids. The C-terminal half contains a large FRAP-ATM (607585)-TRRAP (603015) (FAT) domain, followed by the FKB12- and rapamycin-binding domain, a serine/threonine kinase catalytic domain, a negative regulatory domain, and a C-terminal FAT (FATC) domain necessary for MTOR activity.GENE FUNCTION
FKBP12-rapamycin associated protein (FRAP) is one of a family of proteins involved in cell cycle progression, DNA recombination, and DNA damage detection. In rat, it is a 245-kD protein (symbolized RAFT1) with significant homology to the Saccharomyces cerevisiae protein TOR1 and has been shown to associate with the immunophilin FKBP12 (186945) in a rapamycin-dependent fashion (Sabatini et al., 1994). Brown et al. (1994) noted that the FKBP12-rapamycin complex was known to inhibit progression through the G1 cell cycle stage by interfering with mitogenic signaling pathways involved in G1 progression in several cell types, as well as in yeast. The authors stated that the binding of FRAP to FKBP12-rapamycin correlated with the ability of these ligands to inhibit cell cycle progression. Rapamycin is an efficacious anticancer agent against solid tumors. In a hypoxic environment, the increase in mass of solid tumors is dependent on the recruitment of mitogens and nutrients. When nutrient concentrations change, particularly those of essential amino acids, the mammalian target of rapamycin (mTOR/FRAP) functions in regulatory pathways that control ribosome biogenesis and cell growth. In bacteria, ribosome biogenesis is independently regulated by amino acids and ATP. Dennis et al. (2001) demonstrated that the human mTOR pathway is influenced by the intracellular concentration of ATP, independent of the abundance of amino acids, and that mTOR/FRAP itself is an ATP sensor. Castedo et al. (2001) delineated the apoptotic pathway resulting from human immunodeficiency viru ... More on the omim web site
May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 601231 was added.