Mammalian target of rapamycin
Encyclopedia
The mammalian target of rapamycin (mTOR) also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 (FRAP1) is a protein
which in humans is encoded by the FRAP1 gene
. mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility
, cell survival, protein synthesis, and transcription
. mTOR belongs to the phosphatidylinositol 3-kinase-related kinase
protein family.
, growth factors (such as IGF-1 and IGF-2), and amino acid
s. mTOR also senses cellular nutrient and energy levels and redox
status. The mTOR pathway is dysregulated in human diseases, especially certain cancer
s. Rapamycin is a bacterial product that can inhibit mTOR by associating with its intracellular receptor FKBP12
. The FKBP12
-rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR.
mTOR is the catalytic subunit of two molecular complexes.
mTOR stands for mammalian Target Of Rapamycin and was named based on the precedent that Tor was first discovered via genetic and molecular studies of rapamycin-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of rapamycin and provided robust support that the FKBP12-rapamycin complex binds to and inhibits the cellular functions of Tor1 and Tor2.
), mammalian LST8/G-protein β-subunit like protein (mLST8/GβL) and the recently identified partners PRAS40 and DEPTOR. This complex is characterized by the classic features of mTOR by functioning as a nutrient/energy/redox sensor and controlling protein synthesis. The activity of this complex is stimulated by insulin, growth factors, serum
, phosphatidic acid, amino acids (particularly leucine
), and oxidative stress
.
mTORC1 is inhibited by low nutrient levels, growth factor deprivation, reductive stress, rapamycin, and farnesylthiosalicylic acid (FTS). The two best characterized targets of mTORC1 are p70-S6 Kinase 1
(S6K1) and 4E-BP1, the eukaryotic initiation factor 4E
(eIF4E) binding protein 1.
mTORC1 phosphorylates S6K1 on at least two residues, with the most critical modification occurring on a threonine
residue (T389) . This event stimulates the subsequent phosphorylation of S6K1 by PDK1. Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the ribosome
) and other components of the translational machinery. S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites; phosphorylation at these sites appears to stimulate mTOR activity.
mTORC1 has been shown to phosphorylate at least four residues of 4E-BP1 in a hierarchical manner. Non-phosphorylated 4E-BP1 binds tightly to the translation initiation factor eIF4E, preventing it from binding to 5'-capped mRNAs and recruiting them to the ribosomal initiation complex
. Upon phosphorylation by mTORC1, 4E-BP1 releases eIF4E, allowing it to perform its function. The activity of mTORC1 appears to be regulated through a dynamic interaction between mTOR and Raptor, one which is mediated by GβL
. Raptor and mTOR share a strong N-terminal interaction and a weaker C-terminal interaction near mTOR's kinase domain. When stimulatory signals are sensed, such as high nutrient/energy levels, the mTOR-Raptor C-terminal interaction is weakened and possibly completely lost, allowing mTOR kinase activity to be turned on. When stimulatory signals are withdrawn, such as low nutrient levels, the mTOR-Raptor C-terminal interaction is strengthened, essentially shutting off kinase function of mTOR .
). mTORC2 has been shown to function as an important regulator of the cytoskeleton
through its stimulation of F-actin
stress fibers, paxillin
, RhoA
, Rac1
, Cdc42
, and protein kinase C
α (PKCα
). mTORC2 also appears to possess the activity of a previously elusive protein known as "PDK2
". mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB
at a serine residue S473 . Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308 residue by PDK1 and leads to full Akt activation; curcumin inhibits both by preventing phosphorylation of the serine.
mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels. Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation. However, subsequent studies have shown that, at least in some cell lines, chronic exposure to rapamycin, while not affecting pre-existing mTORC2s, promotes rapamycin inhibition of free mTOR molecules, thus inhibiting the formation of new mTORC2.
and knockouts
were found to produce the following phenotypes:
]
Decreased TOR activity has been found to slow aging in S. cerevisiae
, C. elegans
, and D. melanogaster
. The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice by independent groups at the Jackson Laboratory
, University of Texas Health Science Center, and the University of Michigan
.
It's hypothesized that some dietary regimes, like caloric restriction and methionine
restriction, cause lifespan extension by decreasing mTOR activity. But infusion of leucine
into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway.
mTOR inhibitors, e.g. rapamycin, are already used to prevent transplant rejection
. Rapamycin is also related to the therapeuty of glycogen storage disease (GSD). Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS(glycogen storage) can be increased in skeletal muscle.This discovery represents a potential novel therapeutic approach for glycogen storage diseases that involve glycogen accumulation in muscle. Various natural compounds, including epigallocatechin gallate
(EGCG), caffeine
, curcumin
, and resveratrol
, have also been reported to inhibit mTOR when applied to isolated cells in culture; however, there is as yet no evidence that these substances inhibit mTOR when taken as dietary supplements.
Some (e.g. Temsirolimus
) are beginning to be used in the treatment of cancer. mTOR inhibitors may also be useful for treating several age-associated diseases.
mTOR inhibitors in clinical development include : Ridaforolimus and Everolimus
.
with:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the FRAP1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. mTOR is a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility
Motility
Motility is a biological term which refers to the ability to move spontaneously and actively, consuming energy in the process. Most animals are motile but the term applies to single-celled and simple multicellular organisms, as well as to some mechanisms of fluid flow in multicellular organs, in...
, cell survival, protein synthesis, and transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
. mTOR belongs to the phosphatidylinositol 3-kinase-related kinase
Phosphatidylinositol 3-kinase-related kinase
Phosphatidylinositol 3-kinase-related kinases are a family of Ser/Thr-protein kinases with sequence similarity to phosphatidylinositol-3 kinases .- Members :The human PIKK family includes six members:- Structure :...
protein family.
Function
mTOR integrates the input from upstream pathways, including insulinInsulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, growth factors (such as IGF-1 and IGF-2), and amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s. mTOR also senses cellular nutrient and energy levels and redox
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
status. The mTOR pathway is dysregulated in human diseases, especially certain cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s. Rapamycin is a bacterial product that can inhibit mTOR by associating with its intracellular receptor FKBP12
FKBP
FKBP, or FK506 binding protein, is a family of proteins that have prolyl isomerase activity and are related to the cyclophilins in function, though not in amino acid sequence. FKBPs have been identified in many eukaryotes from yeast to humans and function as protein folding chaperones for proteins...
. The FKBP12
FKBP
FKBP, or FK506 binding protein, is a family of proteins that have prolyl isomerase activity and are related to the cyclophilins in function, though not in amino acid sequence. FKBPs have been identified in many eukaryotes from yeast to humans and function as protein folding chaperones for proteins...
-rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR.
mTOR is the catalytic subunit of two molecular complexes.
mTOR stands for mammalian Target Of Rapamycin and was named based on the precedent that Tor was first discovered via genetic and molecular studies of rapamycin-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of rapamycin and provided robust support that the FKBP12-rapamycin complex binds to and inhibits the cellular functions of Tor1 and Tor2.
mTORC1
mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR (RaptorKIAA1303
Regulatory-associated protein of mTOR is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long....
), mammalian LST8/G-protein β-subunit like protein (mLST8/GβL) and the recently identified partners PRAS40 and DEPTOR. This complex is characterized by the classic features of mTOR by functioning as a nutrient/energy/redox sensor and controlling protein synthesis. The activity of this complex is stimulated by insulin, growth factors, serum
Serous fluid
In physiology, the term serous fluid is used for various bodily fluids that are typically pale yellow and transparent, and of a benign nature, that fill the inside of body cavities. Serous fluid originates from serous glands, with secretions enriched with proteins and water. Serous fluid may also...
, phosphatidic acid, amino acids (particularly leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
), and oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
.
mTORC1 is inhibited by low nutrient levels, growth factor deprivation, reductive stress, rapamycin, and farnesylthiosalicylic acid (FTS). The two best characterized targets of mTORC1 are p70-S6 Kinase 1
P70-S6 Kinase 1
Ribosomal protein S6 kinase beta-1 is an enzyme that in humans is encoded by the RPS6KB1 gene.-Interactions:P70-S6 Kinase 1 has been shown to interact with CSNK2B, EIF3B, COASY, KIAA1303, POLDIP3, Mammalian target of rapamycin, PPP2R2A, RBX1 and Ubiquitin C.-References:...
(S6K1) and 4E-BP1, the eukaryotic initiation factor 4E
EIF4E
Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein which in humans is encoded by the eIF4E gene.- Function :...
(eIF4E) binding protein 1.
mTORC1 phosphorylates S6K1 on at least two residues, with the most critical modification occurring on a threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
residue (T389) . This event stimulates the subsequent phosphorylation of S6K1 by PDK1. Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
) and other components of the translational machinery. S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites; phosphorylation at these sites appears to stimulate mTOR activity.
mTORC1 has been shown to phosphorylate at least four residues of 4E-BP1 in a hierarchical manner. Non-phosphorylated 4E-BP1 binds tightly to the translation initiation factor eIF4E, preventing it from binding to 5'-capped mRNAs and recruiting them to the ribosomal initiation complex
Eukaryotic translation
Eukaryotic translation is the process by which messenger RNA is translated into proteins in eukaryotes. It consists of initiation, elongation and termination Translation-Initiation:-Cap-dependent initiation:...
. Upon phosphorylation by mTORC1, 4E-BP1 releases eIF4E, allowing it to perform its function. The activity of mTORC1 appears to be regulated through a dynamic interaction between mTOR and Raptor, one which is mediated by GβL
MLST8
Target of rapamycin complex subunit LST8, also known as G protein beta subunit-like , is a protein that in humans is encoded by the MLST8 gene....
. Raptor and mTOR share a strong N-terminal interaction and a weaker C-terminal interaction near mTOR's kinase domain. When stimulatory signals are sensed, such as high nutrient/energy levels, the mTOR-Raptor C-terminal interaction is weakened and possibly completely lost, allowing mTOR kinase activity to be turned on. When stimulatory signals are withdrawn, such as low nutrient levels, the mTOR-Raptor C-terminal interaction is strengthened, essentially shutting off kinase function of mTOR .
mTORC2
mTOR Complex 2 (mTORC2) is composed of mTOR, rapamycin-insensitive companion of mTOR (Rictor), GβL, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1MAPKAP1
Target of rapamycin complex 2 subunit MAPKAP1 is a protein that in humans is encoded by the MAPKAP1 gene.-Further reading:...
). mTORC2 has been shown to function as an important regulator of the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
through its stimulation of F-actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
stress fibers, paxillin
Paxillin
Paxillin is a signal transduction adaptor protein discovered in 1990 in the laboratory of Keith Burridge and should not be confused with the neurotoxin paxilline. The C-terminal region of paxillin contains four LIM domains that target paxillin to focal adhesions, it is presumed through a direct...
, RhoA
RHOA
Ras homolog gene family, member A is a small GTPase protein known to regulate the actin cytoskeleton in the formation of stress fibers. In humans, it is encoded by the gene RHOA....
, Rac1
RAC1
Ras-related C3 botulinum toxin substrate 1 also known as Rac1 is a protein that in humans is encoded by the RAC1 gene. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined.- Function :Rac1 is...
, Cdc42
CDC42
Cell division control protein 42 homolog also known as CDC42 is a protein involved in regulation of the cell cycle. In humans, CDC42 is encoded by the CDC42 gene.- Function :...
, and protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
α (PKCα
PKC alpha
Protein kinase C alpha , also known as PRKCA, refers to both a human gene and the protein that is encoded by it.-Background:...
). mTORC2 also appears to possess the activity of a previously elusive protein known as "PDK2
PDK2
Pyruvate dehydrogenase kinase isoform 2 also known as [pyruvate dehydrogenase [lipoamide]] kinase isozyme 2, mitochondrial is an enzyme that in humans is encoded by the PDK2 gene. PDK2 is an isozyme of pyruvate dehydrogenase kinase....
". mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
at a serine residue S473 . Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308 residue by PDK1 and leads to full Akt activation; curcumin inhibits both by preventing phosphorylation of the serine.
mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels. Originally, mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation. However, subsequent studies have shown that, at least in some cell lines, chronic exposure to rapamycin, while not affecting pre-existing mTORC2s, promotes rapamycin inhibition of free mTOR molecules, thus inhibiting the formation of new mTORC2.
Physiological significance (KO phenotypes)
The mTORC2 signaling pathway is less clearly defined than the mTORC1 signaling pathway. Therefore, performing knockout experiments is a good way to shed light on more specific molecules and their roles in this pathway. Protein function inhibition using knockdownsGene knockdown
Gene knockdown refers to techniques by which the expression of one or more of an organism's genes is reduced, either through genetic modification or by treatment with a reagent such as a short DNA or RNA oligonucleotide with a sequence complementary to either an mRNA transcript or a gene...
and knockouts
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
were found to produce the following phenotypes:
- NIP7NIP760S ribosome subunit biogenesis protein NIP7 homolog is a protein that in humans is encoded by the NIP7 gene.-Further reading:...
: knockdown reduced mTORC2 activity which is indicated by decreased phosphorylation of mTORC2 substrates. - RICTORRICTORRapamycin-insensitive companion of mTOR is a protein that in humans is encoded by the RICTOR gene.-Interactions:RICTOR has been shown to interact with Mammalian target of rapamycin and KIAA1303.-Further reading:...
: overexpression leads to metastasis and knockdown inhibits growth factor induced PKC-phosphorylation. - mTOR: inhibition of mTORC1 and mTORC2 by PP242 [2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol] leads to autophagy or apoptosis; inhibition of mTORC2 alone by PP242 prevents phosphorylation of Ser-473 site on AKT and arrests the cells in G1 phaseG1 phaseThe G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
of the cell cycleCell cycleThe cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
. - PDK1PDK1[Pyruvate dehydrogenase [lipoamide]] kinase isozyme 1, mitochondrial is an enzyme that in humans is encoded by the PDK1 gene. It codes for an isozyme of pyruvate dehydrogenase kinase ....
: knockout is lethal; hypomorphic allele results in smaller organ volume and organism size, but normal AKT activation. - AKTAKTAkt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
: knockout mice experience spontaneous apoptosis (AKT1AKT1RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for this gene.- Function :...
), severe diabetes (AKT2AKT2RAC-beta serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT2 gene.-Interactions:AKT2 has been shown to interact with TCL1A, APPL1, SH3RF1 and CHUK.-Further reading:...
), small brains (AKT3AKT3RAC-gamma serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT3 gene.-Interactions:AKT3 has been shown to interact with Protein kinase Mζ.-Further reading:...
), and growth deficiency (AKT1/AKT2)
Aging
Decreased TOR activity has been found to slow aging in S. cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
, C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
, and D. melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
. The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice by independent groups at the Jackson Laboratory
Jackson Laboratory
The Jackson Laboratory was founded in Bar Harbor, Maine in 1929 by former University of Maine and University of Michigan president C. C. Little under the name Roscoe B...
, University of Texas Health Science Center, and the University of Michigan
University of Michigan
The University of Michigan is a public research university located in Ann Arbor, Michigan in the United States. It is the state's oldest university and the flagship campus of the University of Michigan...
.
It's hypothesized that some dietary regimes, like caloric restriction and methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
restriction, cause lifespan extension by decreasing mTOR activity. But infusion of leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway.
mTOR inhibitors as therapies
mTOR inhibitors, e.g. rapamycin, are already used to prevent transplant rejection
Transplant rejection
Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after...
. Rapamycin is also related to the therapeuty of glycogen storage disease (GSD). Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS(glycogen storage) can be increased in skeletal muscle.This discovery represents a potential novel therapeutic approach for glycogen storage diseases that involve glycogen accumulation in muscle. Various natural compounds, including epigallocatechin gallate
Epigallocatechin gallate
Epigallocatechin gallate , also known as epigallocatechin 3-gallate, is the ester of epigallocatechin and gallic acid, and is a type of catechin....
(EGCG), caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
, curcumin
Curcumin
Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family . The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric...
, and resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
, have also been reported to inhibit mTOR when applied to isolated cells in culture; however, there is as yet no evidence that these substances inhibit mTOR when taken as dietary supplements.
Some (e.g. Temsirolimus
Temsirolimus
Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma , developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration in late May 2007, and was also approved by the European Medicines Agency on November 2007...
) are beginning to be used in the treatment of cancer. mTOR inhibitors may also be useful for treating several age-associated diseases.
mTOR inhibitors in clinical development include : Ridaforolimus and Everolimus
Everolimus
Everolimus is the 40-O- derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor....
.
Interactions
Mammalian target of rapamycin has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- Abl geneAbl geneV-abl Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9.- Function :...
, - AKT1AKT1RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for this gene.- Function :...
, - CLIP1CLIP1CAP-GLY domain containing linker protein 1, also known as CLIP1, is a protein which in humans is encoded by the CLIP1 gene.-Interactions:CLIP1 has been shown to interact with IQGAP1, Mammalian target of rapamycin and PAFAH1B1.-Further reading:...
, - EIF3FEIF3FEukaryotic translation initiation factor 3 subunit F is a protein that in humans is encoded by the EIF3F gene.-Interactions:EIF3F has been shown to interact with Mammalian target of rapamycin and EIF3A.-Further reading:...
- EIF4EBP1EIF4EBP1Eukaryotic translation initiation factor 4E-binding protein 1 is a protein that in humans is encoded by the EIF4EBP1 gene.-Interactions:EIF4EBP1 has been shown to interact with Mammalian target of rapamycin, EIF4E and KIAA1303.-Further reading:...
, - FKBP1AFKBP1APeptidyl-prolyl cis-trans isomerase FKBP1A is an enzyme that in humans is encoded by the FKBP1A gene.-Interactions:FKBP1A has been shown to interact with RYR1, Mammalian target of rapamycin, TGF beta receptor 1, GLMN, ITPR1 and KIAA1303....
, - GPHNGPHNGPHN is a human gene that encodes the protein gephyrin.-Interactions:GPHN has been shown to interact with Mammalian target of rapamycin and ARHGEF9.-Further reading:...
, - KIAA1303KIAA1303Regulatory-associated protein of mTOR is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long....
, - P70-S6 Kinase 1P70-S6 Kinase 1Ribosomal protein S6 kinase beta-1 is an enzyme that in humans is encoded by the RPS6KB1 gene.-Interactions:P70-S6 Kinase 1 has been shown to interact with CSNK2B, EIF3B, COASY, KIAA1303, POLDIP3, Mammalian target of rapamycin, PPP2R2A, RBX1 and Ubiquitin C.-References:...
, - PRKCDPRKCDProtein kinase C delta type is an enzyme that in humans is encoded by the PRKCD gene.- Function :Protein kinase C is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol...
, - RHEBRHEBGTP-binding protein Rheb also known as Ras homolog enriched in brain is a protein that in humans is encoded by the RHEB gene.- Function :Rheb is a recently discovered member of the Ras superfamily that may be involved in neural plasticity...
, - RICTORRICTORRapamycin-insensitive companion of mTOR is a protein that in humans is encoded by the RICTOR gene.-Interactions:RICTOR has been shown to interact with Mammalian target of rapamycin and KIAA1303.-Further reading:...
, - STAT1STAT1STAT1 is a member of the Signal Transducers and Activators of Transcription family of transcription factors. STAT1 is involved in upregulating genes due to a signal by either type I, type II or type III interferons...
, - STAT3STAT3Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
, and - UBQLN1UBQLN1Ubiquilin-1 is a protein that in humans is encoded by the UBQLN1 gene.Ubiquilins contain a N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain...
.