mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a
protein complex
A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain.
Protein c ...
that functions as a nutrient/energy/redox sensor and controls protein synthesis.
mTOR Complex 1 (mTORC1) is composed of the
mTOR
The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MT ...
protein complex,
regulatory-associated protein of mTOR (commonly known as raptor), mammalian lethal with SEC13 protein 8 (
MLST8
Target of rapamycin complex subunit LST8, also known as mammalian lethal with SEC13 protein 8 (mLST8) or TORC subunit LST8 or G protein beta subunit-like (GβL or Gable), is a protein that in humans is encoded by the ''MLST8'' (MTOR associated pro ...
),
PRAS40 and
DEPTOR
DEP domain-containing mTOR-interacting protein (DEPTOR) also known as DEP domain-containing protein 6 (DEPDC6) is a protein that in humans is encoded by the ''DEPTOR'' gene.
Structure
The gene ''DEPTOR'' can be found only in vertebrates. In hu ...
.
This complex embodies the classic functions of mTOR, namely as a nutrient/energy/redox sensor and controller of protein synthesis.
[ The activity of this complex is regulated by ]rapamycin
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, ...
, insulin, growth factors, phosphatidic acid Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty ac ...
, certain amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
and their derivatives (e.g., -leucine and β-hydroxy β-methylbutyric acid
β-Hydroxy β-methylbutyric acid (HMB), otherwise known as its conjugate base, , is a naturally produced substance in humans that is used as a dietary supplement and as an ingredient in certain medical foods that are intended to promote wou ...
), mechanical stimuli, and oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
. Recently it has been also demonstrated that cellular bicarbonate metabolism can be regulated by mTORC1 signaling.
The role of mTORC1 is to activate translation of proteins. In order for cells to grow and proliferate by manufacturing more proteins, the cells must ensure that they have the resources available for protein production. Thus, for protein production, and therefore mTORC1 activation, cells must have adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for mRNA translation to begin.
Activation at the lysosome
The TSC complex
Almost all of the variables required for protein synthesis affect mTORC1 activation by interacting with the TSC1/TSC2 protein complex. TSC2
Tuberous Sclerosis Complex 2 (TSC2), also known as Tuberin, is a protein that in humans is encoded by the ''TSC2'' gene.
Function
Mutations in this gene lead to tuberous sclerosis. Its gene product is believed to be a tumor suppressor and is a ...
is a GTPase
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
activating protein ( GAP). Its GAP activity interacts with a G protein called Rheb by hydrolyzing the GTP of the active Rheb-GTP complex, converting it to the inactive Rheb-GDP complex. The active Rheb-GTP activates mTORC1 through unelucidated pathways. Thus, many of the pathways that influence mTORC1 activation do so through the activation or inactivation of the TSC1/TSC2 heterodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
. This control is usually performed through phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of the complex. This phosphorylation can cause the dimer to dissociate and lose its GAP activity, or the phosphorylation can cause the heterodimer to have increased GAP activity, depending on which amino acid residue becomes phosphorylated. Thus, the signals that influence mTORC1 activity do so through activation or inactivation of the TSC1/TSC2 complex, upstream of mTORC1.
The Ragulator-Rag complex
mTORC1 interacts at the Ragulator-Rag complex
The Ragulator-Rag complex is a regulator of lysosomal signalling and trafficking in eukaryotic cells, which plays an important role in regulating cell metabolism and growth in response to nutrient availability in the cell. The Ragulator-Rag Complex ...
on the surface of the lysosome in response to amino acid levels in the cell. Even if a cell has the proper energy for protein synthesis, if it does not have the amino acid building blocks for proteins, no protein synthesis will occur. Studies have shown that depriving amino acid levels inhibits mTORC1 signaling to the point where both energy abundance and amino acids are necessary for mTORC1 to function. When amino acids are introduced to a deprived cell, the presence of amino acids causes Rag GTPase heterodimers to switch to their active conformation. Active Rag heterodimers interact with raptor, localizing mTORC1 to the surface of late endosome
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...
s and lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
s where the Rheb-GTP is located. This allows mTORC1 to physically interact with Rheb. Thus the amino acid pathway as well as the growth factor/energy pathway converge on endosomes and lysosomes. Thus the Ragulator-Rag complex recruits mTORC1 to lysosomes to interact with Rheb.
Regulation of the Ragulator-Rag complex
Rag activity is regulated by at least two highly conserved complexes: the "GATOR1" complex containing DEPDC5
DEPDC5 (or DEP domain-containing 5) is a human protein of poorly understood function but has been associated with cancer in several studies. It is encoded by a gene of the same name, located on chromosome 22.
Function
The function of DEPDC5 is n ...
, NPRL2
Nitrogen permease regulator 2-like protein (NPRL2) also known as tumor suppressor candidate 4 (TUSC4) is a protein that in humans is encoded by the ''NPRL2'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene ...
and NPRL3
Nitrogen permease regulator-like 3 is a protein that in humans is encoded by the NPRL3 gene.
Function
NPRL3 is a human protein of poorly understood function but has been associated with cancer.
The most prominent function ascribed to Nprl3 to ...
and the ""GATOR2" complex containing Mios
Mios (; oc-gsc, Miòs) is a commune in the Gironde department in Nouvelle-Aquitaine in southwestern France.
Population
Its inhabitants are called ''Miossais''.
Sights
The Saint Brice chapel has a bell dating from 1700 classed as a '' monumen ...
, WDR24
WD repeat-containing protein 24 is a protein that in humans is encoded by the ''WDR24'' gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generati ...
, WDR59, Seh1L, Sec13. GATOR1 inhibits Rags (it is a GTPase-activating protein GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are a ...
for Rag subunits A/B) and GATOR2 activates Rags by inhibiting DEPDC5
DEPDC5 (or DEP domain-containing 5) is a human protein of poorly understood function but has been associated with cancer in several studies. It is encoded by a gene of the same name, located on chromosome 22.
Function
The function of DEPDC5 is n ...
.
Upstream signaling
Receptor tyrosine kinases
Akt/PKB pathway
Insulin-like growth factors can activate mTORC1 through the receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase ...
(RTK)-Akt/PKB signaling pathway The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K (phosphatidylinositol 3-kinase) and Akt ( protein kinas ...
. Ultimately, Akt
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...
phosphorylates TSC2 on serine residue 939, serine residue 981, and threonine residue 1462. These phosphorylated sites will recruit the cytosolic anchoring protein 14-3-3
14-3-3 proteins are a family of conserved regulatory molecules that are expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and trans ...
to TSC2, disrupting the TSC1/TSC2 dimer. When TSC2 is not associated with TSC1, TSC2 loses its GAP activity and can no longer hydrolyze Rheb-GTP. This results in continued activation of mTORC1, allowing for protein synthesis via insulin signaling.
Akt will also phosphorylate PRAS40, causing it to fall off of the Raptor protein located on mTORC1. Since PRAS40 prevents Raptor from recruiting mTORC1's substrates 4E-BP1
Eukaryotic translation initiation factor 4E-binding protein 1 (also known as 4E-BP1) is a protein that in humans is encoded by the ''EIF4EBP1'' gene.
Function
This gene encodes one member of a family of translation repressor proteins. The prot ...
and S6K1
Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase (p70S6K, p70-S6K), is an enzyme (specifically, a protein kinase) that in humans is encoded by the ''RPS6KB1'' gene. It is a serine/threonine kinase that acts downstream of PIP3 ...
, its removal will allow the two substrates to be recruited to mTORC1 and thereby activated in this way.
Furthermore, since insulin is a factor that is secreted by pancreatic beta cells
Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...
upon glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
elevation in the blood, its signaling ensures that there is energy for protein synthesis to take place. In a negative feedback loop
Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by other ...
on mTORC1 signaling, S6K1 is able to phosphorylate the insulin receptor
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeo ...
and inhibit its sensitivity to insulin. This has great significance in diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, which is due to insulin resistance
Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
.
MAPK/ERK pathway
Mitogens
A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...
, such as insulin like growth factor 1 (IGF1
Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.
IGF-1 is a protein that in humans is ...
), can activate the MAPK/ERK pathway
The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
The signal starts when a signaling ...
, which can inhibit the TSC1/TSC2 complex, activating mTORC1. In this pathway, the G protein Ras is tethered to the plasma membrane via a farnesyl
Farnesol is a natural 15-carbon organic compound which is an acyclic sesquiterpene alcohol. Under standard conditions, it is a colorless liquid. It is hydrophobic, and thus insoluble in water, but miscible with oils.
Farnesol is produced from 5- ...
group and is in its inactive GDP state. Upon growth factor binding to the adjacent receptor tyrosine kinase, the adaptor protein GRB2 binds with its SH2 domain
The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains allow proteins containing those domains to dock to phosphory ...
s. This recruits the GEF called Sos, which activates the Ras G protein. Ras activates Raf
The Royal Air Force (RAF) is the United Kingdom's air and space force. It was formed towards the end of the First World War on 1 April 1918, becoming the first independent air force in the world, by regrouping the Royal Flying Corps (RFC) and ...
(MAPKKK), which activates Mek (MAPKK), which activates Erk (MAPK). Erk can go on to activate RSK. Erk will phosphorylate the serine residue 644 on TSC2, while RSK will phosphorylate serine residue 1798 on TSC2. These phosphorylations will cause the heterodimer to fall apart, and prevent it from deactivating Rheb, which keeps mTORC1 active.
RSK has also been shown to phosphorylate raptor
Raptor or RAPTOR may refer to:
Animals
The word "raptor" refers to several groups of bird-like dinosaurs which primarily capture and subdue/kill prey with their talons.
* Raptor (bird) or bird of prey, a bird that primarily hunts and feeds on v ...
, which helps it overcome the inhibitory effects of PRAS40.
JNK pathway
c-Jun N-terminal kinase (JNK
c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and ar ...
) signaling is part of the mitogen-activated protein kinase (MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
) signaling pathway essential in stress signaling pathways relating to gene expression, neuronal development, and cell survival. Recent studies have shown there is a direct molecular interaction where JNK phosphorylates Raptor
Raptor or RAPTOR may refer to:
Animals
The word "raptor" refers to several groups of bird-like dinosaurs which primarily capture and subdue/kill prey with their talons.
* Raptor (bird) or bird of prey, a bird that primarily hunts and feeds on v ...
at Ser-696, Thr-706, and Ser-863. Therefore, mTORC1 activity is JNK-dependent. Thus, JNK activation plays a role in protein synthesis via subsequent downstream effectors of mTORC1 such as S6 kinase and eIFs.
Wnt pathway
The Wnt pathway
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling p ...
is responsible for cellular growth and proliferation during organismal development; thus, it could be reasoned that activation of this pathway also activates mTORC1. Activation of the Wnt pathway inhibits glycogen synthase kinase 3 beta (GSK3B
Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the ''GSK3B'' gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased suscept ...
). When the Wnt pathway is not active, GSK3B is able to phosphorylate TSC2 on Ser1341 and Ser1337 in conjunction with AMPK phosphorylation of Ser1345. It has been found that the AMPK is required to first phosphorylate Ser1345 before GSK3B can phosphorylate its target serine residues. This phosphorylation of TSC2 would activate this complex, if GSK3B were active. Since the Wnt pathway inhibits GSK3 signaling, the active Wnt pathway is also involved in the mTORC1 pathway. Thus, mTORC1 can activate protein synthesis
Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...
for the developing organism.
Cytokines
Cytokines
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
like tumor necrosis factor alpha
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
(TNF-alpha) can induce mTOR activity through IKK beta, also known as IKK2
IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the ''IKBKB'' (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta) gene.
Function
IKK-β is an enzy ...
. IKK beta can phosphorylate TSC1 at serine residue 487 and TSC1 at serine residue 511. This causes the heterodimer TSC complex to fall apart, keeping Rheb in its active GTP-bound state.
Energy and oxygen
Energy status
In order for translation to take place, abundant sources of energy, particularly in the form of ATP, need to be present. If these levels of ATP are not present, due to its hydrolysis into other forms like AMP #REDIRECT Amp
{{Redirect category shell, {{R from other capitalisation{{R from ambiguous page ...
, and the ratio of AMP to ATP molecules gets too high, AMPK AMPK may refer to:
* AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate gl ...
will become activated. AMPK will go on to inhibit energy consuming pathways such as protein synthesis.
AMPK can phosphorylate TSC2 on serine residue 1387, which activates the GAP activity of this complex, causing Rheb-GTP to be hydrolyzed into Rheb-GDP. This inactivates mTORC1 and blocks protein synthesis through this pathway.
AMPK can also phosphorylate Raptor on two serine residues. This phosphorylated Raptor recruits 14-3-3 to bind to it and prevents Raptor from being part of the mTORC1 complex. Since mTORC1 cannot recruit its substrates without Raptor, no protein synthesis via mTORC1 occurs.
LKB1, also known as STK11
Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the ''STK11'' gene.
Expression
Testosterone and DHT treatment of murine 3T3-L1 or human ...
, is a known tumor suppressor
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
that can activate AMPK. More studies on this aspect of mTORC1 may help shed light on its strong link to cancer.
Hypoxic stress
When oxygen levels in the cell are low, it will limit its energy expenditure through the inhibition of protein synthesis. Under hypoxic
Hypoxia means a lower than normal level of oxygen, and may refer to:
Reduced or insufficient oxygen
* Hypoxia (environmental), abnormally low oxygen content of the specific environment
* Hypoxia (medical), abnormally low level of oxygen in the tis ...
conditions, hypoxia inducible factor one alpha (HIF1A
Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the ''HIF1A'' gene. The Nobel Prize in Physiology or Medicine 2019 was awarded ...
) will stabilize and activate transcription of REDD1, also known as DDIT4. After translation, this REDD1 protein will bind to TSC2, which prevents 14-3-3 from inhibiting the TSC complex. Thus, TSC retains its GAP activity towards Rheb, causing Rheb to remain bound to GDP and mTORC1 to be inactive.
Due to the lack of synthesis of ATP in the mitochondria under hypoxic stress or hypoxia, AMPK will also become active and thus inhibit mTORC1 through its processes.
Downstream signaling
mTORC1 activates transcription and translation through its interactions with p70-S6 Kinase 1
Ribosomal protein S6 kinase beta-1 (S6K1), also known as p70S6 kinase (p70S6K, p70-S6K), is an enzyme (specifically, a protein kinase) that in humans is encoded by the ''RPS6KB1'' gene. It is a serine/threonine kinase that acts downstream of PIP3 ...
(S6K1) and 4E-BP1
Eukaryotic translation initiation factor 4E-binding protein 1 (also known as 4E-BP1) is a protein that in humans is encoded by the ''EIF4EBP1'' gene.
Function
This gene encodes one member of a family of translation repressor proteins. The prot ...
, the eukaryotic initiation factor 4E (eIF4E) binding protein 1, primarily via phosphorylation and dephosphorylation of its downstream targets. S6K1 and 4E-BP1 modulate translation in eukaryotic cells. Their signaling will converge at the translation initiation complex on the 5' end of mRNA, and thus activate translation.
4E-BP1
Activated mTORC1 will phosphorylate translation repressor protein 4E-BP1
Eukaryotic translation initiation factor 4E-binding protein 1 (also known as 4E-BP1) is a protein that in humans is encoded by the ''EIF4EBP1'' gene.
Function
This gene encodes one member of a family of translation repressor proteins. The prot ...
, thereby releasing it from eukaryotic translation initiation factor 4E (eIF4E
Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the ''EIF4E'' gene.
Structure and function
Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine fi ...
). eIF4E is now free to join the eukaryotic translation initiation factor 4G (eIF4G
Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeast ...
) and the eukaryotic translation initiation factor 4A (eIF4A
The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that f ...
). This complex then binds to the 5' cap of mRNA and will recruit the helicase
Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separatin ...
eukaryotic translation initiation factor A (eIF4A) and its cofactor eukaryotic translation initiation factor 4B (eIF4B
Eukaryotic translation initiation factor 4B is a protein that in humans is encoded by the ''EIF4B'' gene.
Interactions
eIF4B has been shown to interact with and stimulate the activity of eIF4A and bind to the eIF3 complex through the eIF3A subu ...
). The helicase is required to remove hairpin loops that arise in the 5' untranslated regions of mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
, which prevent premature translation of proteins. Once the initiation complex is assembled at the 5' cap of mRNA, it will recruit the 40S
The eukaryotic small ribosomal subunit (40S) is the smaller subunit of the eukaryotic 80S ribosomes, with the other major component being the large ribosomal subunit (60S). The "40S" and "60S" names originate from the convention that ribosomal pa ...
small ribosomal subunit that is now capable of scanning for the AUG start codon
The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and Archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids. The ...
start site, because the hairpin loop
Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence wh ...
has been degraded by the eIF4A helicase. Once the ribosome reaches the AUG codon, translation can begin.
S6K
Previous studies suggest that S6K signaling is mediated by mTOR in a rapamycin-dependent manner wherein S6K is displaced from the eIF3 complex upon binding of mTOR with eIF3. Hypophosphorylated S6K is located on the eIF3
Eukaryotic initiation factor 3 (eIF3) is a multiprotein complex that functions during the initiation phase of eukaryotic translation. It is essential for most forms of Eukaryotic translation#Cap-dependent initiation, cap-dependent and Eukaryotic t ...
scaffold complex. Active mTORC1 gets recruited to the scaffold, and once there, will phosphorylate S6K to make it active.
mTORC1 phosphorylates
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...
S6K1 on at least two residues, with the most critical modification occurring on a threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COOâ ...
residue (T389). This event stimulates the subsequent phosphorylation of S6K1 by PDPK1
In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the ''PDPK1'' gene in humans. It is implicated in the development and progression of melanomas.
Function
PD ...
. Active S6K1 can in turn stimulate the initiation of protein synthesis through activation of S6 Ribosomal protein (a component of the ribosome
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
) and eIF4B, causing them to be recruited to the pre-initiation complex.
Active S6K can bind to the SKAR scaffold protein
In biology, scaffold proteins are crucial regulators of many key signalling pathways. Although scaffolds are not strictly defined in function, they are known to interact and/or bind with multiple members of a signalling pathway, tethering them in ...
that can get recruited to exon junction complexes ( EJC). Exon junction complexes span the mRNA region where two exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
come together after an intron
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
has been spliced out. Once S6K binds to this complex, increased translation on these mRNA regions occurs.
S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites thr-2446 and ser-2448; phosphorylation at these sites appears to stimulate mTOR activity.
S6K also can phosphorylate programmed cell death 4 (PDCD4
Programmed cell death protein 4 is a protein that in humans is encoded by the ''PDCD4'' gene. It is one of the targets of an oncomiR, MIRN21.
Function
This gene encodes a protein localized to the nucleus in proliferating cells. Expression of t ...
), which marks it for degradation by ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
Beta-TrCP ( BTRC). PDCD4 is a tumor suppressor that binds to eIF4A and prevents it from being incorporated into the initiation complex.
Role in disease and aging
mTOR was found to be related to aging in 2001 when the ortholog of S6K, SCH9, was deleted in ''S. cerevisiae'', doubling its lifespan. This greatly increased the interest in upstream signaling and mTORC1. Studies in inhibiting mTORC1 were thus performed on the model organisms of ''C. elegans'', fruitflies, and mice. Inhibition of mTORC1 showed significantly increased lifespans in all model species. Disrupting the gut microbiota of infant mice was found to lead to reduced longevity with signaling of mTORC1 implicated as a potential mechanism.
Based on upstream signaling of mTORC1, a clear relationship between food consumption and mTORC1 activity has been observed. Most specifically, carbohydrate consumption activates mTORC1 through the insulin growth factor
The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF ...
pathway. In addition, amino acid consumption will stimulate mTORC1 through the branched chain amino acid/Rag pathway. Thus dietary restriction inhibits mTORC1 signaling through both upstream pathways of mTORC that converge on the lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
.
Dietary restriction has been shown to significantly increase lifespan in the human model of Rhesus monkeys
The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally b ...
as well as protect against their age related decline. More specifically, Rhesus monkeys on a calorie restricted diet had significantly less chance of developing cardiovascular disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
, diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, and age related cognitive decline than those monkeys who were not placed on the calorie restricted diet.
Autophagy
Autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
is the major degradation pathway in eukaryotic cells
Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
and is essential for the removal of damaged organelles
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
via macroautophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
or proteins and smaller cellular debris via microautophagy from the cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
. Thus, autophagy is a way for the cell to recycle old and damaged materials by breaking them down into their smaller components, allowing for the resynthesis of newer and healthier cellular structures. Autophagy can thus remove protein aggregates and damaged organelles that can lead to cellular dysfunction.
Upon activation, mTORC1 will phosphorylate autophagy-related protein 13
Autophagy-related protein 13 also known as ATG13 is a protein that in humans is encoded by the ''KIAA0652'' gene.
ATG13 is an autophagy factor required for phagosome formation. ATG13 is a target of the TOR kinase signaling pathway that regulate ...
(Atg 13), preventing it from entering the ULK1
ULK1 is an enzyme that in humans is encoded by the ''ULK1'' gene.
Unc-51 like autophagy activating kinase (ULK1/2) are two similar isoforms of an enzyme that in humans are encoded by the ''ULK1/2'' genes. .html" ;"title="/sup>">/sup> .html" ;"t ...
kinase complex, which consists of Atg1
AuTophaGy related 1 (Atg1) is a 101.7kDa serine/threonine kinase in ''S.cerevisiae'', encoded by the gene ATG1.
It is essential for the initial building of the autophagosome and Cvt vesicles.
In a non-kinase role it is - through complex formation ...
, Atg17, and Atg101. This prevents the structure from being recruited to the preautophagosomal structure at the plasma membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
, inhibiting autophagy.
mTORC1's ability to inhibit autophagy while at the same time stimulate protein synthesis and cell growth can result in accumulations of damaged proteins and organelles, contributing to damage at the cellular level. Because autophagy appears to decline with age, activation of autophagy may help promote longevity in humans. Problems in proper autophagy processes have been linked to diabetes, cardiovascular disease, neurodegenerative diseases, and cancer.
Lysosomal damage
mTORC1 is positioned on lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...
s and is inhibited when lysosomal membrane is damaged through a protein complex termed GALTOR. GALTOR contains galectin-8
Galectin-8 is a protein of the galectin family that in humans is encoded by the ''LGALS8'' gene.
Function
This gene encodes a member of the galectin family. Galectins are beta-galactoside-binding animal lectins with conserved carbohydrate recog ...
, a cytosolic lectin, which recognizes damaged lysosomal membranes by binding to the exposed glycoconjugates normally facing lysosomal lumen. Under homeostatic conditions, Galectin-8
Galectin-8 is a protein of the galectin family that in humans is encoded by the ''LGALS8'' gene.
Function
This gene encodes a member of the galectin family. Galectins are beta-galactoside-binding animal lectins with conserved carbohydrate recog ...
associates with active mTOR. Following membrane damage galectin-8 no longer interacts with mTOR but instead switches to complexes containing SLC38A9, RRAGA
Ras-related GTP-binding protein A is a protein that in humans is encoded by the ''RRAGA'' gene.
Interactions
RRAGA has been shown to interact with NOL8 and RRAGC
Ras-related GTP binding C, also known as RRAGC, is a protein which in humans is ...
/RRAGB
Ras-related GTP-binding protein B is a protein that in humans is encoded by the ''RRAGB'' gene.
Ras-homologous GTPases constitute a large family of signal transducers that alternate between an activated, GTP-binding state and an inactivated, GDP ...
, and LAMTOR1
Late endosomal/lysosomal adaptor, MAPK and MTOR activator 1 is a protein that in humans is encoded by the LAMTOR1 gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of here ...
(a component of Ragulator) thus inhibiting mTOR
Tor, TOR or ToR may refer to:
Places
* Tor, Pallars, a village in Spain
* Tor, former name of Sloviansk, Ukraine, a city
* Mount Tor, Tasmania, Australia, an extinct volcano
* Tor Bay, Devon, England
* Tor River, Western New Guinea, Indonesia
Sc ...
, mTOR inhibition in turn activates autophagy
Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...
and starts a quality control program that removes damaged lysosomes, referred to as lysophagy,
Reactive oxygen species
Reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
can damage the DNA and proteins in cells. A majority of them arise in the mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
.
Deletion of the TOR1 gene in yeast increases cellular respiration
Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...
in the mitochondria by enhancing the translation of mitochondrial DNA
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...
that encodes for the complexes involved in the electron transport chain
An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...
. When this electron transport chain is not as efficient, the unreduced oxygen molecules in the mitochondrial cortex may accumulate and begin to produce reactive oxygen species. It is important to note that both cancer cells as well as those cells with greater levels of mTORC1 both rely more on glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
in the cytosol for ATP production rather than through oxidative phosphorylation
Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...
in the inner membrane of the mitochondria.
Inhibition of mTORC1 has also been shown to increase transcription of the NFE2L2
Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regul ...
(''NRF2'') gene, which is a transcription factor that is able to regulate the expression of electrophilic
In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carri ...
response elements as well as antioxidants in response to increased levels of reactive oxygen species.
Though AMPK induced eNOS has been shown to regulate mTORC1 in endothelium. Unlike the other cell type in endothelium eNOS induced mTORC1 and this pathway is required for mitochondrial biogenesis.
Stem cells
Conservation of stem cells
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
in the body has been shown to help prevent against premature aging
Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...
. mTORC1 activity plays a critical role in the growth and proliferation of stem cells. Knocking out mTORC1 results in embryo
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
nic lethality
Lethality (also called deadliness or perniciousness) is how capable something is of causing death. Most often it is used when referring to diseases, chemical weapons, biological weapons, or their toxic chemical components. The use of this ter ...
due to lack of trophoblast
The trophoblast (from Greek : to feed; and : germinator) is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the pl ...
development. Treating stem cells with rapamycin will also slow their proliferation, conserving the stem cells in their undifferentiated condition.
mTORC1 plays a role in the differentiation and proliferation of hematopoietic stem cells
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
. Its upregulation has been shown to cause premature aging in hematopoietic stem cells. Conversely, inhibiting mTOR restores and regenerates the hematopoietic stem cell line. The mechanisms of mTORC1's inhibition on proliferation and differentiation of hematopoietic stem cells has yet to be fully elucidated.
Rapamycin is used clinically as an immunosuppressant and prevents the proliferation of T cells and B cells. Paradoxically, even though rapamycin is a federally approved immunosuppressant
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system.
Classification
Immunosuppressive drugs can be classified in ...
, its inhibition of mTORC1 results in better quantity and quality of functional memory T cells
Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.
Function
Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...
. mTORC1 inhibition with rapamycin improves the ability of naïve T cells to become precursor memory T cells
Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.
Function
Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...
during the expansion phase of T cell development . This inhibition also allows for an increase in quality of these memory T cells
Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.
Function
Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...
that become mature T cells during the contraction phase of their development. mTORC1 inhibition with rapamycin has also been linked to a dramatic increase of B cells
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
in old mice, enhancing their immune systems
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters ...
. This paradox
A paradox is a logically self-contradictory statement or a statement that runs contrary to one's expectation. It is a statement that, despite apparently valid reasoning from true premises, leads to a seemingly self-contradictory or a logically u ...
of rapamycin inhibiting the immune system response has been linked to several reasons, including its interaction with regulatory T cells
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosup ...
.
As a biomolecular target
Activators
Resistance exercise
Strength training or resistance training involves the performance of physical exercises that are designed to improve strength and endurance. It is often associated with the lifting of weights. It can also incorporate a variety of training te ...
, the amino acid -leucine, and beta-hydroxy beta-methylbutyric acid
β-Hydroxy β-methylbutyric acid (HMB), otherwise known as its conjugate base, , is a naturally produced substance in humans that is used as a dietary supplement and as an ingredient in certain medical foods that are intended to promote wou ...
(HMB) are known to induce signaling cascade
A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that ...
s in skeletal muscle cells that result in mTOR phosphorylation, the activation of mTORC1, and subsequently the initiation of myofibril
A myofibril (also known as a muscle fibril or sarcostyle) is a basic rod-like organelle of a muscle cell. Skeletal muscles are composed of long, tubular cells known as muscle fibers, and these cells contain many chains of myofibrils. Each myofib ...
lar protein synthesis
Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...
(i.e., the production of proteins such as myosin
Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility.
The first myosin ...
, titin
Titin (contraction for Titan protein) (also called connectin) is a protein that in humans is encoded by the ''TTN'' gene. Titin is a giant protein, greater than 1 µm in length, that functions as a molecular spring that is responsible for t ...
, and actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
), thereby facilitating muscle hypertrophy
Muscle hypertrophy or muscle building involves a hypertrophy or increase in size of skeletal muscle through a growth in size of its component cells. Two factors contribute to hypertrophy: sarcoplasmic hypertrophy, which focuses more on increase ...
.
The NMDA receptor antagonist
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...
ketamine
Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ne ...
has been found to activate the mTORC1 pathway in the medial prefrontal cortex
In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46, ...
(mPFC) of the brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
as an essential downstream mechanism in the mediation of its rapid-acting antidepressant effects. NV-5138
NV-5138 is an orally and centrally active small-molecule drug which is under development by Navitor Pharmaceuticals for the treatment of major depressive disorder (MDD). It directly and selectively activates the mammalian target of rapamycin c ...
is a ligand
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
and modulator
In electronics and telecommunications, modulation is the process of varying one or more properties of a periodic waveform, called the ''carrier signal'', with a separate signal called the ''modulation signal'' that typically contains informatio ...
of sestrin2
Sestrin-2 also known as Hi95 is a protein that in humans is encoded by the ''SESN2'' gene.
Function
This gene encodes a member of the sestrin family of PA26-related proteins. The encoded protein may function in the regulation of cell growth and ...
, a leucine amino acid sensor and upstream regulatory pathway of mTORC1, and is under development for the treatment of depression. The drug has been found to directly and selectively activate the mTORC1 pathway, including in the mPFC, and to produce rapid-acting antidepressant effects similar to those of ketamine.
Inhibitors
There have been several dietary compounds that have been suggested to inhibit mTORC1 signaling including EGCG
Epigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is the ester of epigallocatechin and gallic acid, and is a type of catechin.
EGCG – the most abundant catechin in tea – is a polyphenol under basic research for its ...
, resveratrol
Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Sources ...
, curcumin
Curcumin is a bright yellow chemical produced by plants of the ''Curcuma longa'' species. It is the principal curcuminoid of turmeric (''Curcuma longa''), a member of the ginger family, Zingiberaceae. It is sold as a herbal supplement, cosmetic ...
, caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
, and alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
.
First generation drugs
Rapamycin
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, ...
was the first known inhibitor of mTORC1, considering that mTORC1 was discovered as being the target of rapamycin. Rapamycin will bind to cytosolic FKBP12 and act as a scaffold
Scaffolding, also called scaffold or staging, is a temporary structure used to support a work crew and materials to aid in the construction, maintenance and repair of buildings, bridges and all other man-made structures. Scaffolds are widely use ...
molecule, allowing this protein to dock on the FRB regulatory region (FKBP12-Rapamycin Binding region/domain) on mTORC1. The binding of the FKBP12-rapamycin complex to the FRB regulatory region inhibits mTORC1 through processes not yet known. mTORC2 is also inhibited by rapamycin in some cell culture lines and tissues, particularly those that express high levels of FKBP12 and low levels of FKBP51.
Rapamycin itself is not very water soluble
In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution.
The extent of the solubil ...
and is not very stable, so scientists developed rapamycin analogs, called rapalogs, to overcome these two problems with rapamycin. These drugs are considered the first generation inhibitors of mTOR. These other inhibitors include everolimus
Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours.
It is the 40 ...
and temsirolimus
Temsirolimus, sold under the brand name Torisel, is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration (FDA) in May 2007, and was also appro ...
. Compared with the parent compound rapamycin
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, ...
, everolimus is more selective for the mTORC1 protein complex, with little impact on the mTORC2 complex. mTORC1 inhibition by everolimus has been shown to normalize tumor blood vessels, to increase tumor-infiltrating lymphocytes
Tumor-infiltrating lymphocytes (TIL) are white blood cells that have left the bloodstream and cell migration, migrated towards a tumor. They include T cells and B cells and are part of the larger category of ‘tumor-infiltrating immune cells’ wh ...
, and to improve adoptive cell transfer therapy.
Sirolimus
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, ...
, which is the drug name for rapamycin, was approved by the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) in 1999 to prevent against transplant rejection
Transplant rejection occurs when Organ transplant, 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 don ...
in patients undergoing kidney transplantation
Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantati ...
. In 2003, it was approved as a stent
In medicine, a stent is a metal or plastic tube inserted into the lumen of an anatomic vessel or duct to keep the passageway open, and stenting is the placement of a stent. A wide variety of stents are used for different purposes, from expandab ...
covering for widening arteries to prevent against future heart attacks
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tra ...
. In 2007, mTORC1 inhibitors began being approved for treatments against cancers such as renal cell carcinoma
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...
. In 2008 they were approved for treatment of mantle cell lymphoma
Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph n ...
. mTORC1 inhibitors have recently been approved for treatment of pancreatic cancer
Pancreatic cancer arises when cell (biology), cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a Neoplasm, mass. These cancerous cells have the malignant, ability to invade other parts of t ...
. In 2010 they were approved for treatment of tuberous sclerosis
Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination ...
.
Second generation drugs
The second generation of inhibitors were created to overcome problems with upstream signaling upon the introduction of first generation inhibitors to the treated cells. One problem with the first generation inhibitors of mTORC1 is that there is a negative feedback loop
Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by other ...
from phosphorylated S6K, that can inhibit the insulin RTK via phosphorylation. When this negative feedback loop is no longer there, the upstream regulators of mTORC1 become more active than they would otherwise would have been under normal mTORC1 activity. Another problem is that since mTORC2 is resistant to rapamycin, and it too acts upstream of mTORC1 by activating Akt. Thus signaling upstream of mTORC1 still remains very active upon its inhibition via rapamycin and the rapalogs. Rapamycin and its analogues also have procoagulant side effects caused by off-target binding of the activated immunophilin FKBP12
Peptidyl-prolyl cis-trans isomerase FKBP1A is an enzyme that in humans is encoded by the ''FKBP1A'' gene.
Function
The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basi ...
, which are not produced by structurally unrelated inhibitors of mTORC such as gedatolisib, WYE-687 and XL-388.
Second generation inhibitors are able to bind to the ATP-binding motif
An ATP-binding motif is a 250-residue sequence within an ATP-binding protein’s primary structure. The binding motif is associated with a protein’s structure and/or function. ATP is a molecule of energy, and can be a coenzyme, involved in a num ...
on the kinase domain of the mTOR core protein itself and abolish activity of both mTOR complexes. In addition, since the mTOR and the PI3K proteins are both in the same phosphatidylinositol 3-kinase-related kinase
Phosphatidylinositol 3-kinase-related kinases (PIKKs) are a family of Ser/Thr-protein kinases with sequence similarity to phosphatidylinositol-3 kinases ( PI3Ks).
Members
The human PIKK family includes six members:
Structure
PIKKs protei ...
(PIKK) family of kinases, some second generation inhibitors have dual inhibition towards the mTOR complexes as well as PI3K, which acts upstream of mTORC1. As of 2011, these second generation inhibitors were in phase II of clinical trials
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
.
Third generation drugs
The third generation of inhibitors were created following the realization that many of the side effects of rapamycin and rapamycin analogs were mediated not as a result of direct inhibition of mTORC1, but as a consequence of off-target inhibition of mTORC2. Rapamycin analogs such as DL001, that are more selective for mTORC1 than sirolimus, have been developed and in mice have reduced side effects. mTORC1 inhibitors that have novel mechanisms of action, for example peptides like PRAS40 and small molecules like HY-124798
HY-124798 (Rheb inhibitor NR1) is the first compound to be developed that acts as a potent and selective inhibitor of Rheb, a GTP-binding protein which acts as an endogenous activator of the mechanistic target of rapamycin (mTOR) subtype mTORC1. ...
(Rheb inhibitor NR1), which inhibit the interaction of mTORC1 with its endogenous activator Rheb, are also being developed. Some glucose transporter
Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Because glucose is a vital source of energy for all life, these transporter ...
inhibitors such as NV-5440 and NV-6297 are also selective inhibitors of mTORC1
There have been over 1,300 clinical trials conducted with mTOR inhibitors since 1970.
References
External links
*
{{Portal bar, Biology, border=no
Protein complexes
EC 2.7.11
Tor signaling pathway
Human proteins