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The mammalian target of
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 lymphangioleiomyomatosi ...
(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 In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
that in humans is encoded by the ''MTOR''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. mTOR is a member of the
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 ...
family of
protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
s. mTOR links with other proteins and serves as a core component of two distinct
protein complexes 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 ...
,
mTOR complex 1 mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis. mTOR Complex 1 (mTORC1) is compo ...
and mTOR complex 2, which regulate different cellular processes. In particular, as a core component of both complexes, mTOR functions as a
serine/threonine protein kinase A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human prote ...
that regulates cell growth,
cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...
, cell
motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
, cell survival,
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 ...
,
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
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
. As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of
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 ho ...
s and
insulin-like growth factor 1 receptor The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 ( IGF-1) and by a related hormone called IGF-2. ...
s. mTORC2 has also been implicated in the control and maintenance of the
actin cytoskeleton Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other ...
.


Discovery


Rapa Nui (Easter Island - Chile)

The study of TOR originated in the 1960s with an expedition to
Easter Island Easter Island ( rap, Rapa Nui; es, Isla de Pascua) is an island and special territory of Chile in the southeastern Pacific Ocean, at the southeasternmost point of the Polynesian Triangle in Oceania. The island is most famous for its nearl ...
(known by the island inhabitants as
Rapa Nui Easter Island ( rap, Rapa Nui; es, Isla de Pascua) is an island and special territory of Chile in the southeastern Pacific Ocean, at the southeasternmost point of the Polynesian Triangle in Oceania. The island is most famous for its nearly ...
), with the goal of identifying natural products from plants and soil with possible therapeutic potential. In 1972, Suren Sehgal identified a small molecule, from a soil bacterium '' Streptomyces hygroscopicus'', that he purified and initially reported to possess potent antifungal activity. He appropriately named it rapamycin, noting its original source and activity (Sehgal et al., 1975). However, early testing revealed that rapamycin also had potent immunosuppressive and cytostatic anti-cancer activity. Rapamycin did not initially receive significant interest from the pharmaceutical industry until the 1980s, when Wyeth-Ayerst supported Sehgal's efforts to further investigate rapamycin's effect on the immune system. This eventually led to its FDA approval as an immunosuppressant following kidney transplantation. However, prior to its FDA approval, how rapamycin worked remained completely unknown.


Subsequent history

The discovery of TOR and mTOR stemmed from independent studies of the natural product rapamycin by
Joseph Heitman Joseph Heitman is an American physician-scientist focused on research in genetics, microbiology, and infectious diseases. He is the James B. Duke Professor and Chair of the Department of Molecular Genetics and Microbiology at Duke University School ...
, Rao Movva, and
Michael N. Hall Michael Nip Hall (born 1953) is an American-Swiss molecular biologist and professor at the Biozentrum University of Basel, Switzerland. Life Hall grew up in South America (Venezuela, Peru). He earned a Bachelor of Science in Zoology from the ...
; by
David M. Sabatini David M. Sabatini (born January 27, 1968) is an American scientist and a former professor of biology at the Massachusetts Institute of Technology. From 2002 to 2021, he was a member of the Whitehead Institute for Biomedical Research. He was also ...
, Hediye Erdjument-Bromage, Mary Lui, Paul Tempst, and Solomon H. Snyder; and by Candace J. Sabers, Mary M. Martin, Gregory J. Brunn, Josie M. Williams, Francis J. Dumont, Gregory Wiederrecht, and Robert T. Abraham. In 1993, Robert Cafferkey, George Livi, and colleagues, and Jeannette Kunz,
Michael N. Hall Michael Nip Hall (born 1953) is an American-Swiss molecular biologist and professor at the Biozentrum University of Basel, Switzerland. Life Hall grew up in South America (Venezuela, Peru). He earned a Bachelor of Science in Zoology from the ...
, and colleagues independently cloned genes that mediate the toxicity of rapamycin in fungi, known as the TOR/DRR genes. However, the molecular target of the FKBP12-rapamycin complex in mammals was not known. In 1994, researchers working in the labs of Stuart L. Schreiber, Solomon H. Snyder and Robert T. Abraham independently discovered a protein that directly interacts with FKBP12-rapamycin, which became known as mTOR due to its homology to the yeast TOR/DRR genes. Rapamycin arrests fungal activity at the
G1 phase The G1 phase, gap 1 phase, or growth 1 phase, is the first of four phases of the cell cycle that takes place in eukaryotic cell division. In this part of interphase, the cell synthesizes mRNA and proteins in preparation for subsequent steps lead ...
of the cell cycle. In mammals, it suppresses the immune system by blocking the G1 to S phase transition in
T-lymphocytes A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
. Thus, it is used as an
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 ...
following organ transplantation. Interest in rapamycin was renewed following the discovery of the structurally related immunosuppressive natural product
FK506 Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After allogeneic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also ...
in 1987. In 1989–90, FK506 and rapamycin were determined to inhibit
T-cell receptor The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding b ...
(TCR) and
IL-2 receptor The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called IL-2. Composition IL-2 binds to the IL-2 receptor, which ha ...
signaling pathways, respectively. The two natural products were used to discover the FK506- and rapamycin-binding proteins, including FKBP12, and to provide evidence that FKBP12–FK506 and FKBP12–rapamycin might act through gain-of-function mechanisms that target distinct cellular functions. These investigations included key studies by Francis Dumont and Nolan Sigal at Merck contributing to show that FK506 and rapamycin behave as reciprocal antagonists. These studies implicated FKBP12 as a possible target of rapamycin, but suggested that the complex might interact with another element of the mechanistic cascade. In 1991,
calcineurin Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase). It activates the T cells of the immune system and can be block ...
was identified as the target of FKBP12-FK506. That of FKBP12-rapamycin remained mysterious until genetic and molecular studies in yeast established FKBP12 as the target of rapamycin, and implicated TOR1 and TOR2 as the targets of FKBP12-rapamycin in 1991 and 1993, followed by studies in 1994 when several groups, working independently, discovered the mTOR kinase as its direct target in mammalian tissues. Sequence analysis of mTOR revealed it to be the direct ortholog of proteins encoded by the yeast ''target of rapamycin 1 and 2 (TOR1 and TOR2'') genes, which Joseph Heitman, Rao Movva, and
Michael N. Hall Michael Nip Hall (born 1953) is an American-Swiss molecular biologist and professor at the Biozentrum University of Basel, Switzerland. Life Hall grew up in South America (Venezuela, Peru). He earned a Bachelor of Science in Zoology from the ...
had identified in August 1991 and May 1993. Independently, George Livi and colleagues later reported the same genes, which they called ''dominant rapamycin resistance 1 and 2 (DRR1 and DRR2)'', in studies published in October 1993. The protein, now called mTOR, was originally named FRAP by Stuart L. Schreiber and RAFT1 by David M. Sabatini; ''FRAP1'' was used as its official gene symbol in humans. Because of these different names, mTOR, which had been first used by Robert T. Abraham, was increasingly adopted by the community of scientists working on the mTOR pathway to refer to the protein and in homage to the original discovery of the TOR protein in yeast that was named TOR, the Target of Rapamycin, by Joe Heitman, Rao Movva, and Mike Hall. TOR was originally discovered at the Biozentrum and Sandoz Pharmaceuticals in 1991 in Basel, Switzerland, and the name TOR pays further homage to this discovery, as TOR means doorway or gate in German, and the city of Basel was once ringed by a wall punctuated with gates into the city, including the iconic Spalentor. "mTOR" initially meant "mammalian target of rapamycin," but the meaning of the "m" was later changed to "mechanistic". Similarly, with subsequent discoveries the zebra fish TOR was named zTOR, the Arabidopsis thaliana TOR was named AtTOR, and the Drosophila TOR was named dTOR. In 2009 the FRAP1 gene name was officially changed by the
HUGO Gene Nomenclature Committee The HUGO Gene Nomenclature Committee (HGNC) is a committee of the Human Genome Organisation (HUGO) that sets the standards for human gene nomenclature. The HGNC approves a ''unique'' and ''meaningful'' name for every known human gene, based on a ...
(HGNC) to mTOR, which stands for mechanistic target of rapamycin. The discovery of TOR and the subsequent identification of mTOR opened the door to the molecular and physiological study of what is now called the mTOR pathway and had a catalytic effect on the growth of the field of chemical biology, where small molecules are used as probes of biology.


Function

mTOR integrates the input from upstream pathways, including
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
,
growth factors A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
(such as
IGF-1 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 ...
and
IGF-2 Insulin-like growth factor 2 (IGF-2) is one of three protein hormones that share structural similarity to insulin. The MeSH definition reads: "A well-characterized neutral peptide believed to be secreted by the liver and to circulate in the blo ...
), and
amino acid 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 ...
s. mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as
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 ...
,
obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
, depression, and certain
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 ...
s.
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 lymphangioleiomyomatosi ...
inhibits mTOR by associating with its intracellular receptor
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 ...
. The
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 ...
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 lymphangioleiomyomatosi ...
complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.


mTOR in plants

Plants express the mechanistic target of rapamycin (mTOR) and have a TOR kinase complex. In plants, only the TORC1 complex is present unlike that of mammalian target of rapamycin which also contains the TORC2 complex. Plant species have TOR proteins in the protein kinase and FKBP-rapamycin binding (FRB) domains that share a similar amino acid sequence to mTOR in mammals. Role of mTOR in plants The TOR kinase complex has been known for having a role in the metabolism of plants. The TORC1 complex turns on when plants are living the proper environmental conditions to survive. Once activated, plant cells undergo particular anabolic reactions. These include plant development, translation of mRNA and the growth of cells within the plant. However, the TORC1 complex activation stops catabolic processes such as autophagy from occurring. TOR kinase signaling in plants has been found to aid in senescence, flowering, root and leaf growth, embryogenesis, and the meristem activation above the root cap of a plant. mTOR is also found to be highly involved in developing embryo tissue in plants.


Complexes

mTOR is the
catalytic Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
subunit of two structurally distinct complexes: mTORC1 and mTORC2. The two complexes localize to different subcellular compartments, thus affecting their activation and function. Upon activation by Rheb, mTORC1 localizes to the Ragulator-Rag complex on the lysosome surface where it then becomes active in the presence of sufficient amino acids.


mTORC1

mTOR Complex 1 (mTORC1) is composed of mTOR, regulatory-associated protein of mTOR (
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 ...
), 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 ...
) and the non-core components 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 functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 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 lymphangioleiomyomatosi ...
, 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 ...
.


mTORC2

mTOR Complex 2 (mTORC2) is composed of MTOR, rapamycin-insensitive companion of MTOR (
RICTOR Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the ''RICTOR'' gene. RICTOR and mTOR are components of a protein complex that integrates nutrient- and growth factor-derived s ...
),
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 ...
, and mammalian stress-activated protein kinase interacting protein 1 ( mSIN1). mTORC2 has been shown to function as an important regulator of the
actin cytoskeleton Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other ...
through its stimulation of F-
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 ...
stress fibers,
paxillin Paxillin is a protein that in humans is encoded by the ''PXN'' gene. Paxillin is expressed at focal adhesions of non-striated cells and at costameres of striated muscle cells, and it functions to adhere cells to the extracellular matrix. Mutation ...
,
RhoA Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the ''RHOA'' gene. While the effects of RhoA activity are not all well known, it is ...
, Rac1, Cdc42, and
protein kinase C In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
α ( PKCα). mTORC2 also phosphorylates the serine/threonine protein kinase Akt/PKB on serine residue Ser473, thus affecting metabolism and survival. Phosphorylation of Akt's serine residue Ser473 by mTORC2 stimulates Akt phosphorylation on threonine residue Thr308 by
PDK1 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 (PDK). Pyruvate dehydrogenase (PDH) is a part of a mitochondri ...
and leads to full Akt activation. In addition, mTORC2 exhibits tyrosine protein kinase activity and phosphorylates the
insulin-like growth factor 1 receptor The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 ( IGF-1) and by a related hormone called IGF-2. ...
(IGF-1R) and
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 ho ...
(InsR) on the tyrosine residues Tyr1131/1136 and Tyr1146/1151, respectively, leading to full activation of IGF-IR and InsR.


Inhibition by rapamycin

Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Rapamycin has a more complex effect on mTORC2, inhibiting it only in certain cell types under prolonged exposure. Disruption of mTORC2 produces the diabetic-like symptoms of decreased glucose tolerance and insensitivity to insulin.


Gene deletion experiments

The mTORC2 signaling pathway is less defined than the mTORC1 signaling pathway. The functions of the components of the mTORC complexes have been studied using knockdowns and knockouts and were found to produce the following phenotypes: *
NIP7 60S ribosome subunit biogenesis protein NIP7 homolog is a protein that in humans is encoded by the ''NIP7'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity... ...
: Knockdown reduced mTORC2 activity that is indicated by decreased phosphorylation of mTORC2 substrates. *
RICTOR Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the ''RICTOR'' gene. RICTOR and mTOR are components of a protein complex that integrates nutrient- and growth factor-derived s ...
: Overexpression leads to metastasis and knockdown inhibits growth factor-induced PKC-phosphorylation. Constitutive deletion of Rictor in mice leads to embryonic lethality, while tissue specific deletion leads to a variety of phenotypes; a common phenotype of Rictor deletion in liver, white adipose tissue, and pancreatic beta cells is systemic glucose intolerance and insulin resistance in one or more tissues. Decreased Rictor expression in mice decreases male, but not female, lifespan. * mTOR: Inhibition of mTORC1 and mTORC2 by PP242 -(4-Amino-1-isopropyl-1H-pyrazolo[3,4-dyrimidin-3-yl)-1H-indol-5-ol.html" ;"title=",4-d.html" ;"title="-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d">-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-dyrimidin-3-yl)-1H-indol-5-ol">,4-d.html" ;"title="-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d">-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-dyrimidin-3-yl)-1H-indol-5-olleads to
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 ...
or apoptosis; inhibition of mTORC2 alone by PP242 prevents phosphorylation of Ser-473 site on AKT and arrests the cells in
G1 phase The G1 phase, gap 1 phase, or growth 1 phase, is the first of four phases of the cell cycle that takes place in eukaryotic cell division. In this part of interphase, the cell synthesizes mRNA and proteins in preparation for subsequent steps lead ...
of the
cell cycle The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and subs ...
. Genetic reduction of mTOR expression in mice significantly increases lifespan. *
PDK1 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 (PDK). Pyruvate dehydrogenase (PDH) is a part of a mitochondri ...
: Knockout is lethal; hypomorphic allele results in smaller organ volume and organism size but normal AKT activation. *
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, tran ...
: Knockout mice experience spontaneous apoptosis (
AKT1 RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It ...
), severe diabetes (
AKT2 AKT2, also known as RAC-beta serine/threonine-protein kinase, is an enzyme that in humans is encoded by the ''AKT2'' gene. It influences metabolite storage as part of the insulin signal transduction pathway. Function This gene is a putative o ...
), small brains (
AKT3 RAC-gamma serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT3'' gene. Function The protein encoded by this gene is a member of the AKT subfamily of serine/threonine protein kinases. AKT kinases are known to be ...
), and growth deficiency (AKT1/AKT2). Mice heterozygous for AKT1 have increased lifespan. *TOR1, the ''
S. cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have bee ...
'' orthologue of mTORC1, is a regulator of both carbon and nitrogen metabolism; TOR1 KO strains regulate response to nitrogen as well as carbon availability, indicating that it is a key nutritional transducer in yeast.


Clinical significance


Aging

] Decreased TOR activity has been found to increase life span in ''
S. cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have bee ...
'', '' Caenorhabditis elegans, C. elegans,'' and ''
D. melanogaster ''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the " vinegar fly" or "pomace fly". Starting with ...
''. The mTOR inhibitor
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 lymphangioleiomyomatosi ...
has been confirmed to increase lifespan in mice. It is hypothesized that some dietary regimes, like
caloric restriction Calorie restriction (caloric restriction or energy restriction) is a dietary regimen that reduces intake of energy from caloric foods & beverages without incurring malnutrition. "Reduce" can be defined relative to the subject's previous intake be ...
and
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
restriction, cause lifespan extension by decreasing mTOR activity. Some studies have suggested that mTOR signaling may increase during aging, at least in specific tissues like adipose tissue, and rapamycin may act in part by blocking this increase. An alternative theory is mTOR signaling is an example of antagonistic pleiotropy, and while high mTOR signaling is good during early life, it is maintained at an inappropriately high level in old age. Calorie restriction and methionine restriction may act in part by limiting levels of essential amino acids including leucine and methionine, which are potent activators of mTOR. The administration of
leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- ca ...
into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway in the hypothalamus. According to the free radical theory of aging,
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 ...
cause damage to mitochondrial proteins and decrease ATP production. Subsequently, via ATP sensitive
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 ...
, the mTOR pathway is inhibited and ATP-consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating 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 ...
. Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits mitochondrial respiration. These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates removal of dysfunctional cellular components via
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 ...
. mTOR is a key initiator of the
senescence-associated secretory phenotype Senescence-associated secretory phenotype (SASP) is a phenotype associated with senescent cells wherein those cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases. SASP may also consist of exosom ...
(SASP). Interleukin 1 alpha (IL1A) is found on the surface of
senescent cells Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approxi ...
where it contributes to the production of SASP factors due to a
positive feedback loop Positive feedback (exacerbating feedback, self-reinforcing feedback) is a process that occurs in a feedback loop which exacerbates the effects of a small disturbance. That is, the effects of a perturbation on a system include an increase in the ...
with NF-κB. Translation 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 ...
for IL1A is highly dependent upon mTOR activity. mTOR activity increases levels of IL1A, mediated by
MAPKAPK2 MAP kinase-activated protein kinase 2 is an enzyme that in humans is encoded by the ''MAPKAPK2'' gene. Function This gene encodes a member of the Ser/Thr protein kinase family. This kinase is regulated through direct phosphorylation by p38 MA ...
. mTOR inhibition of
ZFP36L1 Butyrate response factor 1 is a protein that in humans is encoded by the ''ZFP36L1'' gene. Function This gene is a member of the TIS11 family of early response genes. Family members are induced by various agonists such as the phorbol ester TP ...
prevents this protein from degrading transcripts of numerous components of SASP factors.


Cancer

Over-activation of mTOR signaling significantly contributes to the initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas. Reasons for constitutive activation are several. Among the most common are mutations in tumor suppressor ''PTEN'' gene. PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
, an upstream effector of mTOR. Additionally, mTOR activity is deregulated in many cancers as a result of increased activity of
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
or
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, tran ...
. Similarly, overexpression of downstream mTOR effectors
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 ...
,
S6K 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 Phosp ...
and
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 ...
leads to poor cancer prognosis. Also, mutations in
TSC TSC may refer to: Organizations * Technology Service Corporation, a US engineering company * Terrorist Screening Center, a division of the National Security Branch of the US Federal Bureau of Investigation * The Shopping Channel, a Canadian televi ...
proteins that inhibit the activity of mTOR may lead to a condition named
tuberous sclerosis complex 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 ...
, which exhibits as benign lesions and increases the risk of
renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the Proximal tubule, 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 cance ...
. Increasing mTOR activity was shown to drive cell cycle progression and increase cell proliferation mainly due to its effect on protein synthesis. Moreover, active mTOR supports tumor growth also indirectly by inhibiting
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 ...
. Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of
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 awarde ...
and supporting
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
. mTOR also aids in another metabolic adaptation of cancerous cells to support their increased growth rate—activation of glycolytic metabolism.
Akt2 AKT2, also known as RAC-beta serine/threonine-protein kinase, is an enzyme that in humans is encoded by the ''AKT2'' gene. It influences metabolite storage as part of the insulin signal transduction pathway. Function This gene is a putative o ...
, a substrate of mTOR, specifically of mTORC2, upregulates expression of the glycolytic enzyme
PKM2 Pyruvate kinase isozymes M1/M2 (PKM1/M2), also known as pyruvate kinase muscle isozyme (PKM), pyruvate kinase type K, cytosolic thyroid hormone-binding protein (CTHBP), thyroid hormone-binding protein 1 (THBP1), or opa-interacting protein 3 (OIP3) ...
thus contributing to the Warburg effect.


Central nervous system disorders / Brain function


Autism

mTOR is implicated in the failure of a 'pruning' mechanism of the excitatory synapses in
autism spectrum The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
disorders.


Alzheimer's disease

mTOR signaling intersects with
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
(AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression. In general, findings demonstrate mTOR signaling hyperactivity in AD brains. For example, postmortem studies of human AD brain reveal dysregulation in PTEN, Akt, S6K, and mTOR. mTOR signaling appears to be closely related to the presence of soluble amyloid beta (Aβ) and tau proteins, which aggregate and form two hallmarks of the disease, Aβ plaques and neurofibrillary tangles, respectively. In vitro studies have shown Aβ to be an activator of the PI3K/AKT pathway, which in turn activates mTOR. In addition, applying Aβ to N2K cells increases the expression of p70S6K, a downstream target of mTOR known to have higher expression in neurons that eventually develop neurofibrillary tangles. Chinese hamster ovary cells transfected with the 7PA2 familial AD mutation also exhibit increased mTOR activity compared to controls, and the hyperactivity is blocked using a gamma-secretase inhibitor. These in vitro studies suggest that increasing Aβ concentrations increases mTOR signaling; however, significantly large, cytotoxic Aβ concentrations are thought to decrease mTOR signaling. Consistent with data observed in vitro, mTOR activity and activated p70S6K have been shown to be significantly increased in the cortex and hippocampus of animal models of AD compared to controls. Pharmacologic or genetic removal of the Aβ in animal models of AD eliminates the disruption in normal mTOR activity, pointing to the direct involvement of Aβ in mTOR signaling. In addition, by injecting Aβ oligomers into the hippocampi of normal mice, mTOR hyperactivity is observed. Cognitive impairments characteristic of AD appear to be mediated by the phosphorylation of PRAS-40, which detaches from and allows for the mTOR hyperactivity when it is phosphorylated; inhibiting PRAS-40 phosphorylation prevents Aβ-induced mTOR hyperactivity. Given these findings, the mTOR signaling pathway appears to be one mechanism of Aβ-induced toxicity in AD. The hyperphosphorylation of tau proteins into neurofibrillary tangles is one hallmark of AD. p70S6K activation has been shown to promote tangle formation as well as mTOR hyperactivity through increased phosphorylation and reduced dephosphorylation. It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins. Synaptic plasticity is a key contributor to learning and memory, two processes that are severely impaired in AD patients. Translational control, or the maintenance of protein homeostasis, has been shown to be essential for neural plasticity and is regulated by mTOR. Both protein over- and under-production via mTOR activity seem to contribute to impaired learning and memory. Furthermore, given that deficits resulting from mTOR overactivity can be alleviated through treatment with rapamycin, it is possible that mTOR plays an important role in affecting cognitive functioning through synaptic plasticity. Further evidence for mTOR activity in neurodegeneration comes from recent findings demonstrating that eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition. Some evidence points to mTOR's role in reduced Aβ clearance as well. mTOR is a negative regulator of autophagy; therefore, hyperactivity in mTOR signaling should reduce Aβ clearance in the AD brain. Disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, including AD. Studies using mouse models of Huntington's disease demonstrate that treatment with rapamycin facilitates the clearance of huntingtin aggregates. Perhaps the same treatment may be useful in clearing Aβ deposits as well.


Lymphoproliferative diseases

Hyperactive mTOR pathways have been identified in certain lymphoproliferative diseases such as
autoimmune lymphoproliferative syndrome Autoimmune lymphoproliferative syndrome (ALPS) is a form of lymphoproliferative disorder (LPDs). It affects lymphocyte apoptosis. It is a rare genetic disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis. Normally ...
(ALPS), multicentric
Castleman disease Castleman disease (CD) describes a group of rare lymphoproliferative disorders that involve enlarged lymph nodes, and a broad range of inflammatory symptoms and laboratory abnormalities. Whether Castleman disease should be considered an autoimmun ...
, and
post-transplant lymphoproliferative disorder Post-transplant lymphoproliferative disorder (PTLD) is the name given to a B cell proliferation due to therapeutic immunosuppression after organ transplantation. These patients may develop infectious mononucleosis-like lesions or polyclonal polymor ...
(PTLD).


Protein synthesis and cell growth

mTORC1 activation is required for myofibrillar muscle protein synthesis and skeletal
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 ...
in humans in response to both
physical exercise Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness. It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athletic ...
and ingestion of 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 ...
or amino acid derivatives. Persistent inactivation of mTORC1 signaling in skeletal muscle facilitates the loss of muscle mass and strength during
muscle wasting Muscle atrophy is the loss of skeletal muscle mass. It can be caused by immobility, aging, malnutrition, medications, or a wide range of injuries or diseases that impact the musculoskeletal or nervous system. Muscle atrophy leads to muscle weakness ...
in old age,
cancer cachexia Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart fa ...
, and muscle atrophy from
physical inactivity Physical inactivity refers to the lack of moderate-to-vigorous physical activity in a person's lifestyle. It is distinct from sedentary behavior. Health effects The World Health Organization (WHO) has defined physical inactivity as a global public ...
. mTORC2 activation appears to mediate
neurite A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture ...
outgrowth in differentiated mouse neuro2a cells. Intermittent mTOR activation in prefrontal neurons by β-hydroxy β-methylbutyrate inhibits age-related cognitive decline associated with dendritic pruning in animals, which is a phenomenon also observed in humans.


Lysosomal damage inhibits mTOR and induces autophagy

Active
mTORC1 mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis. mTOR Complex 1 (mTORC1) is compo ...
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.
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 ...
is inhibited when lysosomal membrane is damaged by various exogenous or endogenous agents, such as invading
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
, membrane-permeant chemicals yielding osmotically active products (this type of injury can be modeled using membrane-permeant dipeptide precursors that polymerize in lysosomes),
amyloid Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a beta sheet (β-sheet) Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Staining, ...
protein aggregates (see above section on
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
) and cytoplasmic organic or inorganic inclusions including
urate Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown o ...
crystals and
crystalline silica Silicon dioxide, also known as silica, is an oxide of silicon with the chemical formula , most commonly found in nature as quartz and in various living organisms. In many parts of the world, silica is the major constituent of sand. Silica is one ...
. The process of mTOR inactivation following lysosomal/endomembrane is mediated by the protein complex termed GALTOR. At the heart of GALTOR is galectin-8, a member of β-galactoside binding superfamily of cytosolic lectins termed
galectin Galectins are a class of proteins that bind specifically to β-galactoside sugars, such as ''N''-acetyllactosamine (Galβ1-3GlcNAc or Galβ1-4GlcNAc), which can be bound to proteins by either N-linked or O-linked glycosylation. They are also t ...
s, which recognizes lysosomal membrane damage by binding to the exposed
glycan The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate p ...
s on the lumenal side of the delimiting endomembrane. Following membrane damage, galectin-8, which normally associates with mTOR under homeostatic conditions, no longer interacts with mTOR but now instead binds to 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, 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 ...
, inhibiting Ragulator's (LAMTOR1-5 complex) guanine nucleotide exchange function-
TOR 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 ...
is a negative regulator of autophagy in general, best studied during response to starvation, which is a metabolic response. During lysosomal damage however, mTOR inhibition 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 ...
response in its quality control function, leading to the process termed lysophagy that removes damaged lysosomes. At this stage another
galectin Galectins are a class of proteins that bind specifically to β-galactoside sugars, such as ''N''-acetyllactosamine (Galβ1-3GlcNAc or Galβ1-4GlcNAc), which can be bound to proteins by either N-linked or O-linked glycosylation. They are also t ...
,
galectin-3 Galectin-3 is a protein that in humans is encoded by the ''LGALS3'' gene. Galectin-3 is a member of the lectin family, of which 14 mammalian galectins have been identified. Galectin-3 is approximately 30 kDa and, like all galectins, contains a ca ...
, interacts with TRIM16 to guide selective autophagy of damaged lysosomes. TRIM16 gathers
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 ...
and principal components (Beclin 1 and ATG16L1) of other complexes ( Beclin 1-
VPS34 Class III PI 3-kinase is a subgroup of the enzyme family, phosphoinositide 3-kinase that share a common protein domain structure, substrate specificity and method of activation. There is only one known class III PI 3-kinase, Vps34, which is also th ...
- ATG14 and ATG16L1-
ATG5 Autophagy related 5 (ATG5) is a protein that, in humans, is encoded by the ''ATG5'' gene located on Chromosome 6. It is an E3 ubi autophagic cell death. ATG5 is a key protein involved in the extension of the phagophoric membrane in autophagic ve ...
-
ATG12 Autophagy related 12 is a protein that in humans is encoded by the ''ATG12'' gene. Autophagy is a process of bulk protein degradation in which cytoplasmic components, including organelles, are enclosed in double-membrane structures called autopha ...
) initiating
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 ...
, many of them being under negative control of mTOR directly such as the ULK1-ATG13 complex, or indirectly, such as components of t he class III PI3K (Beclin 1, ATG14 and VPS34) since they depend on activating phosphorylations by
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 ...
when it is not inhibited by mTOR. These
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 ...
-driving components physically and functionally link up with each other integrating all processes necessary for autophagosomal formation: (i) 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 ...
- ATG13- FIP200/RB1CC1 complex associates with the LC3B/
GABARAP Gamma-aminobutyric acid receptor-associated protein is a protein that in humans is encoded by the ''GABARAP'' gene. Function Gamma-aminobutyric acid A receptors ABA(A) receptorsare ligand-gated chloride channels that mediate inhibitory neurot ...
conjugation machinery through direct interactions between FIP200/RB1CC1 and ATG16L1, (ii)
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 ...
- ATG13- FIP200/RB1CC1 complex associates with the Beclin 1-
VPS34 Class III PI 3-kinase is a subgroup of the enzyme family, phosphoinositide 3-kinase that share a common protein domain structure, substrate specificity and method of activation. There is only one known class III PI 3-kinase, Vps34, which is also th ...
- ATG14 via direct interactions between ATG13's HORMA domain and ATG14, (iii) ATG16L1 interacts with
WIPI2 WD repeat domain phosphoinositide-interacting protein 2 is a protein that in humans is encoded by the ''WIPI2'' gene. Function WD40 repeat proteins are key components of many essential biologic functions. They regulate the assembly of multipro ...
, which binds to PI3P, the enzymatic product of the class III PI3K Beclin 1-
VPS34 Class III PI 3-kinase is a subgroup of the enzyme family, phosphoinositide 3-kinase that share a common protein domain structure, substrate specificity and method of activation. There is only one known class III PI 3-kinase, Vps34, which is also th ...
- ATG14. Thus, mTOR inactivation, initiated through GALTOR upon lysosomal damage, plus a simultaneous activation via galectin-9 (which also recognizes lysosomal membrane breach) of
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 ...
that directly phosphorylates and activates key components (
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 ...
, Beclin 1) of the autophagy systems listed above and further inactivates mTORC1, allows for strong autophagy induction and autophagic removal of damaged lysosomes. Additionally, several types of ubiquitination events parallel and complement the galectin-driven processes:
Ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
of TRIM16-ULK1-Beclin-1 stabilizes these complexes to promote autophagy activation as described above. ATG16L1 has an intrinsic binding affinity for
ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
); whereas ubiquitination by a glycoprotein-specific FBXO27-endowed ubiquitin ligase of several damage-exposed glycosylated lysosomal membrane proteins such as
LAMP1 Lysosomal-associated membrane protein 1 (LAMP-1) also known as lysosome-associated membrane glycoprotein 1 and CD107a (Cluster of Differentiation 107a), is a protein that in humans is encoded by the ''LAMP1'' gene. The human ''LAMP1'' gene is locat ...
, LAMP2, GNS/
N-acetylglucosamine-6-sulfatase ''N''-acetylglucosamine-6-sulfatase (EC 3.1.6.14, glucosamine (''N''-acetyl)-6-sulfatase, systematic name ''N''-acetyl-D-glucosamine-6-sulfate 6-sulfohydrolase) is an enzyme that in humans is encoded by the GNS gene. It is deficient in Sanfilippo ...
, TSPAN6/ tetraspanin-6, PSAP/
prosaposin Prosaposin, also known as PSAP, is a protein which in humans is encoded by the ''PSAP'' gene. This highly conserved glycoprotein is a precursor for 4 cleavage products: saposins A, B, C, and D. Saposin is an acronym for Sphingolipid Activator Pr ...
, and TMEM192/transmembrane protein 192 may contribute to the execution of lysophagy via autophagic receptors such as p62/
SQSTM1 Sequestosome-1 is a protein that in humans is encoded by the ''SQSTM1'' gene. Also known as the ubiquitin-binding protein p62, it is an autophagosome cargo protein that targets other proteins that bind to it for selective autophagy. By interacti ...
, which is recruited during lysophagy, or other to be determined functions.


Scleroderma

Scleroderma Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...
, also known as systemic sclerosis, is a chronic
systemic autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
characterised by hardening (''sclero'') of the skin (''derma'') that affects internal organs in its more severe forms. mTOR plays a role in
fibrotic Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
diseases and autoimmunity, and blockade of the mTORC pathway is under investigation as a treatment for scleroderma.


mTOR inhibitors as therapies


Transplantation

mTOR inhibitors, e.g.
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 lymphangioleiomyomatosi ...
, are already used to prevent
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 ...
.


Glycogen storage disease

Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS (glycogen synthase) can be increased in skeletal muscle. This discovery represents a potential novel therapeutic approach for
glycogen storage disease A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by an enzyme deficiency affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells. GSD has ...
that involve glycogen accumulation in muscle.


Anti-cancer

There are two primary mTOR inhibitors used in the treatment of human cancers,
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 ...
and
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 ...
. mTOR inhibitors have found use in the treatment of a variety of malignancies, including
renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the Proximal tubule, 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 cance ...
(temsirolimus) and
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 ...
,
breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
, and renal cell carcinoma (everolimus). The complete mechanism of these agents is not clear, but they are thought to function by impairing tumour
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
and causing impairment of the
G1/S transition The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the sub ...
.


Anti-aging

mTOR inhibitors may be useful for treating/preventing several age-associated conditions, including neurodegenerative diseases such as
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
and
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
. After a short-term treatment with the mTOR inhibitors
dactolisib Dactolisib (codenamed NVP-BEZ235 and BEZ-235, also known as RTB101) is an imidazoquinoline derivative acting as a PI3K inhibitor. It also inhibits mTOR. It is being investigated as a possible cancer treatment. It has been shown to be toxic to ...
and
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 ...
, in elderly (65 and older), treated subjects had a reduced number of infections over the course of a year. Various natural compounds, including
epigallocatechin gallate 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 ...
(EGCG),
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 ...
,
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 ...
,
berberine Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as ''Berberis vulgaris'' (barberry), '' Berberis aristata'' (tree turmeric), '' Mahonia aquifolium'' (Oregon grape), '' Hyd ...
,
quercetin Quercetin is a plant flavonol from the flavonoid group of polyphenols. It is found in many fruits, vegetables, leaves, seeds, and grains; capers, red onions, and kale are common foods containing appreciable amounts of it. It has a bitter flavor a ...
,
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 ...
and
pterostilbene Pterostilbene () (trans-3,5-dimethoxy-4-hydroxystilbene) is a stilbenoid chemically related to resveratrol. In plants, it serves a defensive phytoalexin role. Natural occurrence Pterostilbene is found in almonds, various ''Vaccinium'' berries ( ...
, have been reported to inhibit mTOR when applied to isolated cells in culture. As yet no high quality evidence exists that these substances inhibit mTOR signaling or extend lifespan when taken as dietary supplements by humans, despite encouraging results in animals such as fruit flies and mice. Various trials are ongoing.


Interactions

Mechanistic target of rapamycin has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with: *
ABL1 Tyrosine-protein kinase ABL1 also known as ABL1 is a protein that, in humans, is encoded by the ''ABL1'' gene (previous symbol ''ABL'') located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian ...
, *
AKT1 RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It ...
, * IGF-IR, *
InsR 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 ho ...
, *
CLIP1 CAP-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 Platelet-a ...
, *
EIF3F Eukaryotic translation initiation factor 3 subunit F (eIF3f) 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 Eukaryotic translation initi ...
*
EIF4EBP1 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 ...
, * FKBP1A, *
GPHN Gephyrin is a protein that in humans is encoded by the ''GPHN'' gene. This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subu ...
, *
KIAA1303 Regulatory-associated protein of mTOR also known as raptor or KIAA1303 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 (isoform 1) and 1177 (isoform ...
, *
PRKCD Protein kinase C delta type (or PKC-δ) is an enzyme that in humans is encoded by the ''PRKCD'' gene. Function Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by the second messeng ...
, * RHEB, *
RICTOR Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the ''RICTOR'' gene. RICTOR and mTOR are components of a protein complex that integrates nutrient- and growth factor-derived s ...
, * RPS6KB1, *
STAT1 Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family. Function All STAT molecules are phosphorylated by receptor associ ...
, *
STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respons ...
, *
Two-pore channels Two-pore channels (TPCs) are eukaryotic intracellular voltage-gated and ligand gated cation selective ion channels. There are two known paralogs in the human genome, TPC1s and TPC2s. In humans, TPC1s are sodium selective and TPC2s conduct so ...
: TPCN1; TPCN2, and * UBQLN1.


References


Further reading

*


External links

* * * {{DEFAULTSORT:Mammalian Target Of Rapamycin EC 2.7.11 Signal transduction Tor signaling pathway Human proteins Aging-related proteins