mTOR (mechanistic target of rapamycin) is a protein kinase that plays a key role in regulating cell growth and metabolism.

The mammalian target of rapamycin (mTOR).

It acts as a central component of signaling pathways that respond to various environmental cues like nutrient availability, growth factors, and stress.

mTOR integrates these signals to regulate processes such as protein synthesis, autophagy, and lipid metabolism.

Dysregulation of mTOR signaling has been implicated in various diseases including cancer, metabolic disorders, and neurodegenerative diseases.

When mTOR is activated, it promotes cell growth and division, protein synthesis, and glucose metabolism.

Dysregulated mTOR signaling has been linked to various diseases, including cancer, metabolic disorders, and neurological disorders.

A kinase that in humans is encoded by the MTOR gene.

mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

Chromosome 1

mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription.

As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin-like growth factor 1 receptors.

mTORC2 has also been implicated in the control and maintenance of the actin cytoskeleton.

mTOR suppresses the immune system by blocking the G1 to S phase transition in T-lymphocytes.

It is used as an immunosuppressant following organ transplantation.

It inhibits T-cell receptor (TCR) and IL-2 receptor signaling pathways, respectively.

Caloric restriction leads to longer lifespans in various species, probably mediated by the nutrient-sensing function of the mTOR pathway.

mTOR, a protein that inhibits autophagy, has been linked to aging through the insulin signalling pathway.

mTOR functions through nutrient and growth cues suggesting that dietary restriction and mTOR are related in terms of longevity.

There are two distinct complexes of mTOR, mTORC1, and mTORC2, which have different functions and downstream targets.

Rapamycin and its analogs, called mTOR inhibitors, have been developed as immunosuppressants and anticancer drugs by targeting mTOR signaling.

mTOR functions as a serine/threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription.

As a core component of mTORC2, mTOR also functions as a tyrosine protein kinase that promotes the activation of insulin receptors and insulin-like growth factor 1 receptors.

mTORC2 has also been implicated in the control and maintenance of the actin cytoskeleton.

Rapamycin blocks the G1 to S phase transition in T-lymphocytes, and is used as an immunosuppressant following organ transplantation.

mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids.

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, obesity, depression, and certain cancers.

The TOR kinase complex has been known for having a role in the metabolism of plants.

The mTOR complex functions as a nutrient/energy/redox sensor and controls protein synthesis.

The activity of mTORC1 is regulated by rapamycin, insulin growth factors, phosphatidic acid, certain amino acids and their derivatives mechanical stimuli, and oxidative stress.

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.

The mTORC1 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, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (of l-leucine and β-hydroxy β-methylbutyric acid, mechanical stimuli, and oxidative stress.

Cellular bicarbonate metabolism can be regulated by mTORC1 signaling.

The role of mTORC1 is to activate translation of proteins to allow cells to grow and proliferate by manufacturing more proteins.

For protein production mTORC1 activated cells must have adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for mRNA translation to begin.

Insulin signaling ensures that there is energy for protein synthesis to take place.

Mitogens, such as insulin like growth factor 1 (IGF1), can activate the MAPK/ERK pathway, which can inhibit the TSC1/TSC2 complex, activating mTORC1.

Cytokines like tumor necrosis factor alpha (TNF-alpha) can induce mTOR activity.

Based on upstream signaling of mTORC1, a clear relationship between food consumption and mTORC1 activity has been observed.

Carbohydrate consumption activates mTORC1 through the insulin growth factor pathway.

Amino acid consumption stimulates 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.

Dietary restriction has been shown to significantly increase lifespan in the human model of Rhesus monkeys 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, diabetes, cancer, and age related cognitive decline than those monkeys who were not placed on the calorie restricted diet.

Autophagy, the major degradation pathway in eukaryotic cells.

Autophagy is essential for the removal of damaged organelles via macroautophagy or proteins and smaller cellular debris via microautophagy from the cytoplasm.

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 (Atg 13), preventing the structure from being recruited to the preautophagosomal structure at the plasma membrane, 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.

mTORC1 is positioned on lysosomes and is inhibited when lysosomal membrane is damaged through a protein complex.

mTOR inhibition activates autophagy and starts a quality control program that removes damaged lysosomes, lysophagy.

Reactive oxygen species can damage the DNA and proteins in cells, and a majority of them arise in the mitochondria.

Both cancer cells as well as those cells with greater levels of mTORC1 both rely more on glycolysis in the cytosol for ATP production rather than through oxidative phosphorylation in the inner membrane of the mitochondria.

Conservation of stem cells in the body help prevent against premature aging, and mTORC1 activity plays a critical role in the growth and proliferation of stem cells.

Knocking out mTORC1 results in embryonic lethality due to lack of trophoblast development.

Treating stem cells with rapamycin will also slow their proliferation, conserving the stem cells in their undifferentiated state.

mTORC1 plays a role in the differentiation and proliferation of hematopoietic stem cells, and upregulation has been shown to cause premature aging in hematopoietic stem cells.

Conversely, inhibiting mTOR restores and regenerates the hematopoietic stem cell line.

Rapamycin is used clinically as an immunosuppressant and prevents the proliferation of T cells and B cells, while paradoxically, even though rapamycin’s inhibition of mTORC1 results in better quantity and quality of functional memory T cells.

mTORC1 inhibition with rapamycin improves the ability of naïve T cells to become precursor memory T cells during the expansion phase of T cell development .

This mTORC1 inhibition allows for an increase in quality of memory T cells that become mature T cells during the contraction phase of their development.

Resistance exercise, the amino acid l-leucine induces signaling cascades in skeletal muscle cells that result in mTOR phosphorylation, the activation of mTORC1, and subsequently the initiation of myofibrillar protein synthesis such as myosin, titin, and actin, thereby facilitating muscle hypertrophy.

The NMDA receptor antagonist ketamine activates the mTORC1 pathway in the medial prefrontal cortex (mPFC) of the brain.

The mTORC1 pathway is an essential downstream mechanism in the mediation of its rapid-acting antidepressant effects.

Dietary compounds that have been suggested to inhibit mTORC1 signaling include: resveratrol, curcumin, caffeine, and alcohol.

Rapamycin was the first known inhibitor of mTORC1.

Rapamycin itself is not very water soluble and is not very stable,and is a first generation inhibitor of mTOR.

Other inhibitors include everolimus and temsirolimus.

Compared with rapamycin, everolimus is more selective for the mTORC1 protein complex, with little impact on the mTORC2 complex.

mTORC1 inhibition by everolimus normalizes tumor blood vessels, increases tumor-infiltrating lymphocytes, and improves adoptive cell transfer therapy.

Sirolimus, is the drug name for rapamycin.

Sirolimus is approved to prevent against transplant rejection in patients undergoing kidney transplantation.

It is approved as a stent covering.

mTORC1 inhibitors are approved for treatments against cancers such as renal cell carcinoma, mantle cell lymphoma, and pancreatic cancer.

mTORC1 inhibitors are approved for the treatment of tuberous sclerosis.

The second and third generation of inhibitors were created to overcome problems with upstream signaling upon the introduction of first generation inhibitors to the treated cells.

The subsequent 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.

mTORC2 has been shown to function as an important regulator of the actin cytoskeleton through its stimulation of F-actin stress fibers.

mTOR Complex 2 is an acutely rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling.

The complex itself is rather large, consisting of seven protein subunits.

mTOR Complex 2 (mTORC2) is a protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling.

mTORC2 responds to growth factors to modulate cell metabolism and cell survival, thanks to its activation of the survival kinase Akt.

mTORC2 activation by growth factors and plays a role as an important regulator in the organization of the actin cytoskeleton.

mTORC2 also regulates cellular proliferation and metabolism.

The precise localization of mTORC2 inside cells is unclear.

mTORC2 appears to be regulated by insulin, growth factors, and serum.

In contrast to mTORC1, which is mainly stimulated by nutrients, TORC2 is mainly stimulated by growth factors.

mTORC2 can be inhibited by chronic treatment with rapamycin, both in cancer cells and normal tissues such as the liver and adipose tissue.

mTORC2 signaling is also regulated by mTORC1 due to the presence of a negative feedback loop between mTORC1 and insulin/PI3K signaling.

mTORC2 controls cell survival and proliferation mainly through phosphorylation of several members of the AGC (PKA/PKG/PKC) protein kinase family.

mTORC2 regulates actin cytoskeleton.

mTORC2 plays a crucial role in metabolic regulation, it can be linked to many human pathologies.

Deregulation of mTOR signaling, including mTORC2, affects transduction of insulin signal and therefore can disrupt its biological functions and lead to metabolic disorders, such as type 2 diabetes mellitus.

In many types of cancer, hyperactivation of mTORC2 caused by mutations and aberrant amplifications of mTORC2 core components is observed.

On metabolic level, activation of mTORC2 stimulates processes related to alteration of glucose metabolism in cancer cells, the Warburg effect.

mTORC2-mediated lipogenesis has been linked to promotion of hepatocellular carcinoma through stimulation of glycerophospholipid and sphingolipid synthesis.

Although mTORC2 is acutely insensitive to rapamycin.

Chronic rapamycin treatment abrogates mTORC2 signaling, leading to insulin resistance and glucose intolerance.

The mTORC2 pathways plays a crucial role in pathogenesis of lung fibrosis.

Chronic mTORC2 activity may play a role in systemic lupus erythematosus by impairing lysosome function.

mTOR has a critical role in the regulation of glucose homeostasis.

Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug.

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.

It is likely that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity.

Studies suggest 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.

In the free radical theory of aging, reactive oxygen species cause damage to mitochondrial proteins and decrease ATP production.

Disruption of mTORC1 directly inhibits mitochondrial respiration.

Decreased mTOR activity upregulates removal of dysfunctional cellular components via autophagy.

mTOR is a key initiator of the senescence-associated secretory phenotype (SASP).

Over-activation of mTOR signaling contributes to the initiation and development of tumors.

mTOR activity is deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas.

Among the most common are mutations in cancer are tumor suppressor PTEN genes.

PTEN phosphatase negatively affects mTOR signalling through interfering with the effect of PI3K, an upstream effector of mTOR.

mTOR activity is deregulated in many cancers as a result of increased activity of PI3K or Akt.

The overexpression of downstream mTOR effectors leads to poor cancer prognosis.

Also, mutations in TSC proteins that inhibit the activity of mTOR may lead to a condition named tuberous sclerosis complex, which exhibits as benign lesions and increases the risk of renal cell carcinoma.[91]

Increased mTOR activity drives cell cycle progression and increase cell due to its effect on protein synthesis.

mTOR asupports tumor growth also indirectly by inhibiting autophagy.

Constitutively activated mTOR functions in supplying carcinoma cells with oxygen and nutrients by increasing the translation of HIF1A and supporting angiogenesis.

mTOR also aids in the metabolic adaptation of cancerous cells to support their increased growth rate—activation of glycolytic metabolism.

mTORC2, upregulates expression of the glycolytic enzymes contributing to the Warburg effect.

mTOR is implicated in the failure of a pruning mechanism of the excitatory synapses in autism spectrum disorders.

mTOR signaling hyperactivity is noted in Alzheimer disease brains.

mTOR signaling is 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.

Increasing Aβ concentrations increases mTOR signaling.

It has also been proposed that mTOR contributes to tau pathology by increasing the translation of tau and other proteins.

Protein homeostasis is essential for neural plasticity and is regulated by mTOR, and it plays an important role in affecting cognitive functioning through synaptic plasticity.

Both protein over- and under-production via mTOR activity contribute to impaired learning and memory.

eIF2α-P, an upstream target of the mTOR pathway, mediates cell death in prion diseases through sustained translational inhibition.

mTOR is a negative regulator of autophagy.

Hyperactivity in mTOR signaling should reduce Aβ clearance in the Alzheimer’s brain.

Disruptions in autophagy may be a potential source of pathogenesis in protein misfolding diseases, such as AD.

Hyperactive mTOR pathways have been identified in certain lymphoproliferative diseases: autoimmune lymphoproliferative syndrome (ALPS), multicentric Castleman disease, and post-transplant lymphoproliferative disorder.

mTORC1 activation is required for myofibrillar muscle protein synthesis and skeletal muscle hypertrophy in response to both physical exercise and ingestion of certain amino acids or amino acid derivatives.

Persistent inactivation of mTORC1 signaling in skeletal muscle facilitates the loss of muscle mass and strength during in old age, cancer cachexia, and muscle atrophy from physical inactivity.

Lysosomal damage inhibits mTOR and induces autophagy.

mTOR is inhibited when lysosomal membrane is damaged by various exogenous or endogenous agents, such as invading bacteria, membrane-permeant chemicals yielding osmotically active products aggregates and cytoplasmic organic or inorganic inclusions including urate crystals and crystalline silica.

mTOR is a negative regulator of autophagy in general, and is best studied during response to starvation, which is a metabolic response.

During lysosomal damage however, mTOR inhibition activates autophagy response leading to the process termed lysophagy that removes damaged lysosomes.

mTOR inhibitors, e.g. rapamycin, are already used to prevent transplant rejection.

There are two primary mTOR inhibitors used in the treatment of human cancers, temsirolimus and everolimus: renal cell carcinoma (temsirolimus) and pancreatic cancer, breast cancer, and renal cell carcinoma (everolimus).

They are thought to function by impairing tumour angiogenesis and causing impairment of the G1/S transition.

mTOR inhibitors may be useful for treating/preventing several age-associated conditions, including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.

The mTOR inhibitors dactolisib and everolimus, in elderly treated subjects had a reduced number of infections over the course of a year.

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.



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