Clinical Significance
- Any flaws in mTOR function can result in the development of cancer since mTOR actively participates in the activation of genes linked to cell proliferation. For instance, some genes that mTORC1 and mTORC2 activate can stop cells from dying naturally and enhance food intake, leading to unchecked cell proliferation and tumor development.
- Another major cause of heart hypertrophy, which is a major risk factor for cardiac morbidity and cardiac-related mortality, is considered to be hyperactivation of the mTOR pathway.
- The mTOR pathway has been demonstrated to play a crucial part in the complicated process of aging, which is influenced by several elements at the cellular level as well as in human living. Regulation and upkeep of mTOR are essential for health due to their function in immune response and cellular senescence. It has also been demonstrated that mTOR signaling is involved in studies that try to lengthen the tissue’s lifetime.
Energy and Glucose Sensing
By lowering ATP levels, the decreased glycolytic flux brought on by glucose restriction suppresses mTORC1. mTORC1 is inhibited by 2-Deoxy-Glucose (2DG), a hexokinase inhibitor, or the mitochondrial uncoupler FCCP in wild-type cells but not in cells lacking TSC2. Low ATP levels are sent to TSC2 by the 5′AMP-activated protein kinase (AMPK). Reduced ATP production and an increase in the AMP/ATP ratio cause the heterotrimeric kinase AMPK to become active. When there is a shortage of glucose, AMPK phosphorylates TSC2 directly, activating it by an unknown method and suppressing mTORC1 in the process. For cells to survive, this procedure is crucial.
Oxygen Detection
Low oxygen levels, or hypoxia, inhibit mTORC1 signaling in a variety of mechanisms. Hypoxia also inhibits mTORC1 via the actions of Redd1/RTP801, which was first discovered in Drosophila as Scylla and Charybdis. These genes generate hypoxia-inducible RNAs that enigmatically suppress the activity of mTORC1. A similar pathway connecting AMPK and PI3K, Redd1’s activation of TSC2, and the ensuing inhibition of mTORC1 have been discovered through genetic research. Injuries other than hypoxia, such as energy deprivation, DNA damage, glucocorticoids, and oxidizing agents, activate Redd1, showing that Redd1 performs a variety of roles in sending stress signals to mTORC1. In addition to AMPK and Redd1, there are alleged other pathways by which hypoxia decreases mTORC1, but these need to be verified and further studied.
Detecting Amino Acids
A lack of amino acids puts cells under stress, and they react by initiating and inhibiting a variety of activities. Low concentrations of amino acids suppress TORC1 signaling in a wide range of organisms, including yeast and humans. Deletion of dTOR in flies mimics amino acid withdrawal by imitating the breakdown and mobilization of nutritional stores, which prevents larval development and causes the accumulation of lipid vesicles in the larval fat body. In C. elegans, the deletion of the intestinal amino-acid transporter pep-2 disrupts insulin and ceTOR signaling, which shortens body length and reduces the number of offspring via sluggish post-embryonic growth. When ceTOR is inhibited, worms are better able to withstand environmental hazards including heat and oxidative damage.
Functions of mTOR in Healthy Brain Development
Because mTOR is required for the development, division, and migration of every cell, it is thought to be essential for organism growth. In fact, mTOR was found to be crucial for good development and survival in studies employing knockout (KO) mice. The first genetic evidence that mTOR is essential for brain development came from a mouse model with ethyl-nitroso-urea-induced mutations. This mutant, called flat-top, was a loss-of-function mTOR mutant brought on by misplacing; it showed a deficit in the development of the telencephalon and died in the midst of pregnancy. The milder phenotype compared to complete KO may be due to the partial loss of mTOR function. In actuality, the mutant mouse’s p70S6K activity was still 10% lower than that of the wild-type mouse.
Functions of mTOR in the formation of Dendrites
The impact of mTOR on neurite formation is thoroughly morphologically investigated by culture studies. Particularly, when constitutively active or dominantly negative forms of PI3K, Akt, and Ras were transfected, it was demonstrated that PI3K-Akt accelerated the development of the soma and dendrites. Ras and PI3K-Akt coupling leads to more complex dendrites in hippocampal neurons. Similar to this, siRNA-mediated inhibition of the phosphatase and tensin homolog (PTEN), the phosphatase for Akt, induced hippocampal dendritic arborization. The dendritic formation induced by these therapies was reduced by chronic rapamycin therapy, siRNA-mediated inhibition of mTOR and p70S6K, and overexpression of phosphorylation-defective mutant 4EBP. These results imply that dendritic maturation and development depend on mTOR, namely mTORC1.
Functions of mTOR in axon extension
Axon orientation is controlled throughout development by a balance of chemotactic inputs from attracting and repellent chemicals. Semaphorin-3 and netrin-1 have been shown to cause growth cone collapse and repulsive turning in Xenopus retinal neurons. The process was stopped by rapamycin as well as the protein synthesis inhibitors cycloheximide and anisomycin. The phosphorylation of 4EBP by growth cones in response to semaphorin-3 and netrin-1 has been observed. Slit2 has been shown to have rapamycin-sensitive effects on 4EBP phosphorylation and growth cone collapse, albeit at a later stage. The aberrant retinogeniculate projection caused by TSC2 haploinsufficiency in mice (TSC-/+) served as a demonstration of the disruption of axon guidance. Since it is known that ephrin-eph communication is crucial for this tract’s axon guidance, the effect of ephrinA on the mTOR pathway was examined.
Gene deletion (gene knockout)
A gene knockout is a genetic procedure in which one of an organism’s genes is rendered inactive (abbreviated as KO) (“knocked out” of the organism). However, the term “KO” can also apply to the creature that contains a gene knockout or the knockout gene itself. Gene function is studied using knockout creatures, or simply knockouts, often by examining the consequences of gene deletion. Researchers deduce conclusions from the distinction between the knockout organism and healthy people.
A gene knock-in is essentially the reverse of the KO approach. A double knockout occurs when two genes are simultaneously deleted from an organism (DKO). In a similar manner, three or four knocked-out genes are referred to as triple knockouts (TKO) or quadruple knockouts (QKO), respectively.
mTOR Signaling Pathway
Cell signaling (cell communication in British English) is the capacity of a cell to receive, process, and transmit messages with its surroundings and with itself. Cell signaling is a basic characteristic of all prokaryotic and eukaryotic cellular life. Cell signaling can take place across short or long distances, and is thus classed as autocrine, juxtacrine, paracrine, and endocrine. Signaling molecules can be produced via a variety of biosynthetic pathways and released by passive or active transporters, as well as cell injury.
Receptors are important in cell signaling because they can sense chemical signals as well as physical inputs. Receptors are proteins that are found on the cell surface or within the cell’s interior, such as the cytoplasm, organelles, and nucleus. Additional enzymatic activity such as proteolytic cleavage, phosphorylation, methylation, and ubiquitinylation may occur as a result of these signaling pathways. Each cell is designed to respond to certain extracellular signal molecules, which serve as the foundation for development, tissue repair, immunology, and homeostasis.