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mTOR Signaling

Types of mTOR

Mechanism of mTOR Signaling Pathway

 

Upstream mTORC1

The Akt/PKB Signaling Pathway

  • Insulin-like growth factors can activate mTORC1 via the RTK-Akt/PKB signaling pathway.
  • Finally, Akt phosphorylates TSC2 on serine 939, serine 981, and threonine 1462. 
  • These phosphorylated regions will attract the cytosolic anchoring protein 14-3-3 to TSC2, breaking the TSC1/TSC2 dimer.
  • When TSC2 is not connected with TSC1, it loses its GAP activity and is unable to hydrolyze Rheb-GTP.
  • This leads to sustained stimulation of mTORC1, allowing for protein synthesis via insulin signaling.
  • Akt will also phosphorylate PRAS40, causing it to detach from the Raptor protein on mTORC1.
  • Because PRAS40 blocks Raptor from attracting mTORC1 substrates 4E-BP1 and S6K1, removing it will allow the two substrates to be recruited to mTORC1 and therefore activated in this way.
  • Furthermore, because insulin is a substance released by pancreatic beta cells in response to blood glucose rise, its signaling guarantees that there is enough energy for protein synthesis to occur.
  • S6K1 has the ability to phosphorylate the insulin receptor and reduce its sensitivity to insulin in a negative feedback loop on mTORC1 signaling.
  • This is extremely important in diabetes mellitus, which is caused by insulin resistance.

MAPK/ERK Signaling Pathway

  • Mitogens such as insulin-like growth factor 1 (IGF1) can activate the MAPK/ERK pathway, which inhibits the TSC1/TSC2 complex and so activates mTORC1.
  • The G protein Ras is linked to the plasma membrane by a farnesyl group in this pathway and is in its inactive GDP form.
  • The adaptor protein GRB2 connects with its SH2 domains when a growth factor binds to the nearby receptor tyrosine kinase, which maintains mTORC1 active.
  • RSK has also been demonstrated to phosphorylate the raptor, which aids in its resistance to PRAS40 inhibition.

JNK Signaling Pathway

  • JNK signaling is a component of the mitogen-activated protein kinase (MAPK) signaling system, which is important in stress signaling pathways including gene expression, neural development, and cell survival.
  • Recent research has revealed a direct molecular connection in which JNK phosphorylates Raptor at Ser-696, Thr-706, and Ser-863.
  • As a result, JNK regulates mTORC1 activity.
  • Thus, JNK activation affects protein synthesis via mTORC1 downstream effectors such as S6 kinase and eIFs.

Downstream TORC1

  •  mTORC1 regulates transcription and translation by interacting with S6K1 and 4E-BP1, the eukaryotic initiation factor 4E (eIF4E) binding protein 1, mostly through phosphorylation and dephosphorylation of its downstream targets.
  • In eukaryotic cells, S6K1 and 4E-BP1 regulate translation.
  • Their signals will converge at the translation initiation complex on the 5′ end of mRNA, resulting in translation activation.

4E-BP1

  • When mTORC1 is activated, it phosphorylates the translation repressor protein 4E-BP1, freeing it from the eukaryotic translation initiation factor 4E. (eIF4E).
  • eIF4E is now free to associate with the eukaryotic translation initiation factors 4G (eIF4G) and 4A (eIF4A) (eIF4A).
  • After binding to the 5′ cap of mRNA, this complex recruits the helicase eukaryotic translation initiation factor A (eIF4A) and its cofactor eukaryotic translation initiation factor 4B. (eIF4B).
  • The helicase is essential to remove hairpin loops that form in the 5′ untranslated regions of mRNA, preventing premature protein translation.

S6K

  • mTOR mediates S6K signaling in a rapamycin-dependent way, with S6K being displaced from the eIF3 complex when mTOR binds to eIF3. 
  • Active S6K1 can then boost protein synthesis by recruiting S6 Ribosomal protein (a ribosomal component) and eIF4B to the pre-initiation complex.
  • S6K1 can interact with mTORC1 in a positive feedback loop by phosphorylating mTOR’s negative regulatory domain at two locations, thr-2446 and ser-2448.
  • Phosphorylation at these locations appears to boost mTOR activity.
  • S6K can also phosphorylate programmed cell death 4 (PDCD4), putting it at risk of degradation by the ubiquitin ligase Beta-TrCP.

mTORC2 Downstream

  • mTORC2 regulates cell survival and proliferation primarily by phosphorylating (PKA/PKG/PKC) protein kinase family.
    mTORC2 controls the actin cytoskeleton via PKC but can also phosphorylate other members of the PKC family that govern cell migration and cytoskeletal remodeling.
  • mTORC2 is involved in the phosphorylation and consequently, activation of Akt, which is a critical signaling component downstream from PI3K once activated, as well as the phosphorylation of SGK1, PKC, and HDACs.

mTORC2’s Upstream

  • mTORC2’s mSin1 subunit, like other PI3K-regulated proteins, has a PH domain that binds phosphoinositides.
  • This domain inhibits mTORC2 catalytic activity in the absence of insulin, which is required for insulin-dependent regulation of mTORC2 activity.
  • The mSin1 subunit can also be phosphorylated by Akt.
  • mTORC1 phosphorylates and thereby activates Grb10, an upstream negative regulator of insulin/IGF-1 receptor signalling.
  • Furthermore, Ric-8B protein and certain lipid metabolites have been discovered as major regulators of mTORC2 activity.

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.

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mTOR

The atypical serine/threonine kinase known as mTOR, which is present in two different complexes, is the target of rapamycin’s molecular action. The first is called mTOR complex 1 (mTORC1) and is suppressed by the drug rapamycin. It is made up of mTOR, Raptor, GL, and DEPTOR. It is a major growth regulator that detects and combines a variety of dietary and environmental stimuli, including growth factors, energy levels, cellular stress, and amino acids. These signals are coupled to the stimulation of cellular growth by phosphorylating substrates that enhance anabolic activities like mRNA translation and lipid synthesis or suppress catabolic processes like autophagy. The tuberous sclerosis heterodimer TSC1/2, the small GTPase Rheb’s GTP-bound state’s GAP, adversely controls the activity of mTORC1 kinase, which is stimulated by the small GTPase Rheb. To control the nucleotide-loading status of Rheb, most upstream inputs are routed through Akt and TSC1/2. On the other hand, amino acids communicate with mTORC1 independently of the PI3K/Akt axis to encourage its movement to the lysosomal surface, where it can be activated in response to Rheb. The coordinated actions of several complexes, particularly the v-ATPase, Ragulator, Rag GTPases, and GATOR1/2, mediate this process. mTOR, Rictor, GL, Sin1, PRR5/Protor-1, and DEPTOR make up the second complex, known as mTOR complex 2 (mTORC2). mTORC2 regulates cytoskeletal dynamics by activating PKC, encourages cellular survival by activating Akt, and promotes ion transport and growth by phosphorylating SGK1. Numerous disease states, such as diabetes, cardiovascular disease, and cancer, are characterized by aberrant mTOR signaling....

m-TOR Signaling

The mammalian target of rapamycin (mTOR), also known as the mechanistic target of rapamycin and also referred to as FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase encoded by the MTOR gene in humans. mTOR is a protein kinase that belongs to the phosphatidylinositol 3-kinase-related kinase family....

Types of mTOR

The Mammalian/mechanistic target of rapamycin is referred to as mTOR. In the middle of the 20th century, a bacteria discovered on Easter Island yielded the immunosuppressive medicine rapamycin. The moniker mTOR was coined since one of the first impacts that rapamycin was shown to have was on TOR genes....

mTOR Signaling

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Mechanism of mTOR Signaling Pathway

Growth factors are mostly used in this pathway as the first signaling molecule needed for activation. The pathway is activated when these growth factors bind to tyrosine kinase receptors in the cell membrane. Phosphorylation, in which a phosphate group is placed onto the target enzyme to make it active and extend the route to further targets, activates many of the enzymes involved in this pathway....

Mechanism of mTOR2

mTORC2 also controls cellular proliferation and metabolism, in part via modulating IGF-IR, InsR, Akt/PKB, and the serum- and glucocorticoid-induced protein kinase SGK. Furthermore, mTORC2 activity has been linked to autophagy control (macroautophagy and chaperone-mediated autophagy). The specific location of mTORC2 within cells is yet unknown. Some discoveries based on its activity indicate cellular endomembranes, such as mitochondria, as a likely location of mTORC2; however, this might be owing to its interaction with Akt. It is unclear whether these membranes exhibit mTORC2 activity in the cellular setting or contribute to the phosphorylation of mTORC2 substrates....

Regulation of mTOR

Growth factors, as well as amounts of amino acids, glucose, and oxygen, are just a few of the upstream signals that control mTORC1 activity. Most signals regulate mTORC1 largely by one of two mechanisms: direct mTORC1 component alteration or control of Rheb, a small GTPase that, when coupled to GTP, directly interacts with and activates mTORC1. A fascinating process that involves Rheb, but also the Rag GTPases, and is covered in its own section below, is how amino acid signaling to mTORC1 works. Akt phosphorylates TSC2 together with other kinases involved in growth factor signaling, including MAPK and p90 RSK1. The GTPase activating protein (GAP) for Rheb is TSC2, also known as tuberin, and along with TSC1 (also known as hamartin), they make up the heterodimeric tuberous sclerosis complex (TSC)....

mTOR Inhibitors

The mechanistic target of rapamycin (mTOR), a serine/threonine-specific protein kinase that is a member of the phosphatidylinositol-3 kinase (PI3K) related kinase family, is inhibited by a class of medications known as mTOR inhibitors (PIKKs). Two protein complexes, mTORC1, and mTORC2, which mTOR forms and signals through, control cellular metabolism, growth, and proliferation. The so-called rapalogs (rapamycin and its analogs), which have demonstrated tumor responses in human studies against a variety of tumor types, are the most well-established mTOR inhibitors....

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....

Inhibition by Rapamycin

The mechanism underlying the cell specificity of rapamycin-induced mTORC2 inhibition is unknown, which is particularly significant given that many of the negative metabolic side effects of rapamycin reported in mouse studies and human clinical trials have recently been attributed to mTORC2 inhibition. The expression levels of several FK506-binding proteins (FKBPs), especially FKBP12 and FKBP51, are identified as important factors for rapamycin-mediated inhibition of mTORC2. In support of this, reducing FKBP12 totally changes a cell line that is sensitive to mTORC2 inhibition to an insensitive cell line, while increasing FKBP12 expression can augment mTORC2 inhibition....

FAQs on mTOR Signaling

Question 1: How does mTOR inhibition work?...

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Types of mTOR

Mechanism of mTOR Signaling Pathway