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Human signaling  mTOR Pathway and cell behaviors

mTOR pathway (mamalien or mechanistic target of rapamycin mTOR), an atypical serine/threonine kinase, through two distinct protein complexes mTORC1 and mTORC2, coordinates eukaryotic cell growth and metabolism with environmental inputs including nutrients and growth factors. Other external stresses, such as oxygen deprivation (hypoxia), radiation, high salt concentration, DNA topoisomerase inhibitors, and histone deacetylase inhibitors, also regulate this pathway (1,6).

The distinct roles of mechanistic target of rapamycin were identified in gene transcription, protein synthesis, tissue regeneration and repair, oxidative stress, immunity, aging, and cell death that include autophagy and apoptosis, insulin resistance, adipogenesis, and T-lymphocyte activation (2,4).

mTOR-Pathway-mTORC2.png

 
The structures, regulatory mechanism and functions of mTORC2 (4)
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mTOR-Signaling-mTORC1

Regulatory mechanism and function of the mammalian target of rapamycin complex 1 (mTORC1). (A) The structures and regulatory mechanism of mTORC1. (B) The downstream functions of mTORC1 (4).

Human Signaling  Regulation of mTOR complexes

mTOR is an atypical serine/threonine protein kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family. It interacts with several proteins to form two distinct complexes mTOR complex 1 (mTORC1) and 2 (mTORC2).
  • mTORC1 is composed of three core components including mTOR, Raptor, and mLST8. The mTORC1 plays important roles in metabolism and cell growth in response to nutrients. This complexe responds to mitogen, energy and nutrient signals through the upstream regulators tuberous sclerosis complex 1/2 (TSC1/2) and Rheb. Many factors, including growth factors, amino acids, energy, oxygen, and DNA damage, are negative regulators of mTORC1.
    Amino acids activate the mTORC1 via an amino acid sensing cascade involving the vacuolar H+-ATPase (v-ATPase), RAG GTPases (small guanosine triphosphatase) and Regulator. The mTORC1 activation is closely linked to the variation of amino acid concentrations. The activated mTORC1 enhances protein synthesis through direct phosphorylation of the ribosomal S6 kinase (S6K) and 4E-BP1.
  • mTORC2 is composed of mTOR, mLST8 and Rictor. It is activated by Akt via phosphorylation of mSin1 at T86. This complexe controls cell migration, cell survival and metabolism, cytoskeleton and phosphorylation and activation of Akt and SGK1.
    Activated mTORC2 stimulates Akt through phosphorylation of Akt at S473, which forms a positive feedback regulatory loop (1,4,5).

Human Signaling  mTOR Signaling Pathway and diseases

The de-regulated activity of mamalien target of rapamycin is involved in many pathophysiological conditions, such as aging, Alzheimer’s disease, obesity, diabetic complications, pulmonary hypertension, cardiovascular diseases, neurodegeneration, and cancer.
Through diverse mechanisms (promotion of growth factor receptor signaling, angiogenesis, glyolytic metabolism, lipid metabolism, cancer cell migration, and suppression of autophagy), recent studies suggest that mechanistic target of rapamycin signaling pathway plays an essential role in the regulation of tumor cell motility, invasion and metastasis. Hence, this pathway is a promising target for cancer therapy by developing mTOR inhibitors.
The best-known inhibitor for mTOR is rapamycin. It does not directly inhibit the kinase activity of mTORC1 but, instead, it binds, together with a small protein, an immunophilin termed FKBP12, masking the substrate binding site and inhibiting some of its functions (2,3,5,7).
(1) Saxton RA  et  Sabatini  DM. mTOR  Signaling in  Growth,  Metabolism, and  Disease. Cell. (2017)9;168(6):960-976.
(2) Das A  et  al. mTOR  Signaling  in  Cardiometabolic  Disease,  Cancer,  and  Aging. Oxid Med Cell Longev. (2017).
(3) Chamcheu JC et al. Role and Therapeutic Targeting of  the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic  Agents  Therapy. Cells. (2019)31;8(8).
(4) Wei X  et  al.  Roles  of  mTOR  Signaling  in  Tissue  Regeneration. Cells. (2019)12;8(9).
(5) Kwasnicki A et al. Involvement of mTOR signaling pathways in regulating growth and dissemination  of  metastatic  brain  tumors  via  EMT. Anticancer Res. (2015);35(2):689-96.
(6) Paquette  M  e t  al.  mTOR  Pathways  in  Cance r  and  Autophagy. Cancers (Basel). (2018);10(1).
(7) Hua H  e t  al.  Targeting  mTOR  for  cancer  therapy.  J Hematol Oncol. (2019);12(1):71.

  • Biomarker list

You can check the biomarker list included in this pathway, see below:

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