DEFINITION
The Mammalian target of rapamycin (mTor) (or FK506 binding protein 12-rapamycin associated protein 1: FRAP1) is a protein which in humans is encoded by the FRAP1 gene. mTOR is a serine/threonine protein kinase with pleiotropic functions that belongs to the phosphatidylinositol 3-kinase-related kinase protein family.
Bella tesina 2007
THE GENE
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
Protein Aminoacids Percentage
SYNTHESIS AND TURNOVER
mRNA synthesis
protein synthesis
post-translational modifications
degradation
CELLULAR FUNCTIONS
cellular localization,
biological function
mTOR is the Kinase subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals.
| mTORC1 | mTORC2 |
| mTOR catalytic subunit | mTOR catalytic subunit |
| mLST8 | mLST8 |
| Deptor | Deptor |
| Rictor |
| mSIN1 |
| mLST8 |
|
|
and at least five accessory proteins. , , and Protor are unique subunits of mTORC2. In contrast, are shared subunits of mTORC1 and mTORC2. Rictor, mSIN1, and (in addition to mTOR) are the core essential components of the complex and are required for maintaining structural integrity. In contrast, mTORC2 activity does not require Deptor and Protor, which may function as regulatory proteins. Deptor seems to negatively regulate mTORC2, whereas the function of Protor is unknown. (
mTOR Complex1–S6K1 signaling: at the crossroads of obesity, diabetes and cancer
Abstract
Regulation of growth and proliferation in higher eukaryotic cells results from an integration of nutritional, energy, and mitogenic signals. Biochemical processes underlying cell growth and proliferation are governed by the phosphatidylinositol 3-kinase (PI3K) and target of rapamycin (TOR) signaling pathways. The importance of the interplay between these two pathways is underscored by the discovery that the TOR inhibitor rapamycin is effective against tumors caused by misregulation of the PI3K pathway. We review here recent data concerning the convergence of the PI3K and TOR pathways, the role of these pathways in cell growth and proliferation, and the regulation of growth by downstream TOR targets.
Full Text
Proto-oncogenes that affect the mTOR Complex1–S6K1 pathway
| Gene | Syndrome | Molecular function |
| PI3K | Ovarian and gastrointestinal cancer | Activates PKB/Akt via PIP3 |
| PKB/Akt | Breast and ovarian cancer | Activates mTOR Complex1 |
| RAS | Pancreatic and colon cancer | Activates PI3K |
mTOR1 and mTOR2 2007
The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism.
Two structurally and functionally distinct mTOR-containing multiprotein complexes have been identified. mTOR exists in two complexes: mTOR Complex1, which is rapamycin-sensitive and phosphorylates S6K1 and initiation factor 4E binding proteins (4E-BPs), and mTOR Complex2, which is rapamycin-insensitive and phosphorylates protein kinase B (PKB, also known as Akt).
Tuberous sclerosis complex: linking cancer to metabolism. 2010
Trends Mol Med. 2010 Jun 2. [Epub ahead of print]
Mieulet V, Lamb RF.
The TSC1/TSC2 tumor-suppressor complex regulates cell growth via controlling the mTOR (mammalian target of rapamycin) signaling pathway, which contributes to several disease processes, including cancer and diabetes. Abnormal activation of mTOR uncouples anabolic cell growth processes such as protein and lipid synthesis from external growth factor or nutrient cues. However, abnormal activation of mTOR upon loss of TSC1/TSC2 complex function is now known to lead to compensatory mechanisms that restrict the development of malignant tumors . The rare occurrence of complete loss of TSC1/TSC2 function in human tumors suggests that retaining growth suppressor activity might be beneficial during tumour evolution, perhaps by promoting survival when cells grow in a nutrient-limited environment. Copyright © 2010 Elsevier Ltd. All rights reserved.
Upstream mTOR (FRAP1)
Leucine
This model (from Reynolds et al. 2007) shows postulated roles for three types of transporter (right-hand side of figure) in regulating the kinase TOR, which is central to cell growth pathways. General amino-acid transporters (AAT) may deliver nutrients; CD98-related transporters are specifically involved in delivery of leucine (through system L) to intracellular sensors; additionally, there is a distinct role of PAT-related transporters in activating insulin signalling pathways, possibly by protein–protein interactions that may depend on intracellular trafficking of this class of transporter. Note the general significance of such interactions, both in normal and abnormal physiology, as indicated by the number of potential ‘disease' phenotypes (indicated in capitals). The left-hand side of the figure outlines the classical insulin regulated signalling pathways. inR, insulin receptor; TOR, target of rapamycin; PAT, proton-coupled amino acid transporter.
Facts, fantasies and fun in epithelial physiology 2008
mTOR patway is down-regulated by AMPK (activated by AMP, Metformin, AICAR)
AMPK activation depends on:
- AMP
- Metformin
- AICAR
- purine biosynthesis
- histidine catabolism
TSC1/2, rheb, and AMPK are upstream regulators of mTOR (FRAP1). TSC1 and TSC2 receive input from several signalling pathways, including the PI3K–Akt (insulin-signalling) pathway, the ERK1/2 pathway, the p38MAPK–MK2 pathway and the LKB1–AMPK (energy-sensing) pathway, as well as GSK3β. Also, there is probably direct input from signalling in response to hypoxia.
Downstream mTOR (FRAP1)
In response to these signals, TSC1–2 acts as a GTPase-activating protein (GAP) for Rheb, which, in turn, regulates mTOR. Activated mTOR has many main downstream targets, RPS6KB1 (S6K1), 4E-BP1 (cell growth and proliferation), ATG1 (autophagocytosis) and HIF.
Metabolic pathways
The mammalian target of rapamycin (mTOR or FRAP1) and its effector, S6 kinase 1 (S6K1 or RPS6KB1), lie at the crossroads of a nutrient-hormonal signaling network that is involved in specific pathological responses, including obesity, diabetes and cancer.
Both mTOR complexes are stimulated by mitogens, but only mTOR Complex1 is under the control of nutrient and energy inputs. Thus, to orchestrate the control of homeostatic responses, mTOR Complex1 must integrate signals from distinct cues.
- Cell signaling and Ligand transport
- Structural proteins
REGULATION
DIAGNOSTIC USE
Participation of mTOR Complex 1 in TLR2 and TLR4 Induced Neutrophil Activation and Acute Lung Injury. 2009