Mammalian target of rapamycin
Bella tesina 2007
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).
Upstream mTOR (FRAP1)
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.
Participation of mTOR Complex 1 in TLR2 and TLR4 Induced Neutrophil Activation and Acute Lung Injury. 2009