TSC/mTOR signaling pathway
Friday 21 January 2005
The mammalian TOR (mTOR) pathway is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human diseases, including cancer and diabetes.
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)
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 two main downstream targets, RPS6KB1 (S6K1) and 4E-BP1. This process activates cell growth and proliferation.
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.
acute myeloid leukemia (AML) (19951971)
PI3K/PTEN/AKT signaling pathway
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Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med. 2005 Aug;11(8):353-61. PMID: 16002336
Inoki K, Corradetti MN, Guan KL. Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet. 2005 Jan;37(1):19-24. PMID: 15624019