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TSC/mTOR signaling pathway

Friday 21 January 2005

TSC/FRAP1 pathway, mTOR pathway, TSC signaling pathway, mTOR signaling pathway; TSC/mTORC1/AKT/GSK3β/β-catenin/MITF axis

The mammalian TOR (mTOR or 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.

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.

Melanogenesis

- Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation http://www.jci.org/articles/view/84262

  • Tuberous sclerosis complex (TSC) is an autosomal dominant tumor-suppressor gene syndrome caused by inactivating mutations in either TSC1 or TSC2, and the TSC protein complex is an essential regulator of mTOR complex 1 (mTORC1).
  • Patients with TSC develop hypomelanotic macules (white spots), but the molecular mechanisms underlying their formation are not fully characterized.
  • Using human primary melanocytes and a highly pigmented melanoma cell line, authors demonstrate that reduced expression of either TSC1 or TSC2 causes reduced pigmentation through mTORC1 activation, which results in hyperactivation of glycogen synthase kinase 3β (GSK3β), followed by phosphorylation of and loss of β-catenin from the nucleus, thereby reducing expression of microphthalmia-associated transcription factor (MITF), and subsequent reductions in tyrosinase and other genes required for melanogenesis.
  • Genetic suppression or pharmacological inhibition of this signaling cascade at multiple levels restored pigmentation. Importantly, primary melanocytes isolated from hypomelanotic macules from 6 patients with TSC all exhibited reduced TSC2 protein expression, and 1 culture showed biallelic mutation in TSC2, one of which was germline and the second acquired in the melanocytes of the hypomelanotic macule.
  • The TSC/mTORC1/AKT/GSK3β/β-catenin/MITF axis plays a central role in regulating melanogenesis.
  • Interventions that enhance or diminish mTORC1 activity or other nodes in this pathway in melanocytes could potentially modulate pigment production.

By tumors

- acute myeloid leukemia (AML) (19951971)

See also

- PI3K/PTEN/AKT signaling pathway
- mTOR inhibitors

References

- Role of the PI3K/AKT and mTOR signalling pathways in acute myeloid leukemia. Park S, Chapuis N, Tamburini J, Bardet V, Cornillet-Lefebvre P, Willems L, Green A, Mayeux P, Lacombe C, Bouscary D. Haematologica. 2009 Nov 30. PMID: 19951971

- Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends Mol Med. 2007 Oct;13(10):433-42. PMID: 17905659

- Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med. 2005 Aug;11(8):353-61. PMID: 16002336

- Martin DE, Hall MN. The expanding TOR signaling network. Curr Opin Cell Biol. 2005 Apr;17(2):158-66. PMID: 15780592

- Findlay GM, Harrington LS, Lamb RF. TSC1-2 tumour suppressor and regulation of mTOR signalling: linking cell growth and proliferation? Curr Opin Genet Dev. 2005 Feb;15(1):69-76. PMID: 15661536

- 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

Portfolio

  • mTOR pathway and the PI3K/PTEN/AKT signaling pathway (From Biocarta)
  • TSC signaling pathway