Upstream and downstream of mTOR.

By N. Hay, Nahum Sonenberg. Genes & Development, 2004

4,365 citations recorded by the source corpus.

The evolutionarily conserved checkpoint protein kinase, TOR (target of rapamycin), has emerged as a major effector of cell growth and proliferation via the regulation of protein synthesis. Work in the last decade clearly demonstrates that TOR controls protein synthesis through a stunning number of downstream targets. Some of the targets are phosphorylated directly by TOR, but many are phosphorylated indirectly. In this review, we summarize some recent developments in this fast-evolving field. We describe both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis. We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1169d54e013f6646586e94cbc1b213341d420dcd

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In Molecular Biology

1. David M. Sabatini
2. K. Guan
3. M. Laplante
4. Michael N. Hall
5. B. Manning
6. M. Karin
7. A. Budanov
8. D. Hardie

Citations in the corpus

• The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. (2008, background): “mTORC1 (mammalian TORC1) has two well-characterized classes of downstream targets, the ribosomal S6 kinases S6K1 and S6K2, and 4E-BP1 and 4E-BP2 [eIF4E (eukaryotic translation initiation factor 4E)-binding proteins 1 and 2], which possess residues found to be directly phosphorylated by the mTOR kina”
• mTOR, translation initiation and cancer (2006, background): “…factors and hormones) with aminoacid availability and intracellular energy status to control translation rates and additional metabolic processes (Hay and Sonenberg, 2004) (Figure 2). mTOR has received considerable attention, as rapamycin (Rapamune) is a specific inhibitor of mTOR activity (for…”
• Oncogenic PI3K deregulates transcription and translation (2005, background): “The activities of Pol I and of Pol III have long-term effects, but TOR also regulates protein synthesis on a shorter timescale by inducing the phosphorylation of S6K (p70 S6 kinase) and of the 4EBP (translation initiation factor 4E-binding protein) family of protein”
• Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling (2008, background): “Mammalian target of rapamycin (mTOR) is a central cell growth controller (Hay and Sonenberg, 2004; Wullschleger et al, 2006).”
• Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. (2008, background): “Genetic and biochemical data both in Drosophila and in mammalian cells have demonstrated that a major function of the TSC1/2 complex is to inhibit the activity of the checkpoint protein kinase complex TORC1 (target of rapamycin complex 1) (Hay and Sonenberg 2004).”
• Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis (2006, background): “TOR functions as a nutrient sensor that integrates PI3K-mediated growth-factor signalling, glucose availability and amino-acid availabilit”
• Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer (2009, background): “The most extensively characterized downstream targets of mTORC1 are ribosomal protein S6 kinase 1 (S6K1; also known as p70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), both of which are crucial to the regulation of protein synthesis (reviewed in Ref”
• Autophagy in metazoans: cell survival in the land of plenty (2005, background): “This crucial function is carried out by the conserved protein Tor (and its orthologues mTOR in mammals and dTOR in Drosophila melanogaster ), which functions downstream of PI3K and Akt in growth factor signallin”
• Targeting phosphoinositide 3-kinase: moving towards therapy. (2008, background): “As a consequence, protein and lipid biosynthesis are on, and cells can now increase in size and enter the cell cycle [68,69].”
• TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. (2006, background): “Rheb stimulates the phosphorylation of two translation regulators, S6K (ribosomal S6 kinase 1) and 4EBP1 (eukaryotic initiation factor 4E binding protein 1), by activating mTOR (Hay and Sonenberg, 2004; Manning and Cantley, 2003).”
• Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. (2005, background): “Mammalian rpS6 is phosphorylated in response to multiple external signals, which are transduced through the phosphatidylinositol 3-kinase (PI3-kinase)/mTOR pathway(s) (for review, see Fingar and Blenis 2004; Hay and Sonenberg 2004).”
• The mTOR Signalling Pathway in Human Cancer (2012, background): “mTORC1 also regulates translation via S6K1 and 4EBP1, as referred above [21,111].”
• Human eIF4E promotes mRNA restructuring by stimulating eIF4A helicase activity (2013, background): “The overwhelming majority of these mRNAs possess long structured 5′-UTRs that must be unwound to allow ribosome recruitment and scanning (2, 5, 7, 8).”
• A complex interplay between Akt, TSC2, and the two mTOR complexes (2009, background): “mTORC1-mediated phosphorylation of S6K1/2 and 4EBP1/2 stimulates mRNA translation and, ultimately, cell growth and proliferation [6,7].”