A novel pathway regulating the mammalian target of rapamycin (mTOR) signaling |
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Authors: | Chen Jie Fang Yimin |
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Affiliation: | Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, 601 South Goodwin Avenue, B107, Urbana, IL 61801, USA. jiechen@uiuc.edu |
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Abstract: | Originally discovered as an anti-fungal agent, the bacterial macrolide rapamycin is a potent immunosuppressant and a promising anti-cancer drug. In complex with its cellular receptor, the FK506-binding protein (FKBP12), rapamycin binds and inhibits the function of the mammalian target of rapamycin (mTOR). By mediating amino acid sufficiency, mTOR governs signaling to translational regulation and other cellular functions by converging with the phosphatidylinositol 3-kinase (PI3K) pathway on downstream effectors. Whether mTOR receives mitogenic signals in addition to nutrient-sensing has been an unresolved issue, and the mechanism of action of rapamycin remained unknown. Our recent findings have revealed a novel link between mitogenic signals and mTOR via the lipid second messenger phosphatidic acid (PA), and suggested a role for mTOR in the integration of nutrient and mitogen signals. A molecular mechanism for rapamycin inhibition of mTOR signaling is proposed, in which a putative interaction between PA and mTOR is abolished by rapamycin binding. Collective evidence further implicates the regulation of the rapamycin-sensitive signaling circuitry by phospholipase D, and potentially by other upstream regulators such as the conventional protein kinase C, the Rho and ARF families of small G proteins, and calcium ions. As the mTOR pathway has been demonstrated to be an important anti-cancer target, the identification of new components and novel regulatory modes in mTOR signaling will facilitate the future development of diagnostic and therapeutic strategies. |
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Keywords: | FKBP12, FK506-binding protein TOR, target of rapamycin mTOR, mammalian TOR PI3K, phosphatidylinositol 3-kinase PA, phosphatidic acid PLD, phospholipase D PKC, protein kinase C cPKC, conventional PKC S6K1, ribosomal subunit S6 kinase 1 4E-BP1, eukaryotic initiation factor 4E-binding protein 1 ERK, extracellular signal regulated kinase FRB, FKBP12-rapamycin binding LPA, lysophosphatidic acid GPCR, G protein coupled receptor DAG, diacylglycerol DGK, DAG kinase PTEN, phosphatase and tensin homologue deleted from chromosome 10 LPAAT, lysophosphatidic acid acyltransferase. |
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