Mammalian Target of Rapamycin (mTOR): Conducting the Cellular Signaling Symphony (original) (raw)
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The Complexes of Mammalian Target of Rapamycin
Current Protein & Peptide Science, 2010
The mammalian target of rapamycin (mTOR) has attracted substantial attention because of its involvement in a variety of diseases, such as cancer, cardiac hypertrophy, diabetes and obesity. Current knowledge indicates that mTOR functions as two distinct multiprotein complexes, mTORC1 and mTORC2. mTORC1 phosphorylates p70 S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1), and regulates cell growth, proliferation, and survival by integrating hormones, growth factors, nutrients, stressors and energy signals. In contrast, mTORC2 is insensitive to nutrients or energy conditions. However, in response to hormones or growth factors, mTORC2 phosphorylates Akt, and regulates actin cytoskeleton and cell survival. These findings not only reveal the crucial role of mTOR in physiology and pathology, but also reflect the complexity of the mTOR signaling network. In this review, we discuss the advances in studies of the mTOR complexes, including the interacting proteins, the upstream regulators and the downstream effectors of mTOR complexes, as well as their implication in certain human diseases. mTOR, also known as FRAP (FKBP12-rapamcyin-associated protein), RAFT1 (rapamycin and FKBP12 target), RAPT 1 (rapamycin target 1), or SEP (sirolimus effector protein), is a 289 kDa atypical serine/threonine (S/T) kinase . mTOR is considered a member of the phosphatidylinositol 3-kinase (PI3K)-kinase-related kinase (PIKK) superfamily since its Cterminus shares strong homology to the catalytic domain of PI3K . A variety of members in this family, also including MEC1, ATM, ATR, DNA-PKcs, SMG-1 and TRRAP, are associated with diverse cellular functions, such as control of cell growth, cell cycle and DNA damage checkpoints, recombination and maintenance of telomere length [ ] . Cumulative evidence indicates that mTOR acts as a 'master switch' of cellular anabolic and catabolic processes, regulating the rate of cell growth and proliferation by virtue of its ability to sense mitogen, energy and nutrient levels . Deregulation of the mTOR pathway is frequently observed in various human diseases, such as cancer and diabetes. For example, activation of the mTOR pathway was noted in squamous cancers , adenocarcinomas [23], bronchioloalveolar carcinomas [24], colorectal cancers [25], astrocytomas [26] and glioblastomas [27]. A recent immunohistochemical study performed in tissue arrays containing 124 tumors from 8 common human tumor types showed that approximately 26% of tumors (32/124) are predicted to be sensitive to mTOR inhibition [28]. These findings indicate a crucial role of mTOR signaling in tumorigenesis.
Cancer Research, 2009
The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic component of two evolutionarily conserved signaling complexes. mTOR signaling complex 1 (mTORC1) is a key regulator of growth factor and nutrient signaling. S6 kinase is the best-characterized downstream effector of mTORC1. mTOR signaling complex 2 (mTORC2) has a role in regulating the actin cytoskeleton and activating Akt through S473 phosphorylation. Herein, we show that mTOR is phosphorylated differentially when associated with mTORC1 and mTORC2 and that intact complexes are required for these mTORC-specific mTOR phosphorylations. Specifically, we find that mTORC1 contains mTOR phosphorylated predominantly on S2448, whereas mTORC2 contains mTOR phosphorylated predominantly on S2481. Using S2481 phosphorylation as a marker for mTORC2 sensitivity to rapamycin, we find that mTORC2 formation is in fact rapamycin sensitive in several cancer cell lines in which it had been previously reported that mTORC2 assembly and function were rapamycin insensitive. Thus, phospho-S2481 on mTOR serves as a biomarker for intact mTORC2 and its sensitivity to rapamycin. [Cancer Res 2009;69(5):1821-7]
Journal of Biological Chemistry, 2008
Signaling through mammalian target of rapamycin complex 1 (mTORC1) is stimulated by amino acids and insulin. Insulin inactivates TSC1/2, the GTPase-activator complex for Rheb, and Rheb⅐GTP activates mTORC1. It is not clear how amino acids regulate mTORC1. FKBP38 (immunophilin FK506-binding protein, 38 kDa), was recently reported to exert a negative effect on mTORC1 function that is relieved by its binding to Rheb⅐GTP. We confirm that Rheb binds wild type FKBP38, but inactive Rheb mutants showed contrasting abilities to bind FKBP38. We were unable to observe any regulation of FKBP38/ mTOR binding by amino acids or insulin. Furthermore, FKBP38 did not inhibit mTORC1 signaling. The translationally controlled tumor protein (TCTP) in Drosophila was recently reported to act as the guanine nucleotide-exchange factor for Rheb. We have studied the role of TCTP in mammalian TORC1 signaling and its control by amino acids. Reducing TCTP levels did not reproducibly affect mTORC1 signaling in amino acidreplete/insulin-stimulated cells. Moreover, overexpressing TCTP did not rescue mTORC1 signaling in amino acid-starved cells. In addition, we were unable to see any stable interaction between TCTP and Rheb or mTORC1. Accumulation of uncharged tRNA has been previously proposed to be involved in the inhibition of mTORC1 signaling during amino acid starvation. To test this hypothesis, we used a Chinese hamster ovary cell line containing a temperature-sensitive mutation in leucyl-tRNA synthetase. Leucine deprivation markedly inhibited mTORC1 signaling in these cells, but shifting the cells to the nonpermissive temperature for the synthetase did not. These data indicate that uncharged tRNA Leu does not switch off mTORC1 signaling and suggest that mTORC1 is controlled by a distinct pathway that senses the availability of amino acids. Our data also indicate that, in the mammalian cell lines tested here, neither TCTP nor FKBP38 regulates mTORC1 signaling.
Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB
Molecular Cell, 2006
The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a multiprotein complex composed of mTOR, mLST8, and raptor (mTORC1). The distinct complex of mTOR, mLST8, and rictor (mTORC2) does not interact with FKBP12-rapamycin and is not thought to be rapamycin sensitive. mTORC2 phosphorylates and activates Akt/PKB, a key regulator of cell survival. Here we show that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolonged rapamycin treatment reduces the levels of mTORC2 below those needed to maintain Akt/PKB signaling. The proapoptotic and antitumor effects of rapamycin are suppressed in cells expressing an Akt/PKB mutant that is rapamycin resistant. Our work describes an unforeseen mechanism of action for rapamycin that suggests it can be used to inhibit Akt/PKB in certain cell types.
A novel rapamycin analog is highly selective for mTORC1 in vivo
Nature Communications
Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.
Environmental signaling through the mechanistic target of rapamycin complex 1: mTORC1 goes nuclear
Cell Cycle, 2014
Abbreviations: TOR, target of rapamycin; mTOR, mechanistic target of rapamycin; mTORC1/2, mechanistic target of rapamycin complex 1 and 2; DEPTOR, DEP domain containing mTOR interacting protein; PRAS40, proline-rich Akt substrate of 40-kDa; hSMG-1, human suppressor of morphogenesis in genitalia-1; TSC1/2, tuberous sclerosis complex 1 and 2; GEF, guanine nucleotide exchange factor; GAP, GTPase activating protein; eNoSC, energy-dependent nucleolar silencing complex; rDNA, ribosomal DNA; rRNA, ribsosomal RNA; RPs, ribosomal protein genes; NORs, nucleolar organizing regions; RNAPI/II/III, RNA polymerase I/II/ III; HMGs, high mobility group proteins; ERC, extrachromosomal rDNA circle
Signal Transduction and Targeted Therapy
The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain cellular homeostasis. The mTOR signaling cascade consists of two distinct multi-subunit complexes named mTOR complex 1/2 (mTORC1/2). mTOR catalyzes the phosphorylation of several critical proteins like AKT, protein kinase C, insulin growth factor receptor (IGF-1R), 4E binding protein 1 (4E-BP1), ribosomal protein S6 kinase (S6K), transcription factor EB (TFEB), sterol-responsive element-binding proteins (SREBPs), Lipin-1, and Unc-51-like autophagy-activating kinases. mTOR signaling plays a central role in regulating translation, lipid synthesis, nucleotide synthesis, biogenesis of lysosomes, nutrient sensing, and growth factor signaling. The emerging pieces of evidence have revealed that the constitutive activation of the mTOR pathway due to mutations/amplification/deletion in either mTOR and its ...