Mammalian Target of Rapamycin (mTOR): Conducting the Cellular Signaling Symphony

Foster, Kathryn G.; Fingar, Diane C.

doi:10.1074/jbc.r109.094003

Cited by 470 publications

(483 citation statements)

References 98 publications

(134 reference statements)

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“…[5][6][7][8] This study focuses on mTOR, a serine-threonine kinase, a regulator and integrator of many cellular functions, eg, survival, proliferation, protein translation and cellular metabolism. 9 mTOR can form two distinct complexes (mTORC1 and mTORC2), which can be activated by various stimuli (growth factors, hormones, metabolic stress, etc). The activity of these complexes depends on the phosphorylation status of mTOR at S2448.…”

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confidence: 99%

Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

et al. 2012

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Diffuse large B-cell lymphoma is a heterogeneous group of diseases with different responses to therapy. Targeting mTOR (mammalian target of rapamycin) offers a new approach to improve the treatment. mTOR inhibitors are being developed and are in clinical use in mantle cell lymphoma therapy and clinical trials are ongoing in other high-grade lymphomas as well. However, there is limited data about mTOR activity and the expression of its different complexes in diffuse large B-cell lymphomas. Tissue microarray blocks were constructed from paraffin-embedded biopsy specimens. More than 700 immunohistochemical stainings (mTOR signaling-related proteins and phosphoproteins, markers for lymphoma classification) were evaluated from 68 diffuse large B-cell lymphoma biopsies from conventionally treated and followed patients. Approximately 30% of cases were characterized as germinal center-derived diffuse large B-cell lymphomas, which showed virtually no mTOR activity, as determined by phospho-ribosomal S6 expression, the most sensitive marker of mTOR activity. In about 80% of non-germinal center-derived diffuse large B-cell lymphoma cases, positivity of mTOR-related phosphoproteins was observed, denoting mTOR activity. Moreover, Rictor (a characteristic protein of the mTOR complex2) was overexpressed in 43% of all diffuse large B-cell lymphomas and in 63% of mTOR-active nongerminal center diffuse large B-cell lymphoma samples. Rictor overexpression with mTOR activity indicated significantly worse survival for patients than mTOR inactivity or mTOR activity with low Rictor expression. These results suggest that mTOR activity is characteristic in most non-germinal center-derived diffuse large B-cell lymphomas with potentially variable mTOR-inhibitor sensitivity. Taken together, mTOR inhibitors may be useful in addition to regular therapy in diffuse large B-cell lymphomas, however, patient and inhibitor selection criteria must be carefully considered.

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Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

et al. 2012

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“…Translational regulation additionally coordinates cell cycle progression with growth. Because progression through the cell cycle is linked to the attainment of certain size, translational regulation of gene expression couples cell growth and cell cycle progression with the supply of nutrients in the cell's environment [10]. Important signal-transduction pathways linking regulation of protein synthesis to nutrient sensing are mitogen-activated protein kinase and target of rapamycin signalling cascades.…”

Section: Introductionmentioning

confidence: 99%

Translational regulation of the cell cycle: when, where, how and why?

Kronja

Orr‐Weaver

2011

Phil. Trans. R. Soc. B

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Translational regulation contributes to the control of archetypal and specialized cell cycles, such as the meiotic and early embryonic cycles. Late meiosis and early embryogenesis unfold in the absence of transcription, so they particularly rely on translational repression and activation of stored maternal mRNAs. Here, we present examples of cell cycle regulators that are translationally controlled during different cell cycle and developmental transitions in model organisms ranging from yeast to mouse. Our focus also is on the RNA-binding proteins that affect cell cycle progression by recognizing special features in untranslated regions of mRNAs. Recent research highlights the significance of the cytoplasmic polyadenylation element-binding protein (CPEB). CPEB determines polyadenylation status, and consequently translational efficiency, of its target mRNAs in both transcriptionally active somatic cells as well as in transcriptionally silent mature Xenopus oocytes and early embryos. We discuss the role of CPEB in mediating the translational timing and in some cases spindle-localized translation of critical regulators of Xenopus oogenesis and early embryogenesis. We conclude by outlining potential directions and approaches that may provide further insights into the translational control of the cell cycle.

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“…Cellular mTOR regulation remains incompletely defined, however (13,24,31). mTOR senses and integrates signals from diverse environmental cues such as growth factors and hormones (i.e., insulin, insulin-like growth factor [IGF], and epidermal growth factor [EGF]), nutrients (i.e., amino acids and glucose), and cellular stresses (15,22,34,53,72). mTOR interacts with different partner proteins to form at least two functionally distinct signaling complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (2,4).…”

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confidence: 99%

mTOR Kinase Domain Phosphorylation Promotes mTORC1 Signaling, Cell Growth, and Cell Cycle Progression

Ekim

Magnuson

Acosta-Jaquez

et al. 2011

Molecular and Cellular Biology

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107

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The mammalian target of rapamycin complex 1 (mTORC1) functions as an environmental sensor to promote critical cellular processes such as protein synthesis, cell growth, and cell proliferation in response to growth factors and nutrients. While diverse stimuli regulate mTORC1 signaling, the direct molecular mechanisms by which mTORC1 senses and responds to these signals remain poorly defined. Here we investigated the role of mTOR phosphorylation in mTORC1 function. By employing mass spectrometry and phospho-specific antibodies, we demonstrated novel phosphorylation on S2159 and T2164 within the mTOR kinase domain. Mutational analysis of these phosphorylation sites indicates that dual S2159/T2164 phosphorylation cooperatively promotes mTORC1 signaling to S6K1 and 4EBP1. Mechanistically, S2159/T2164 phosphorylation modulates the mTOR-raptor and raptor-PRAS40 interactions and augments mTORC1-associated mTOR S2481 autophosphorylation. Moreover, mTOR S2159/T2164 phosphorylation promotes cell growth and cell cycle progression. We propose a model whereby mTOR kinase domain phosphorylation modulates the interaction of mTOR with regulatory partner proteins and augments intrinsic mTORC1 kinase activity to promote biochemical signaling, cell growth, and cell cycle progression.

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Mammalian Target of Rapamycin (mTOR): Conducting the Cellular Signaling Symphony

Cited by 470 publications

References 98 publications

Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

Translational regulation of the cell cycle: when, where, how and why?

mTOR Kinase Domain Phosphorylation Promotes mTORC1 Signaling, Cell Growth, and Cell Cycle Progression

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