Novel Regulatory Mechanisms of mTOR Signaling

Chen, J.

doi:10.1007/978-3-642-18930-2_14

Cited by 24 publications

(22 citation statements)

References 46 publications

(49 reference statements)

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“…These data suggest that the PI3K/Akt pathway may not be responsible for IGF-Iinduced prolonged activation of p70 S6K . Although it is well accepted that mTOR/p70 S6K resides downstream of PI3K/Akt (51), the mTOR pathway can also be regulated independently of PI3K (52,53). Other signaling molecules, such as newly synthesized amino acids (52,53), may mediate prolonged IGF-I-induced signals associated with activation of mTOR/p70 S6K .…”

Section: Discussionmentioning

confidence: 99%

“…Although it is well accepted that mTOR/p70 S6K resides downstream of PI3K/Akt (51), the mTOR pathway can also be regulated independently of PI3K (52,53). Other signaling molecules, such as newly synthesized amino acids (52,53), may mediate prolonged IGF-I-induced signals associated with activation of mTOR/p70 S6K . These data not only provide direct evidence that identifies an important role for PI3K/Akt in mediating the engagement of IGF-I-stimulated early signaling events to subsequent cell cycle progression, but also suggest that IL-1␤ specifically targets the PI3K/Akt pathway to suppress IGF-I-induced key G 1 -S regulators.…”

Section: Discussionmentioning

confidence: 99%

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IL-1β Suppresses Prolonged Akt Activation and Expression of E2F-1 and Cyclin A in Breast Cancer Cells

Shen

Jackson

Broussard

et al. 2004

The Journal of Immunology

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Cell cycle aberrations occurring at the G1/S checkpoint often lead to uncontrolled cell proliferation and tumor growth. We recently demonstrated that IL-1β inhibits insulin-like growth factor (IGF)-I-induced cell proliferation by preventing cells from entering the S phase of the cell cycle, leading to G0/G1 arrest. Notably, IL-1β suppresses the ability of the IGF-I receptor tyrosine kinase to phosphorylate its major docking protein, insulin receptor substrate-1, in MCF-7 breast carcinoma cells. In this study, we extend this juxtamembrane cross-talk between cytokine and growth factor receptors to downstream cell cycle machinery. IL-1β reduces the ability of IGF-I to activate Cdk2 and to induce E2F-1, cyclin A, and cyclin A-dependent phosphorylation of a retinoblastoma tumor suppressor substrate. Long-term activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, but not the mammalian target of rapamycin or mitogen-activated protein kinase pathways, is required for IGF-I to hyperphosphorylate retinoblastoma and to cause accumulation of E2F-1 and cyclin A. In the absence of IGF-I to induce Akt activation and cell cycle progression, IL-1β has no effect. IL-1β induces p21Cip1/Waf1, which may contribute to its inhibition of IGF-I-activated Cdk2. Collectively, these data establish a novel mechanism by which prolonged Akt phosphorylation serves as a convergent target for both IGF-I and IL-1β; stimulation by growth factors such as IGF-I promotes G1-S phase progression, whereas IL-1β antagonizes IGF-I-induced Akt phosphorylation to induce cytostasis. In this manner, Akt serves as a critical bridge that links proximal receptor signaling events to more distal cell cycle machinery.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IL-1β Suppresses Prolonged Akt Activation and Expression of E2F-1 and Cyclin A in Breast Cancer Cells

Shen

Jackson

Broussard

et al. 2004

The Journal of Immunology

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“…This kinase is a component of signal transduction cascades activated by growth factor receptors and constitutes an intracellular sensor of nutrient availability, hypoxia, DNA damage, and osmotic stress (3,24,44,55). mTOR exists in two different multiprotein complexes differentially sensitive to the inhibitory effect of rapamycin (32,40).…”

mentioning

confidence: 99%

Regulation of mTORC1 Complex Assembly and Signaling by GRp58/ERp57

Ramírez-Rangel¹,

Bracho-Valdés²,

Vázquez-Macías³

et al. 2011

Molecular and Cellular Biology

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The mammalian target of rapamycin (mTOR) regulates cell growth and survival via two different multiprotein complexes, mTORC1 and mTORC2. The assembly of these serine-threonine kinase multiprotein complexes occurs via poorly understood molecular mechanisms. Here, we demonstrate that GRp58/ERp57 regulates the existence and activity of mTORC1. Endogenous mTOR interacts with GRp58/ERp57 in different mammalian cells. In vitro, recombinant GRp58/ERp57 preferentially interacts with mTORC1. GRp58/ERp57 knockdown reduces mTORC1 levels and phosphorylation of 4E-BP1 and p70 S6K in response to insulin. In contrast, GRp58/ERp57 overexpression increases mTORC1 levels and activity. A redox-sensitive mechanism that depends on GRp58/ERp57 expression activates mTORC1. Although GRp58/ERp57 is known as an endoplasmic reticulum (ER) resident, we demonstrate its presence at the cytosol, together with mTOR, Raptor, and Rictor as well as a pool of these proteins associated to the ER. In addition, the presence of GRp58/ERp57 at the ER decreases in response to insulin or leucine. Interestingly, a fraction of p70 S6K, but not 4E-BP1, is associated to the ER and phosphorylated in response to serum, insulin, or leucine. Altogether, our results suggest that GRp58/ERp57 is involved in the assembly of mTORC1 and positively regulates mTORC1 signaling at the cytosol and the cytosolic side of the ER.

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“…AKT in turn phosphorylates and hence inactivates tuberous sclerosis complex 2, a potent inhibitor of mTOR activity (3). Growth factors also have the ability to activate mTOR through an AKT-independent pathway that involves the activation of phospholipase D and the generation of phosphatidic acid (4). Alternatively, mTOR is inhibited when there is a lack of energy stores.…”

mentioning

confidence: 99%

A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

Zheng

Collins

Lutz

et al. 2007

The Journal of Immunology

247

243

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Whether TCR engagement leads to activation or tolerance is determined by the concomitant delivery of multiple accessory signals, cytokines, and environmental cues. In this study, we demonstrate that the mammalian target of rapamycin (mTOR) integrates these signals and determines the outcome of TCR engagement with regard to activation or anergy. In vitro, Ag recognition in the setting of mTOR activation leads to full immune responses, whereas recognition in the setting of mTOR inhibition results in anergy. Full T cell activation is associated with an increase in the phosphorylation of the downstream mTOR target S6 kinase 1 at Thr421/Ser424 and an increase in the mTOR-dependent cell surface expression of transferrin receptor (CD71). Alternatively, the induction of anergy results in markedly less S6 kinase 1 Thr421/Ser424 phosphorylation and CD71 surface expression. Likewise, the reversal of anergy is associated not with proliferation, but rather the specific activation of mTOR. Importantly, T cells engineered to express a rapamycin-resistant mTOR construct are resistant to anergy induction caused by rapamycin. In vivo, mTOR inhibition promotes T cell anergy under conditions that would normally induce priming. Furthermore, by examining CD71 surface expression, we are able to distinguish and differentially isolate anergic and activated T cells in vivo. Overall, our data suggest that by integrating environmental cues, mTOR plays a central role in determining the outcome of Ag recognition.

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Novel Regulatory Mechanisms of mTOR Signaling

Cited by 24 publications

References 46 publications

IL-1β Suppresses Prolonged Akt Activation and Expression of E2F-1 and Cyclin A in Breast Cancer Cells

IL-1β Suppresses Prolonged Akt Activation and Expression of E2F-1 and Cyclin A in Breast Cancer Cells

Regulation of mTORC1 Complex Assembly and Signaling by GRp58/ERp57

A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

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