Environmental signaling through the mechanistic target of rapamycin complex 1

Workman, Jason J.; Chen, Hongfeng; Laribee, R. Nicholas

doi:10.4161/cc.28112

Cited by 25 publications

(23 citation statements)

References 156 publications

(237 reference statements)

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“…In addition, the functional relevance of the nuclear mTORC1 has also been indicated (Workman et al, 2014). However, it is unclear whether functional endogenous mTORC1 exists in the nucleus.…”

Section: Resultsmentioning

confidence: 99%

“…For instance, it has been suggested that there is little intact mTORC1 in the nucleus due to low affinity of nuclear raptor to mTOR than cytoplasmic raptor (Rosner and Hengstschlager, 2008). On the other hand, nuclear mTORC1 signaling has been suggested to play a role in some cellular processes, including promoting the transcription of metabolic genes for ribosome biogenesis, lipid formation, and mitochondrial function (Back and Kim, 2011; Workman et al, 2014). For instance, it has been shown that mTOR binds to TFIIIC, a transcription factor that binds to pol III promoters, leading to enhanced protein synthesis in response to nutrients and growth factors (Kantidakis et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Dynamic Visualization of mTORC1 Activity in Living Cells

et al. 2015

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Summary The mechanistic target of rapamycin complex 1 (mTORC1) senses diverse signals to regulate cell growth and metabolism. It has become increasingly clear that mTORC1 activity is regulated in time and space inside the cell, but direct interrogation of such spatiotemporal regulation is challenging. Here we describe a genetically encoded mTORC1 activity reporter (TORCAR) that exhibits a change in FRET in response to phosphorylation by mTORC1. Co-imaging mTORC1 activity and calcium dynamics revealed that a growth factor-induced calcium transient contributes to mTORC1 activity. Dynamic activity maps generated using subcellularly targeted TORCAR uncovered mTORC1 activity not only in cytosol and at the lysosome but also in nucleus and at the plasma membrane. Furthermore, a wide distribution of activities was observed upon growth factor stimulation, whereas leucine ester, an amino acid surrogate, induces more compartmentalized activities at the lysosome and in nucleus. Thus, mTORC1 activities are spatiotemporally regulated in a signal-specific manner.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dynamic Visualization of mTORC1 Activity in Living Cells

et al. 2015

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“…TORC1 is closely associated with the vacuolar membrane in many different organisms, whereas TORC2 is associated with the plasma membrane (39 -42). More recently, many studies have shown that TORC1 (39,(41)(42)(43)(44)(45) and TORC2 (39 -42) are also found in the nucleus and are required for several nuclear functions. AKT, the kinase acting downstream of mTORC2, was also originally located to the plasma membrane but is currently known to have additional functions in the nucleus (28,32,34,36,46).…”

Section: Torc2-gad8 Is Found In the Nucleus And Ismentioning

confidence: 99%

Gad8 Protein Is Found in the Nucleus Where It Interacts with the MluI Cell Cycle Box-binding Factor (MBF) Transcriptional Complex to Regulate the Response to DNA Replication Stress

Cohen

Kupiec

Weisman

2016

Journal of Biological Chemistry

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The target of rapamycin (TOR) kinase is found at the core of two evolutionarily conserved complexes known as TOR complexes 1 and 2 (TORC1 and TORC2). In fission yeast, TORC2 is dispensable for proliferation under optimal growth conditions but is required for starvation and stress responses. We have previously reported that loss of function of TORC2 renders cells highly sensitive to DNA replication stress; however, the mechanism underlying this sensitivity is unknown. TORC2 has one known direct substrate, the kinase Gad8, which is related to AKT in human cells. Here we show that both TORC2 and its substrate Gad8 are found in the nucleus and are bound to the chromatin. We also demonstrate that Gad8 physically interacts with the MluI cell cycle box-binding factor (MBF) transcription complex that regulates the G 1 /S progression and the response to DNA stress. In mutant cells lacking TORC2 or Gad8, the binding of the MBF complex to its cognate promoters is compromised, and the induction of MBF target genes in response to DNA replication stress is reduced. Consistently, the protein levels of Cdt2 and Cig2, two MBF target genes, are reduced in the absence of TORC2-Gad8 signaling. Taken together, our findings highlight critical functions of TORC2 in the nucleus and suggest a role in surviving DNA replication stress via transcriptional regulation of MBF target genes. Target of rapamycin (TOR)2 is an atypical protein kinase that was isolated as the target of the immunosuppressive and anticancer drug rapamycin. TOR proteins play a central role in growth, proliferation, and survival and can be found in two distinct and evolutionarily conserved complexes, TORC1 and TORC2 (1-3). The two TOR complexes are key regulators of cellular growth; however, they respond to different stimuli and phosphorylate distinct sets of protein substrates (1-3). Human cells contain a single TOR protein, known as mTOR, which functions as the catalytic subunit of both mTORC1 and mTORC2. In the fission yeast, Schizosaccharomyces pombe, there are two genes encoding for TOR proteins. Tor1 interacts with Ste20 (Rictor in human cells) and Sin1 (mSin1 in human cells) to form TORC2, whereas Tor2 interacts with Mip1 (Raptor in human cells) to form TORC1 (4). TORC1 is essential for growth in S. pombe and plays a critical role in regulating the switch between growth and sexual development in response to nitrogen starvation. Consistently, disruption of S. pombe TORC1 results in many features characteristic of nitrogenstarved cells (5-8), and TORC1-dependent phosphorylation of the small ribosomal protein Rps6 is diminished under nitrogen starvation (9).S. pombe TORC2 is not essential for growth but is required for cell survival under a wide variety of stress conditions, including high or low temperatures, oxidative or osmotic stress, and DNA damage or replication stresses (10, 11). TORC2 is also essential for entrance into a stationary (G 0 -like) phase and sexual development, two processes that occur in response to nutritional starvation. Under normal growth ...

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“…To date, a majority of studies have focused on the roles of the TORC signaling pathway as a translational regulator with its location in the cytoplasm (Workman et al 2014). Consequently, the role of mTOR in oncogenesis is thought to be largely due to its activity in the cytoplasm and increased translation of protumorigenic genes (Back & Kim 2011).…”

Section: Functional Connection Between Tor and Mitochondriamentioning

confidence: 99%

Chemical genomics approach to identify genes associated with sensitivity to rapamycin in the fission yeast Schizosaccharomyces pombe

et al. 2015

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Rapamycin and its derivatives have now emerged as an attractive therapeutic strategy with both immunosuppressant and antitumor properties. In addition, rapamycin has been proposed as a calorie restriction mimetic to extend the life span of various organisms. The fission yeast Schizosaccharomyces pombe (S. pombe) serves as a valuable genetic model system to study the mechanism(s) of drug action as well as to determine genetic contexts associated with drug sensitivity or resistance. Here, we identified genes that when deleted modulate the rapamycinsensitive strains in S. pombe. We carried out a chemical genomics screen for rapamycin-sensitive mutants using the genome-deletion library which covers 95.3% of all nonessential fission yeast genes and confirmed 59 genes to be rapamycin sensitive. Gene Ontology (GO) enrichment analysis showed that strains sensitive to rapamycin are highly enriched in processes regulating tRNA modification and mitochondria as well as other ontologies, including cellular metabolic process, chromatin organization, cell cycle, signaling, translation, transport and other cellular processes. Analysis also showed that components of the Elongator complex are overrepresented in the sensitive strains. Here, the data obtained will provide valuable information for speculation on the actions of rapamycin as well as on TORC signaling, thereby presenting a strategy to enhance sensitivity to rapamycin.

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Environmental signaling through the mechanistic target of rapamycin complex 1

Cited by 25 publications

References 156 publications

Dynamic Visualization of mTORC1 Activity in Living Cells

Dynamic Visualization of mTORC1 Activity in Living Cells

Gad8 Protein Is Found in the Nucleus Where It Interacts with the MluI Cell Cycle Box-binding Factor (MBF) Transcriptional Complex to Regulate the Response to DNA Replication Stress

Chemical genomics approach to identify genes associated with sensitivity to rapamycin in the fission yeast Schizosaccharomyces pombe

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