Raptor, a positive regulatory subunit of mTOR complex 1, is a novel phosphoprotein of the rDNA transcription machinery in nucleoli and chromosomal nucleolus organizer regions (NORs)

Vázquez-Martín, Alejandro; Cufí, Sílvia; Oliveras‐Ferraros, Cristina; Menendez, Javier A.

doi:10.4161/cc.10.18.17376

Cited by 33 publications

(26 citation statements)

References 34 publications

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“…Altogether, our findings are in agreement with the notion that mTOR complexes are hyperactive during mitosis and suggest that all or at least part of their components (e.g., raptor) [33][34][35] may physically and functionally interact at the mitotic and cytokinetic apparatus during cell division. It remains to be demonstrated whether the Ser2481 autophosphorylation may allow mTOR to adapt to target other mitotic proteins, and the precise mechanism of regulation of mTOR autophosphorylation at Ser2481 during mitosis and cytokinesis remains unclear.…”

Section: Anti-phospho-mtorsupporting

confidence: 81%

Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis

et al. 2012

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Section: Anti-phospho-mtorsupporting

confidence: 81%

Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis

et al. 2012

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“…However, components of the mTORC1 complex are found in the nucleolus, making the nucleolar phosphorylation of SENP3 a plausible event (36). Interestingly, previous work has demonstrated that mTOR regulates RNA polymerase I-dependent transcription of rRNA by modulating the activity of the transcription factor TIF-IA (10,11).…”

Section: Discussionmentioning

confidence: 99%

mTOR Signaling Regulates Nucleolar Targeting of the SUMO-Specific Isopeptidase SENP3

Raman

Nayak

2014

Molecular and Cellular Biology

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Ribosome biogenesis is a multistep cellular pathway that involves more than 200 regulatory components to ultimately generate translation-competent 80S ribosomes. The initial steps of this process, particularly rRNA processing, take place in the nucleolus, while later stages occur in the nucleoplasm and cytoplasm. One critical factor of 28S rRNA maturation is the SUMO-isopeptidase SENP3. SENP3 tightly interacts with the nucleolar scaffold protein NPM1 and is associated with nucleolar 60S preribosomes. A central question is how changes in energy supply feed into the regulation of ribosome maturation. Here, we show that the nutrient-sensing mTOR kinase pathway controls the nucleolar targeting of SENP3 by regulating its interaction with NPM1. We define an N-terminal domain in SENP3 as the critical NPM1 binding region and provide evidence that mTOR-mediated phosphorylation of serine/threonine residues within this region fosters the interaction of SENP3 with NPM1. The inhibition of mTOR triggers the nucleolar release of SENP3, thereby likely compromising its activity in rRNA processing. Since mTOR activity is tightly coupled to nutrient availability, we propose that this pathway contributes to the adaptation of ribosome maturation in response to the cellular energy status. Ribosomes are large ribonucleoprotein complexes functioning as molecular machines in protein synthesis. Mammalian 80S ribosomes are assembled from the small 40S and the large 60S subunit (1). The 60S subunit is composed of the 28S, the 5.8S, and the 5S rRNA and contains at least 46 ribosomal proteins, while the 40S subunit consists of around 30 ribosomal proteins and the 18S rRNA. The maturation of ribosomes is a highly regulated pathway that involves more than 200 nonribosomal proteins, commonly termed trans-acting factors (2, 3). Ribosome biogenesis is initiated in the nucleolus by RNA polymerase I (Pol I), transcribing a 47S precursor rRNA. This precursor is incorporated into a nucleolar 90S preribosomal particle, where specific bases in the rRNA are covalently modified and initial pre-RNA processing steps take place (4, 5). The 40S and 60S ribosomal subunits subsequently take a separate maturation pathway, which proceeds by a number of processing and remodelling events in the nucleolus and the nucleoplasm. Following export to the cytoplasm, both subunits are assembled to translation-competent 80S particles.As an integral part of protein synthesis, ribosome biogenesis must be tightly coupled to the energy status and nutrient levels of the cell. One key pathway that coordinates energy supply with protein translation is the mammalian target of rapamycin (mTOR) signaling network (6, 7). mTOR is an evolutionarily conserved serine/threonine kinase. In mammalian cells, mTOR is found in two distinct complexes, mTORC1 and mTORC2, that contain specific regulatory subunits and adaptor proteins. For example, Raptor and Rictor are the protein components involved in substrate recruitment and complex assembly of mTORC1 and mTORC2, respectively. mTORC1 positive...

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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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Raptor, a positive regulatory subunit of mTOR complex 1, is a novel phosphoprotein of the rDNA transcription machinery in nucleoli and chromosomal nucleolus organizer regions (NORs)

Cited by 33 publications

References 34 publications

Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis

Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis

mTOR Signaling Regulates Nucleolar Targeting of the SUMO-Specific Isopeptidase SENP3

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

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