The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease

Schmidt, Anja; Beck, Thomas W.; Koller, Antonius; Kunz, Jeannette; Hall, Michael N.

doi:10.1093/emboj/17.23.6924

Cited by 297 publications

(375 citation statements)

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“…The protein kinase Npr1 plays a major role in the sorting of these two classes of permeases. Npr1 is required for stabilization of Gap1 at the plasma membrane and induces the degradation of Tat2, possibly by regulating their ubiquitination (Schmidt et al 1998;Springael and Andre 1998;De Craene et al 2001;Helliwell et al 2001;Soetens et al 2001;Springael et al 2002). TORC1 activity, through control of the Tap42-Sit4 phosphatase complex, promotes the phosphorylation of Npr1 (Schmidt et al 1998;Jacinto et al 2001;Gander et al 2008).…”

Section: Rapamycin-sensitive Signalling Via Torc1mentioning

confidence: 99%

“…Presumably, this phosphorylation inhibits Npr1 which would promote Tat2 stabilization and Gap1 degradation. Accordingly, it was found that rapamycin induces Tat2 targeting to the vacuole and that this process depends on Npr1 (Schmidt et al 1998;Beck et al 1999). For Gap1, it was initially reported that rapamycin-induced inhibition of TORC1 did not affect its sorting (Chen and Kaiser 2002).…”

Section: Rapamycin-sensitive Signalling Via Torc1mentioning

confidence: 99%

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Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

et al. 2010

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Cells of all living organisms contain complex signal transduction networks to ensure that a wide range of physiological properties are properly adapted to the environmental conditions. The fundamental concepts and individual building blocks of these signalling networks are generally well-conserved from yeast to man; yet, the central role that growth factors and hormones play in the regulation of signalling cascades in higher eukaryotes is executed by nutrients in yeast. Several nutrient-controlled pathways, which regulate cell growth and proliferation, metabolism and stress resistance, have been defined in yeast. These pathways are integrated into a signalling network, which ensures that yeast cells enter a quiescent, resting phase (G 0 ) to survive periods of nutrient scarceness and that they rapidly resume growth and cell proliferation when nutrient conditions become favourable again. A series of well-conserved nutrient-sensory protein kinases perform key roles in this signalling network: i.e. Snf1, PKA, Tor1 and Tor2, Sch9 and Pho85-Pho80. In this review, we provide a comprehensive overview on the current understanding of the signalling processes mediated via these kinases with a particular focus on how these individual pathways converge to signalling networks that ultimately ensure the dynamic translation of extracellular nutrient signals into appropriate physiological responses.

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Section: Rapamycin-sensitive Signalling Via Torc1mentioning

confidence: 99%

Section: Rapamycin-sensitive Signalling Via Torc1mentioning

confidence: 99%

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

et al. 2010

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“…In S. cerevisiae, TOR signaling has been proposed to respond to metabolic signals originating from nitrogen and carbon sources (Schmidt et al, 1998;Beck and Hall, 1999;Kuruvilla et al, 2001;Crespo et al, 2002). Glutamine deprivation inhibits TORC1 .…”

Section: Arsenic Inhibits Torc1mentioning

confidence: 99%

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Hosiner

Lempiäinen

Reiter³

et al. 2009

MBoC

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The conserved Target Of Rapamycin (TOR) growth control signaling pathway is a major regulator of genes required for protein synthesis. The ubiquitous toxic metalloid arsenic, as well as mercury and nickel, are shown here to efficiently inhibit the rapamycin-sensitive TORC1 (TOR complex 1) protein kinase. This rapid inhibition of the TORC1 kinase is demonstrated in vivo by the dephosphorylation and inactivation of its downstream effector, the yeast S6 kinase homolog Sch9. Arsenic, mercury, and nickel cause reduction of transcription of ribosome biogenesis genes, which are under the control of Sfp1, a TORC1-regulated transcriptional activator. We report that arsenic stress deactivates Sfp1 as it becomes dephosphorylated, dissociates from chromatin, and exits the nucleus. Curiously, whereas loss of SFP1 function leads to increased arsenic resistance, absence of TOR1 or SCH9 has the opposite effect suggesting that TORC1 has a role beyond down-regulation of Sfp1. Indeed, we show that arsenic activates the transcription factors Msn2 and Msn4 both of which are targets of TORC1 and protein kinase A (PKA). In contrast to TORC1, PKA activity is not repressed during acute arsenic stress. A normal level of PKA activity might serve to dampen the stress response since hyperactive Msn2 will decrease arsenic tolerance. Thus arsenic toxicity in yeast might be determined by the balance between chronic activation of general stress factors in combination with lowered TORC1 kinase activity. INTRODUCTIONThe transition metal arsenic has a long history of human exploitation as both a poison and a medicine. In more recent times EhrlichЈs discovery of the antisyphilitic drug arsphenamine (also known as salvarsan) by systematic chemical modification of arsenic derivatives marked the beginning of modern pharmaceutical research. Arsenic trioxide (ATO) is used today in cancer treatment (Evens et al., 2004;Lu et al., 2007;Wang and Chen, 2008).Exposure to arsenic evokes a broad spectrum of cellular reactions in Saccharomyces cerevisiae Haugen et al., 2004;Jin, 2008;Thorsen et al., 2007) and in higher eukaryotes (Salnikow and Zhitkovich, 2008). A number of mechanisms exist for detoxification, probably because arsenic has always been widespread in the environment. These involve reduction of influx through the aquaglyceroporin Fps1p Thorsen et al., 2006); sequestration into the vacuole in the form of glutathione conjugates, metallothionein, and other metal/protein complexes; and active extrusion (Ghosh et al., 1999). In yeast, genome-wide analysis of the transcription patterns in response to arsenic revealed a complex network of transcription factors controlling the expression of several hundred genes (Haugen et al., 2004;Wysocki et al., 2004;Thorsen et al., 2007). Mitogen-activated protein kinases mediate protective responses involving AP-1-and AP-1-like transcription factors in higher eukaryotes and in fungi (Cavigelli et al., 1996;Rodriguez-Gabriel and Russell, 2005;Thorsen et al., 2006).The mechanisms by which arsenic might influence signalin...

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“…This is based on the observation that tap42-11, a temperaturesensitive allele of TAP42, confers semidominant resistance to rapamycin at the permissive temperature of 25°C (Di Como and Arndt 1996; Duvel et al 2003). Indeed, in tap42-11 cells, the activation of the transcription factors Gcn4, Gln3, Gat1, and Msn2/4, and the kinase Npr1, normally observed after inhibition of TORC1 with rapamycin, is partially or, in some cases, completely blocked (Schmidt et al 1998;Cherkasova and Hinnebusch 2003;Duvel et al 2003;Santhanam et al 2004).…”

mentioning

confidence: 99%

Characterization of the rapamycin-sensitive phosphoproteome reveals that Sch9 is a central coordinator of protein synthesis

Huber¹,

Bodenmiller²,

Uotila³

et al. 2009

Genes Dev.

316

404

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The target of rapamycin complex 1 (TORC1) is an essential multiprotein complex conserved from yeast to humans. Under favorable growth conditions, and in the absence of the macrolide rapamycin, TORC1 is active, and influences virtually all aspects of cell growth. Although two direct effectors of yeast TORC1 have been reported (Tap42, a regulator of PP2A phosphatases and Sch9, an AGC family kinase), the signaling pathways that couple TORC1 to its distal effectors were not well understood. To elucidate these pathways we developed and employed a quantitative, label-free mass spectrometry approach. Analyses of the rapamycin-sensitive phosphoproteomes in various genetic backgrounds revealed both documented and novel TORC1 effectors and allowed us to partition phosphorylation events between Tap42 and Sch9. Follow-up detailed characterization shows that Sch9 regulates RNA polymerases I and III, the latter via Maf1, in addition to translation initiation and the expression of ribosomal protein and ribosome biogenesis genes. This demonstrates that Sch9 is a master regulator of protein synthesis.[Keywords: Maf1; Sch9; TOR; phosphoproteomics; rapamycin; ribosome biogenesis] Supplemental material is available at http://www.genesdev.org.

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The TOR nutrient signalling pathway phosphorylates NPR1 and inhibits turnover of the tryptophan permease

Cited by 297 publications

References 45 publications

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae

Arsenic Toxicity to Saccharomyces cerevisiae Is a Consequence of Inhibition of the TORC1 Kinase Combined with a Chronic Stress Response

Characterization of the rapamycin-sensitive phosphoproteome reveals that Sch9 is a central coordinator of protein synthesis

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