Novel mechanisms in nutrient activation of the yeast Protein Kinase A pathway

Thevelein, Johan M.; Bonini, Beatriz M.; Castermans, Dries; Haesendonckx, Steven; Kriel, Johan; Louwet, Wendy; Palvannan, Thayumanavan; Popova, Yulia; Rubio‐Texeira, Marta; Schepers, Wim; Vandormael, Patrick; Zeebroeck, Griet Van; Verhaert, Peter; Versele, Matthias; Voordeckers, Karin

doi:10.1556/amicr.55.2008.2.1

Cited by 28 publications

(22 citation statements)

References 37 publications

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“…Indeed, glucose can increase Ime2 degradation in sporulating cells through its C terminus (Purnapatre et al 2005;Gray et al 2008) and the DC241 deletion stabilizes Ime2 in mitotic cells (Sari et al 2008). Gpa2 is a Ga-protein that transduces glucose signals from the Gpr1 receptor to adenylate cyclase and PKA (reviewed in Thevelein et al 2008). Gpa2 also binds to Ime2's carboxy terminus and inhibits Ime2 catalytic activity (Donzeau and Bandlow 1999).…”

Section: Discussionmentioning

confidence: 99%

The Ras/cAMP Pathway and the CDK-Like Kinase Ime2 Regulate the MAPK Smk1 and Spore Morphogenesis in Saccharomyces cerevisiae

et al. 2009

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Meiotic development (sporulation) in the yeast Saccharomyces cerevisiae is induced by nutritional deprivation. Smk1 is a meiosis-specific MAP kinase homolog that controls spore morphogenesis after the meiotic divisions have taken place. In this study, recessive mutants that suppress the sporulation defect of a smk1-2 temperature-sensitive hypomorph were isolated. The suppressors are partial function alleles of CDC25 and CYR1, which encode the Ras GDP/GTP exchange factor and adenyl cyclase, respectively, and MDS3, which encodes a kelch-domain protein previously implicated in Ras/cAMP signaling. Deletion of PMD1, which encodes a Mds3 paralog, also suppressed the smk1-2 phenotype, and a mds3-D pmd1-D double mutant was a more potent suppressor than either single mutant. The mds3-D, pmd1-D, and mds3-D pmd1-D mutants also exhibited mitotic Ras/cAMP phenotypes in the same rank order. The effect of Ras/cAMP pathway mutations on the smk1-2 phenotype required the presence of low levels of glucose. Ime2 is a meiosis-specific CDK-like kinase that is inhibited by low levels of glucose via its carboxy-terminal regulatory domain. IME2-DC241, which removes the carboxy-terminal domain of Ime2, exacerbated the smk1-2 spore formation phenotype and prevented cyr1 mutations from suppressing smk1-2. Inhibition of Ime2 in meiotic cells shortly after Smk1 is expressed revealed that Ime2 promotes phosphorylation of Smk1's activation loop. These findings demonstrate that nutrients can negatively regulate Smk1 through the Ras/cAMP pathway and that Ime2 is a key activator of Smk1 signaling.

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Section: Discussionmentioning

confidence: 99%

The Ras/cAMP Pathway and the CDK-Like Kinase Ime2 Regulate the MAPK Smk1 and Spore Morphogenesis in Saccharomyces cerevisiae

et al. 2009

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“…The PKA pathway is activated by high glucose concentrations (72), whereas the TOR pathway is activated by a range of nitrogen and carbon sources (1,52,74). This is consistent with our observation that the transcript levels of glycogen-and trehalose-related genes were low in the presence of excess glucose and ammonia (i.e., in sulfate-, phosphate-, and zinclimited cultures), since the PKA and TOR signaling pathways are expected to be active under these conditions and Msn2p and Msn4p should thus be retained in the cytosol.…”

Section: Discussionmentioning

confidence: 99%

Identity of the Growth-Limiting Nutrient Strongly Affects Storage Carbohydrate Accumulation in Anaerobic Chemostat Cultures of Saccharomyces cerevisiae

Hazelwood

Walsh

Luttik

et al. 2009

Appl Environ Microbiol

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Accumulation of glycogen and trehalose in nutrient-limited cultures of Saccharomyces cerevisiae is negatively correlated with the specific growth rate. Additionally, glucose-excess conditions (i.e., growth limitation by nutrients other than glucose) are often implicated in high-level accumulation of these storage carbohydrates. The present study investigates how the identity of the growth-limiting nutrient affects accumulation of storage carbohydrates in cultures grown at a fixed specific growth rate. In anaerobic chemostat cultures (dilution rate, 0.10 h ؊1 ) of S. cerevisiae, the identity of the growth-limiting nutrient (glucose, ammonia, sulfate, phosphate, or zinc) strongly affected storage carbohydrate accumulation. The glycogen contents of the biomass from glucoseand ammonia-limited cultures were 10-to 14-fold higher than those of the biomass from cultures grown under the other three glucose-excess regimens. Trehalose levels were specifically higher under nitrogen-limited conditions. These results demonstrate that storage carbohydrate accumulation in nutrient-limited cultures of S. cerevisiae is not a generic response to excess glucose but instead is strongly dependent on the identity of the growth-limiting nutrient. While transcriptome analysis of wild-type and msn2⌬ msn4⌬ strains confirmed that transcriptional upregulation of glycogen and trehalose biosynthesis genes is mediated by Msn2p/Msn4p, transcriptional regulation could not quantitatively account for the drastic changes in storage carbohydrate accumulation. The results of assays of glycogen synthase and glycogen phosphorylase activities supported involvement of posttranscriptional regulation. Consistent with the high glycogen levels in ammonia-limited cultures, the ratio of glycogen synthase to glycogen phosphorylase in these cultures was up to eightfold higher than the ratio in the other glucose-excess cultures.Glycogen and trehalose are the major storage carbohydrates in baker's yeast (Saccharomyces cerevisiae) (22). The ability to accumulate these storage carbohydrates is an important criterion for selection of industrial yeast strains because of their involvement in the cellular robustness and quality of yeast extracts (e.g., for food and feed applications) (8,16,61).Based on the observation that glycogen and trehalose accumulate in batch cultures of S. cerevisiae that are starved for carbon, nitrogen, sulfur, or phosphorus, Lillie and Pringle (41) proposed that storage carbohydrate synthesis is a general response to nutrient starvation. Parrou et al. (56), who studied carbohydrate metabolism during nutrient-limited growth rather than during nutrient starvation, found that accumulation of glycogen and trehalose occurred when growth was limited by the carbon or nitrogen source. Because these workers were unable to obtain sulfur-or phosphorus-limited growth with their experimental setup (56), it remained unclear whether accumulation of glycogen and trehalose is a common response to nutrient limitation or whether, instead, nutrient limitations ot...

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“…Biochemistry of the PKA system PKA is evolutionarily conserved, such that analysis of PKA function has been carried out in organisms ranging from yeast (Tamaki 2007, Thevelein et al 2008, through Caenorhabditis elegans and Drosophila (Noveen et al 1996, Vanfleteren & De Vreese 1997, Angelo & Rubin 1998, to mammals (Skalhegg & Tasken 2000). Because the review of each of these model systems is beyond the scope of this review, we will focus on the human PKA system, and how this relates to the genetically tractable mouse system.…”

Section: Components Of the Pka Signaling Systemmentioning

confidence: 99%

Mouse models of altered protein kinase A signaling

Kirschner¹,

Yin²,

Jones³

et al. 2009

Endocrine-Related Cancer

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Protein kinase A (PKA) is an evolutionarily conserved protein which has been studied in model organisms from yeast to man. Although the cAMP-PKA signaling system was the first mammalian second messenger system to be characterized, many aspects of this pathway are still not well understood. Owing to findings over the past decade implicating PKA signaling in endocrine (and other) tumorigenesis, there has been renewed interest in understanding the role of this pathway in physiology, particularly as it pertains to the endocrine system. Because of the availability of genetic tools, mouse modeling has become the pre-eminent system for studying the physiological role of specific genes and gene families as a means to understanding their relationship to human diseases. In this review, we will summarize the current data regarding mouse models that have targeted the PKA signaling system. These data have led to a better understanding of both the complexity and the subtlety of PKA signaling, and point the way for future studies, which may help to modulate this pathway for therapeutic effect.

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Novel mechanisms in nutrient activation of the yeast Protein Kinase A pathway

Cited by 28 publications

References 37 publications

The Ras/cAMP Pathway and the CDK-Like Kinase Ime2 Regulate the MAPK Smk1 and Spore Morphogenesis in Saccharomyces cerevisiae

The Ras/cAMP Pathway and the CDK-Like Kinase Ime2 Regulate the MAPK Smk1 and Spore Morphogenesis in Saccharomyces cerevisiae

Identity of the Growth-Limiting Nutrient Strongly Affects Storage Carbohydrate Accumulation in Anaerobic Chemostat Cultures of Saccharomyces cerevisiae

Mouse models of altered protein kinase A signaling

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