Nitrogen Availability and TOR Regulate the Snf1 Protein Kinase in Saccharomyces cerevisiae

Department of Genetics and Development, Columbia University, New York, New York, United States
Eukaryotic Cell (Impact Factor: 3.18). 12/2006; 5(11):1831-7. DOI: 10.1128/EC.00110-06
Source: PubMed


In the yeast Saccharomyces cerevisiae, the Snf1 protein kinase of the Snf1/AMP-activated protein kinase (AMPK) family regulates a wide range of responses to stress caused by glucose deprivation. The stress signal is relayed via upregulation of Snf1, which depends on phosphorylation of its activation loop Thr210 residue by upstream kinases. Although Snf1 is also required for coping with various stresses unrelated to glucose deprivation, some evidence suggests a role for low-level basal activity of unphosphorylated Snf1, rather than a specific signaling function. We previously found that Snf1 is required for diploid pseudohyphal differentiation, a developmental response to nitrogen limitation. Here, we present evidence that Snf1 is directly involved in nitrogen signaling. First, genetic analyses suggest that pseudohyphal differentiation depends on the stimulatory phosphorylation of Snf1 at Thr210. Second, immunochemical data indicate that nitrogen limitation improves Thr210 phosphorylation. Analyses of pseudohyphal differentiation in cells with catalytically inactive and hyperactive Snf1 support the role of Snf1 activity. Finally, we show that Snf1 is negatively regulated by the rapamycin-sensitive TOR kinase which plays essential roles in signaling nitrogen and amino acid availability. This and other evidence implicate Snf1 in the integration of signals regarding nitrogen and carbon stress. TOR and Snf1/AMPK are highly conserved in evolution, and their novel functional interaction in yeast suggests similar mechanisms in other eukaryotes.

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    • "Under glucose-limiting conditions, active Snf1 crosstalks not only with other nutrient-sensing pathways but also with systems not directly associated with nutrient availability, such as pheromone signaling. Still we do not know all components of yeast signaling networks , and hence also the number and nature of interactions between molecular processes remains to be fully elucidated, as illustrated here with the interaction between Tor and Snf1 (Orlova et al. 2006; Zhang et al. 2011). How various conditions influence the expression of different transcription factors and how sensitive the whole system is to these alterations is not fully understood . "
    [Show abstract] [Hide abstract] ABSTRACT: The yeast Saccharomyces cerevisiae employs different conserved signaling pathways to adapt to altered availability of nutrient and energy sources. Cross-talk between the pathways occurs to integrate different internal and external stimuli and adjust cellular metabolism, growth and proliferation to altered environmental conditions. The main glucose repression pathway, Snf1/Mig1, plays an essential role in adaptation to glucose limitation. However, the Snf1 protein kinase is also involved in regulation of many other cellular processes. We summarize evidence that Snf1 is part of a network of communicating pathways and we suggest research directions that may help elucidating signal flow within this network. © FEMS 2015. All rights reserved. For permissions, please e-mail:
    Preview · Article · May 2015 · FEMS Yeast Research
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    • "However , rapamycin treatment inhibits rather than stimulates filamentation, even at sublethal doses, suggesting at most an indirect role of TORC1 in filamenation. Finally, Snf1 T210 phosphorylation is stimulated not only by glucose limitation but also by nitrogen limitation, even in the presence of high levels of glucose (Orlova et al. 2006, 2010). Thus, Snf1 activation provides the most consistent connection between filamentation and the multiple forms of nutritional deprivation required for filamentation. "
    [Show abstract] [Hide abstract] ABSTRACT: Availability of key nutrients, such as sugars, amino acids, and nitrogen compounds, dictates the developmental programs and the growth rates of yeast cells. A number of overlapping signaling networks-those centered on Ras/protein kinase A, AMP-activated kinase, and target of rapamycin complex I, for instance-inform cells on nutrient availability and influence the cells' transcriptional, translational, posttranslational, and metabolic profiles as well as their developmental decisions. Here I review our current understanding of the structures of the networks responsible for assessing the quantity and quality of carbon and nitrogen sources. I review how these signaling pathways impinge on transcriptional, metabolic, and developmental programs to optimize survival of cells under different environmental conditions. I highlight the profound knowledge we have gained on the structure of these signaling networks but also emphasize the limits of our current understanding of the dynamics of these signaling networks. Moreover, the conservation of these pathways has allowed us to extrapolate our finding with yeast to address issues of lifespan, cancer metabolism, and growth control in more complex organisms.
    Preview · Article · Sep 2012 · Genetics
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    • "Interestingly the highest suppression of the 3-AT toxicity we observed in the yeast strain lacking SNF1 gene but the N-terminal 108 codons [48] growing on agar media containing 10 mM 3-AT and glycerol as a carbon source. This has a sense, because Snf1 kinase is, besides other stimuli, activated during amino acid and generally nitrogen starvation [57], [58] and during the shift from glucose to glycerol media, when its relocation to the nucleus was also reported [59]. Further, the N-terminal 108 amino acids contain almost complete a structurally isolated β-rich lobe of the Snf1 kinase domain comprising of β1-3 strands and a well conserved regulatory αC helix including ATP-binding site and conserved residues Lys84 and Glu103. "
    [Show abstract] [Hide abstract] ABSTRACT: Interleukin-1α (IL-1α) is a proinflammatory cytokine and a key player in host immune responses in higher eukaryotes. IL-1α has pleiotropic effects on a wide range of cell types, and it has been extensively studied for its ability to contribute to various autoimmune and inflammation-linked disorders, including rheumatoid arthritis, Alzheimer's disease, systemic sclerosis and cardiovascular disorders. Interestingly, a significant proportion of IL-1α is translocated to the cell nucleus, in which it interacts with histone acetyltransferase complexes. Despite the importance of IL-1α, little is known regarding its binding targets and functions in the nucleus. We took advantage of the histone acetyltransferase (HAT) complexes being evolutionarily conserved from yeast to humans and the yeast SAGA complex serving as an epitome of the eukaryotic HAT complexes. Using gene knock-out technique and co-immunoprecipitation of the IL-1α precursor with TAP-tagged subunits of the yeast HAT complexes, we mapped the IL-1α-binding site to the HAT/Core module of the SAGA complex. We also predicted the 3-D structure of the IL-1α N-terminal domain, and by employing structure similarity searches, we found a similar structure in the C-terminal regulatory region of the catalytic subunit of the AMP-activated/Snf1 protein kinases, which interact with HAT complexes both in mammals and yeast, respectively. This finding is further supported with the ability of the IL-1α precursor to partially rescue growth defects of snf1Δ yeast strains on media containing 3-Amino-1,2,4-triazole (3-AT), a competitive inhibitor of His3. Finally, the careful evaluation of our data together with other published data in the field allows us to hypothesize a new function for the ADA complex in SAGA complex assembly.
    Full-text · Article · Aug 2012 · PLoS ONE
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