Disease relevance of SNF1

• Together, these observations suggest that metabolic alterations mediated by SNF1 are an important component of innate antiviral defenses and that the inactivation of ADK and SNF1 by the geminivirus proteins represents a dual strategy to counter this defense [1].
• In yeast, SNF1 is one of the main regulators in the shift from fermentation to aerobic metabolism; AMPK, its mammalian counterpart, is a master metabolic regulator involved in a variety of metabolic disorders such as diabetes and obesity [2].
• A snf1 null mutant is sensitive to heat stress and starvation and fails to accumulate glycogen during growth in rich medium [3].

High impact information on SNF1

• The SNF1 complex in yeast is activated in response to the stress of glucose deprivation [4].
• The SNF1 complex acts primarily by inducing expression of genes required for catabolic pathways that generate glucose, probably by triggering phosphorylation of transcription factors [4].
• The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell [4]?
• We have purified a histone H3 serine-10 kinase complex from Saccharomyces cerevisiae and have identified its catalytic subunit as Snf1 [5].
• The Snf1/AMPK family of kinases function in conserved signal transduction pathways [5].

Biological context of SNF1

• The predicted kinase domain of NPK5 is 65% identical in terms of amino acid sequence to that of the SNF1 serine/threonine protein kinase of Saccharomyces cerevisiae, which plays a central role in catabolite repression in yeast cells [6].
• A genetic screen revealed that two genes involved in autophagy, APG1 and APG13, may be regulated by SNF1 [7].
• Elm1p also activated the purified SNF1 complex, and this correlated with phosphorylation of Thr210 in the activation loop [8].
• In addition, derepression of cell cycle genes and signalling via the cAMP-PKA pathway appears to depend upon SNF1 activity during growth on galactose [9].
• Recent data suggest that the plant SNF1-related kinases (SnRK1 family) are key enzymes implicated in the regulation of carbohydrate and lipid metabolism [10].

Anatomical context of SNF1

• No peroxisomes were detected in snf1 and snf4 mutants by immunogold labelling as well as by immunofluorescence [11].
• To examine glucose repression of invasive growth more broadly, we performed genome-wide microarray expression analysis in wild-type cells growing on glucose and galactose, and snf1 Delta cells on galactose [9].
• In liver cells, pharmacological activation by 5-amino-4-imidazolecarboxamide riboside (AICAR) of AMP-activated protein kinase (AMPK), the mammalian homologue of the yeast SNF1 kinase complex, inhibits the effects of glucose, suggesting a key signaling role for this kinase [12].
• The binding affinities of various mutant insulin analogues correlated well with their capacities to activate glycogen synthase and SNF1 kinase in glucose-induced yeast spheroplasts, the ranking of their relative efficacies in yeast and in isolated rat adipocytes being similar [13].
• These results show that in beta cell lines the AMP-activated protein kinase, like its yeast homologue the SNF1 complex, can respond to the level of glucose in the medium, and may be involved in regulating insulin release [14].

Associations of SNF1 with chemical compounds

• The SSN3 and SSN8 genes of Saccharomyces cerevisiae were identified by mutations that suppress a defect in SNF1, a protein kinase required for release from glucose repression [15].
• Cells lacking the SNF1 gene cannot express glucose-repressible genes and do not accumulate the storage polysaccharide glycogen [16].
• Expression and regulation of the AMP-activated protein kinase-SNF1 (sucrose non-fermenting 1) kinase complexes in yeast and mammalian cells: studies using chimaeric catalytic subunits [17].
• The sequence relationships between the mammalian 5'-AMP-activated protein kinase and yeast Snf1p extend to the subunit proteins consistent with conservation of the functional roles of these polypeptides in cellular regulation by this family of metabolite-sensing protein kinases [18].
• Increased gene dosage of SIP1 rescued the ethanol growth defect observed in cells expressing Sip1 as their only beta subunit and increased the in vitro activity of Snf1 kinase purified from these cells [19].
• Glucose-mediated regulation of Snf1 activation loop dephosphorylation is controlled by changes in the ability of the Snf1 activation loop to act as a substrate for Glc7 [20].
• Mutations at several sites relieved glucose inhibition of SNF1, as judged by catalytic activity, phosphorylation of the activation-loop Thr-210, and growth assays, although analogs of the severe human mutations R531G/Q had little effect [21].

Physical interactions of SNF1

• Finally, MSN3 physically interacts with the SNF1 protein kinase, as assayed by a two-hybrid system and by in vitro binding studies [22].
• It is also affected by the HAP2/3/4 transcription factor complex and by SNF1 and SSN6 [23].
• Examination of the protein composition of the purified Snf1 enzyme complexes indicated that the Sip1 protein was present in substoichiometric levels [19].
• Furthermore, Gts1p bound to subunits of Snf1 kinase, whereas it did not bind to DNA [24].
• One molecular function of the Snf1 complex is deactivation by phosphorylation of the general glucose repressor Mig1 [25].

Enzymatic interactions of SNF1

• Together, our data are consistent with a model in which Reg1p and Reg2p control the activity of PP1 toward substrates that are phosphorylated by the Snf1p kinase [26].
• In immune complex assays of Snf1, coprecipitating Mig1 is phosphorylated in a Snf1-dependent reaction [27].
• We have investigated whether the corresponding counterpart of filamentous fungi-the Cre1 protein-is also phosphorylated by Snf1 [28].
• Snf1 can phosphorylate recombinant Gcn5 in vitro [29].
• Here, we show that the C terminus of SSN6 is phosphorylated in vivo and that the SNF1 kinase is not responsible for most of the phosphorylation [30].

Regulatory relationships of SNF1

• The derepression defect of CAT8 in a cat1 mutant could be suppressed by a mutant Mig1p repressor protein [31].
• Expression of CAT8 is carbon source regulated and requires a functional Cat1p (Snf1p) protein kinase [31].
• In two-hybrid assays, one SNF4 mutation enhances the interaction between Snf4 and Snf1 [32].
• The derepression deficiency of a CSRE-dependent reporter gene in a strain lacking the Cat1 (Snf1) protein kinase can be suppressed by Sip4 fused to a strong heterologous activation domain [33].
• Characterization of tobacco protein kinase NPK5, a homolog of Saccharomyces cerevisiae SNF1 that constitutively activates expression of the glucose-repressible SUC2 gene for a secreted invertase of S. cerevisiae [6].

Other interactions of SNF1

• Glucose derepression of gluconeogenesis depends on the active Cat1 (Snf1) protein kinase and the Cat8 zinc cluster activator [34].
• To identify components of the SNF1 pathway, we isolated multicopy suppressors of defects caused by loss of SNF4, an activator of the SNF1 kinase [22].
• Pho85p, a cyclin-dependent protein kinase, and the Snf1p protein kinase act antagonistically to control glycogen accumulation in Saccharomyces cerevisiae [16].
• Previous experimental evidence had indicated that Reg1 might target Glc7 to nuclear substrates such as the Snf1 kinase complex [35].
• The REG2 gene of Saccharomyces cerevisiae encodes a type 1 protein phosphatase-binding protein that functions with Reg1p and the Snf1 protein kinase to regulate growth [26].
• These data indicate that Snf1 functions upstream of Gcn20 to regulate control of GCN4 translation in S. cerevisiae [36].

Analytical, diagnostic and therapeutic context of SNF1

• Various Snf1/Gal83-dependent processes were upregulated, including glycogen accumulation, expression of RNAs encoding glycogen synthase, haploid invasive growth, the transcriptional activator function of Sip4, and activation of the carbon source-responsive promoter element [37].
• Two-hybrid assays showed that Std1p interacts with the catalytic domain of Snf1p, and analysis of mutant kinases suggested that this interaction is incompatible with the autoinhibitory interaction of the regulatory and catalytic domains [38].
• In gel filtration chromatography, the SNF1, SNF1-G53R and SNF1-delta N protein showed different elution profiles, consistent with differential formation of high molecular weight complexes [39].
• They also disclosed that this shift is forestalled by two manipulations that extend life span, caloric restriction and genetic attenuation of the normal age-associated increase in Snf1p activity [40].
• Northern blot analysis suggested that Ctk1 and Snf1 act together in vivo to regulate GSY2 [41].

References