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The AMPK/SNF1/SnRK1 fuel gauge and energy regulator: structure, function and regulation
Article first published online: 26 SEP 2011
DOI: 10.1111/j.1742-4658.2011.08315.x
© 2011 The Authors Journal compilation © 2011 FEBS
Additional Information
How to Cite
Ghillebert, R., Swinnen, E., Wen, J., Vandesteene, L., Ramon, M., Norga, K., Rolland, F. and Winderickx, J. (2011), The AMPK/SNF1/SnRK1 fuel gauge and energy regulator: structure, function and regulation. FEBS Journal, 278: 3978–3990. doi: 10.1111/j.1742-4658.2011.08315.x
Publication History
- Issue published online: 21 OCT 2011
- Article first published online: 26 SEP 2011
- Accepted manuscript online: 25 AUG 2011 12:00AM EST
- (Received 20 July 2011; accepted 22 August 2011)
References
- 1& (1984) Structure and expression of the SNF1 gene of Saccharomyces cerevisiae. Mol Cell Biol 4, 54–60.
- 2& (1986) A yeast gene that is essential for release from glucose repression encodes a protein kinase. Science (New York, NY) 233, 1175–1180.
- 3, , & (2001) Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Mol Cell Biol 21, 5742–5752.
- 4& (1998) Snf1 kinase connects nutritional pathways controlling meiosis in Saccharomyces cerevisiae. Mol Cell Biol 18, 4548–4555.
- 5, & (2002) Snf1 protein kinase and the repressors Nrg1 and Nrg2 regulate FLO11, haploid invasive growth, and diploid pseudohyphal differentiation. Mol Cell Biol 22, 3994–4000.
- 6, , & (2000) Sip2p and its partner snf1p kinase affect aging in S. cerevisiae. Genes Dev 14, 1872–1885.
- 7, & (2009) A network biology approach to aging in yeast. Proc Natl Acad Sci USA 106, 1145–1150.
- 8& (2007) Regulation of snf1 protein kinase in response to environmental stress. J Biol Chem 282, 16838–16845.
- 9& (2008) SNF1/AMPK pathways in yeast. Front Biosci 13, 2408–2420.
- 10, , , , , & (2010) Life in the midst of scarcity: adaptations to nutrient availability in Saccharomyces cerevisiae. Curr Genet 56, 1–32.
- 11, , , & (2004) The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 18, 3004–3009.
- 12& (2009) Caenorhabditis elegans dauers need LKB1/AMPK to ration lipid reserves and ensure long-term survival. Nature 457, 210–214.
- 13, , , , , , , , , et al. (2007) Energy-dependent regulation of cell structure by AMP-activated protein kinase. Nature 447, 1017–1020.
- 14, , , & (2007) LKB1 and AMPK maintain epithelial cell polarity under energetic stress. J Cell Biol 177, 387–392.
- 15, & (2008) Drosophila alicorn is a neuronal maintenance factor protecting against activity-induced retinal degeneration. J Neurosci 28, 6419–6429.
- 16, , , , & (2002) The neurodegeneration mutant lochrig interferes with cholesterol homeostasis and Appl processing. EMBO J 21, 6367–6376.
- 17(2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev 8, 774–785.
- 18& (2009) AMPK in Health and Disease. Physiol Rev 89, 1025–1078.
- 19, , , & (2008) Role of hypothalamic AMP-kinase in food intake regulation. Nutrition (Burbank, Los Angeles County, CA) 24, 786–790.
- 20
- 21, , & (2008) AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med 14, 539–549.
- 22& (2008) Convergent energy and stress signaling. Trends Plant Sci 13, 474–482.
- 23& (2007) SNF1/AMPK/SnRK1 kinases, global regulators at the heart of energy control? Trends Plant Sci 12, 20–28.
- 24, & (2002) Sugar sensing and signaling in plants. Plant Cell 14(Suppl), S185–S205.
- 25, , , , , & (2003) Metabolic signalling and carbon partitioning: role of Snf1-related (SnRK1) protein kinase. J Exp Bot 54, 467–475.
- 26, & (2009) Sugars, senescence, and ageing in plants and heterotrophic organisms. J Exp Bot 60, 1063–1066.
- 27, , & (2003) Geminivirus AL2 and L2 proteins interact with and inactivate SNF1 kinase. Plant Cell 15, 1034–1048.
- 28, , & (2007) A central integrator of transcription networks in plant stress and energy signalling. Nature 448, 938–942.
- 29, & (1990) Location and function of three sites phosphorylated on rat acetyl-CoA carboxylase by the AMP-activated protein kinase. Eur J Biochem 187, 183–190.
- 30, , , , & (1994) Yeast SNF1 is functionally related to mammalian AMP-activated protein kinase and regulates acetyl-CoA carboxylase in vivo. J Biol Chem 269, 19509–19515.
- 31, & (1973) Modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity with cAMP and wth protein fractions of rat liver cytosol. Biochem Biophys Res Commun 54, 1362–1369.
- 32& (1990) Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. EMBO J 9, 2439–2446.
- 33, , & (1994) Biochemical characterization of two forms of 3-hydroxy-3-methylglutaryl-CoA reductase kinase from cauliflower (Brassica oleracia). Eur J Biochem 219, 743–750.
- 34, , & (1995) Immunological evidence that HMG-CoA reductase kinase-A is the cauliflower homologue of the RKIN1 subfamily of plant protein kinases. FEBS Lett 377, 189–192.
- 35, , & (2003) Multiple pathways are co-regulated by the protein kinase Snf1 and the transcription factors Adr1 and Cat8. J Biol Chem 278, 26146–26158.
- 36, & (2009) Genome-wide inhibitory impact of the AMPK activator metformin on [kinesins, tubulins, histones, auroras and polo-like kinases] M-phase cell cycle genes in human breast cancer cells. Cell Cycle (Georgetown, TX) 8, 1633–1636.
- 37& (2010) AMP-activated protein kinase and its downstream transcriptional pathways. Cell Mol Life Sci 67, 3407–3423.
- 38& (2008) AMPK and transcriptional regulation. Front Biosci 13, 3022–3033.
- 39(1999) Glucose repression in yeast. Curr Opin Microbiol 2, 202–207.
- 40, & (2002) Convergence of the target of rapamycin and the Snf1 protein kinase pathways in the regulation of the subcellular localization of Msn2, a transcriptional activator of STRE (Stress Response Element)-regulated genes. J Biol Chem 277, 35650–35656.
- 41(2003) Transcriptional control of nonfermentative metabolism in the yeast Saccharomyces cerevisiae. Curr Genet 43, 139–160.
- 42& (1995) Repression by SSN6-TUP1 is directed by MIG1, a repressor/activator protein. Proc Natl Acad Sci USA 92, 3132–3136.
- 43, & (1997) Regulated nuclear translocation of the Mig1 glucose repressor. Mol Biol Cell 8, 1603–1618.
- 44, & (1998) Snf1 protein kinase regulates phosphorylation of the Mig1 repressor in Saccharomyces cerevisiae. Mol Cell Biol 18, 6273–6280.
- 45, , , & (1999) The SNF1 kinase complex from Saccharomyces cerevisiae phosphorylates the transcriptional repressor protein Mig1p in vitro at four sites within or near regulatory domain 1. FEBS Lett 453, 219–223.
- 46& (1999) The nuclear exportin Msn5 is required for nuclear export of the Mig1 glucose repressor of Saccharomyces cerevisiae. Curr Biol 9, 1231–1241.
- 47, , , & (1996) Dual influence of the yeast Cat1p (Snf1p) protein kinase on carbon source-dependent transcriptional activation of gluconeogenic genes by the regulatory gene CAT8. Nucleic Acids Res 24, 2331–2337.
- 48, , & (1997) Glucose derepression of gluconeogenic enzymes in Saccharomyces cerevisiae correlates with phosphorylation of the gene activator Cat8p. Mol Cell Biol 17, 2502–2510.
- 49& (1998) Sip4, a Snf1 kinase-dependent transcriptional activator, binds to the carbon source-responsive element of gluconeogenic genes. EMBO J 17, 7002–7008.
- 50, , & (2001) Contribution of Cat8 and Sip4 to the transcriptional activation of yeast gluconeogenic genes by carbon source-responsive elements. Curr Genet 39, 68–76.
- 51, , , , & (1994) Expression of the L-type pyruvate kinase gene and the hepatocyte nuclear factor 4 transcription factor in exocrine and endocrine pancreas. J Biol Chem 269, 8944–8951.
- 52, , , , & (2001) Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase. Diabetes 50, 1515–1521.
- 53, , , , , , , , , et al. (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111.
- 54, , & (2010) Transcriptional regulation of nonfermentable carbon utilization in budding yeast. FEMS Yeast Res 10, 2–13.
- 55, , & (2010) Sugar signals and molecular networks controlling plant growth. Curr Opin Plant Biol 13, 274–279.
- 56, & (2000) A regulatory shortcut between the Snf1 protein kinase and RNA polymerase II holoenzyme. Proc Natl Acad Sci USA 97, 7916–7920.
- 57, , , , , , , , & (2010) Signaling Kinase AMPK Activates Stress-Promoted Transcription via Histone H2B Phosphorylation. Science (New York, NY).
- 58, , , , , & (2001) Snf1--a histone kinase that works in concert with the histone acetyltransferase Gcn5 to regulate transcription. Science (New York, NY 293, 1142–1146.
- 59, , & (2006) Snf1p-dependent Spt-Ada-Gcn5-acetyltransferase (SAGA) recruitment and chromatin remodeling activities on the HXT2 and HXT4 promoters. J Biol Chem 281, 4523–4531.
- 60, , & (2009) Exercise-induced histone modifications in human skeletal muscle. J Physiol 587, 5951–5958.
- 61, , , , & (2009) Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator. Mol Syst Biol 5, 319.
- 62, & (2010) Systems biology of energy homeostasis in yeast. Curr Opin Microbiol 13, 382–388.
- 63, , , & (2003) Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc Natl Acad Sci USA 100, 8839–8843.
- 64, & (2005) Function of mammalian LKB1 and Ca2+/calmodulin-dependent protein kinase kinase alpha as Snf1-activating kinases in yeast. J Biol Chem 280, 21804–21809.
- 65(2008) 5′-AMP-activated protein kinase signaling in Caenorhabditis elegans. Exp Biol Med (Maywood, NJ) 233, 12–20.
- 66, , , , , , , , , et al. (2003) The Arabidopsis CDPK-SnRK superfamily of protein kinases. Plant Physiol 132, 666–680.
- 67, , , , & (2002) Identification of SnIP1, a novel protein that interacts with SNF1-related protein kinase (SnRK1). Plant Mol Biol 49, 31–44.
- 68, , , , , , , & (1994) Mammalian AMP-activated protein kinase is homologous to yeast and plant protein kinases involved in the regulation of carbon metabolism. J Biol Chem 269, 11442–11448.
- 69& (2009) Snf1-related protein kinases (SnRKs) act within an intricate network that links metabolic and stress signalling in plants. Biochem J 419, 247–259.
- 70, , & (2010) Identification of a Nuclear Export Signal in the Catalytic Subunit of AMP-activated Protein Kinase. Mol Biol Cell 21, 3433–3442.
- 71& (1996) Glucose regulates protein interactions within the yeast SNF1 protein kinase complex. Genes Dev 10, 3105–3115.
- 72& (1997) The Snf1 protein kinase and its activating subunit, Snf4, interact with distinct domains of the Sip1/Sip2/Gal83 component in the kinase complex. Mol Cell Biol 17, 2099–2106.
- 73, , , , , & (2006) Structure and dimerization of the kinase domain from yeast Snf1, a member of the Snf1/AMPK protein family. Structure 14, 477–485.
- 74, , , , , , , , , et al. (2009) Homo-oligomerization and activation of AMP-activated protein kinase are mediated by the kinase domain alphaG-helix. J Biol Chem 284, 27425–27437.
- 75, , & (2008) Roles of the glycogen-binding domain and Snf4 in glucose inhibition of SNF1 protein kinase. J Biol Chem 283, 19521–19529.
- 76, , , & (2010) Differential Roles of the Glycogen-Binding Domains of beta Subunits in Regulation of the Snf1 Kinase. Eukaryot Cell 9, 173–183.
- 77, , , , , , & (2005) AMP-activated protein kinase beta subunit tethers alpha and gamma subunits via its C-terminal sequence (186-270). J Biol Chem 280, 13395–13400.
- 78, , , , & (2004) AKINbeta3, a plant specific SnRK1 protein, is lacking domains present in yeast and mammals non-catalytic beta-subunits. Plant Mol Biol 56, 747–759.
- 79& (2006) Regulation of the nucleocytoplasmic distribution of Snf1-Gal83 protein kinase. Eukaryot Cell 5, 1950–1956.
- 80, , & (2001) Subcellular localization of the Snf1 kinase is regulated by specific beta subunits and a novel glucose signaling mechanism. Genes Dev 15, 1104–1114.
- 81, & (2003) Sip2, an N-myristoylated beta subunit of Snf1 kinase, regulates aging in Saccharomyces cerevisiae by affecting cellular histone kinase activity, recombination at rDNA loci, and silencing. J Biol Chem 278, 13390–13397.
- 82, & (2010) The beta-subunits of the Snf1 kinase in Saccharomyces cerevisiae, Gal83 and Sip2, but not Sip1, are redundant in glucose derepression and regulation of sterol biosynthesis. Mol Microbiol 77, 371–383.
- 83, , , , , , , & (1997) Posttranslational modifications of the 5′-AMP-activated protein kinase beta1 subunit. J Biol Chem 272, 24475–24479.
- 84, & (2004) Pak1 protein kinase regulates activation and nuclear localization of Snf1-Gal83 protein kinase. Mol Cell Biol 24, 8255–8263.
- 85, & (2004) Cyclic AMP-dependent protein kinase regulates the subcellular localization of Snf1-Sip1 protein kinase. Mol Cell Biol 24, 1836–1843.
- 86, , , , & (2001) Post-translational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzyme activity and cellular localization. Biochem J 354, 275–283.
- 87, , , & (2001) Domain fusion between SNF1-related kinase subunits during plant evolution. EMBO Rep 2, 55–60.
- 88, , , , , & (2006) AKINbetagamma contributes to SnRK1 heterotrimeric complexes and interacts with two proteins implicated in plant pathogen resistance through its KIS/GBD sequence. Plant Physiol 142, 931–944.
- 89, , & (2007) Regulation of AMP-activated protein kinase by a pseudosubstrate sequence on the gamma subunit. EMBO J 26, 806–815.
- 90, & (2003) Yeast Pak1 kinase associates with and activates Snf1. Mol Cell Biol 23, 3909–3917.
- 91, , , , , & (2003) Elm1p is one of three upstream kinases for the Saccharomyces cerevisiae SNF1 complex. Curr Biol 13, 1299–1305.
- 92, & (2006) Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem 281, 25336–25343.
- 93, , & (2007) DNA sequences from Arabidopsis, which encode protein kinases and function as upstream regulators of Snf1 in yeast. J Biol Chem 282, 10472–10479.
- 94& (2006) Geminivirus infection up-regulates the expression of two Arabidopsis protein kinases related to yeast SNF1- and mammalian AMPK-activating kinases. Plant Physiol 142, 1642–1655.
- 95, & (2009) Arabidopsis protein kinases GRIK1 and GRIK2 specifically activate SnRK1 by phosphorylating its activation loop. Plant Physiol 150, 996–1005.
- 96, , , , , & (2008) Access denied: Snf1 activation loop phosphorylation is controlled by availability of the phosphorylated threonine 210 to the PP1 phosphatase. J Biol Chem 283, 222–230.
- 97, & (2011) Roles of two protein phosphatases, Reg1-Glc7 and Sit4, and glycogen synthesis in regulation of SNF1 protein kinase. Proc Natl Acad Sci USA 108, 6349–6354.
- 98, , & (1995) 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS Lett 377, 421–425.
- 99, , , , , , & (1996) Biochemical characterization and deletion analysis of recombinant human protein phosphatase 2C alpha. Biochem J 320(Pt 3), 801–806.
- 100, , & (1999) Regulation of spinach SNF1-related (SnRK1) kinases by protein kinases and phosphatases is associated with phosphorylation of the T loop and is regulated by 5′-AMP. Plant J 19, 433–439.
- 101, , , , & (2006) Dissecting the role of 5′-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J Biol Chem 281, 32207–32216.
- 102, , , & (2007) Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J 403, 139–148.
- 103, , , , , , & (2010) beta-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc Natl Acad Sci USA 107, 19237–19241.
- 104, , , , , , , , , et al. (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230–233.
- 105, , , & (2006) Fatty acids stimulate AMP-activated protein kinase and enhance fatty acid oxidation in L6 myotubes. J Physiol 574, 139–147.
- 106, , , , , , & (1994) Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase. J Biol Chem 269, 2361–2364.
- 107, , , , , , & (2004) Intrasteric control of AMPK via the gamma1 subunit AMP allosteric regulatory site. Protein Sci 13, 155–165.
- 108, & (1996) Glucose repression/derepression in budding yeast: SNF1 protein kinase is activated by phosphorylation under derepressing conditions, and this correlates with a high AMP:ATP ratio. Curr Biol 6, 1426–1434.
- 109, & (2000) Regulation of a plant SNF1-related protein kinase by glucose-6-phosphate. Plant Physiol 123, 403–412.
- 110, , , , , , , , & (2009) Inhibition of SNF1-related protein kinase1 activity and regulation of metabolic pathways by trehalose-6-phosphate. Plant Physiol 149, 1860–1871.
- 111, , , , , , , , & (2006) Sugar-induced increases in trehalose 6-phosphate are correlated with redox activation of ADPglucose pyrophosphorylase and higher rates of starch synthesis in Arabidopsis thaliana. Biochem J 397, 139–148.
- 112, , , & (2003) Trehalose 6-phosphate is indispensable for carbohydrate utilization and growth in Arabidopsis thaliana. Proc Natl Acad Sci USA 100, 6849–6854.
- 113, , , , , , , & (2009) Extensive expression regulation and lack of heterologous enzymatic activity of the Class II trehalose metabolism proteins from Arabidopsis thaliana. Plant Cell Environ 32, 1015–1032.
- 114, & (2004) Arabidopsis trehalose-6-phosphate synthase 1 is essential for normal vegetative growth and transition to flowering. Plant Physiol 135, 969–977.
- 115, , , , , , , & (2002) Trehalose-6-phosphate synthase 1, which catalyses the first step in trehalose synthesis, is essential for Arabidopsis embryo maturation. Plant J 29, 225–235.
- 116, , , & (2006) Delayed embryo development in the ARABIDOPSIS TREHALOSE-6-PHOSPHATE SYNTHASE 1 mutant is associated with altered cell wall structure, decreased cell division and starch accumulation. Plant J 46, 69–84.
- 117, & (2005) The role of trehalose-6-phosphate synthase in Arabidopsis embryo development. Biochem Soc Trans 33, 280–282.
- 118, , , & (1996) Evidence for trehalose-6-phosphate-dependent and -independent mechanisms in the control of sugar influx into yeast glycolysis. Mol Microbiol 20, 981–991.
- 119& (1995) Trehalose synthase: guard to the gate of glycolysis in yeast? Trends Biochem Sci 20, 3–10.
- 120, , , , & (2009) The trehalose pathway regulates mitochondrial respiratory chain content through hexokinase 2 and cAMP in Saccharomyces cerevisiae. J Biol Chem 284, 27229–27234.
- 121, & (2010) Differential importance of trehalose accumulation in Saccharomyces cerevisiae in response to various environmental stresses. J Biosci Bioeng 109, 262–266.
- 122, , , , & (2009) The induction of trehalose and glycerol in Saccharomyces cerevisiae in response to various stresses. Biochem Biophys Res Commun 387, 778–783.
- 123& (2009) Stress-tolerance of baker’s-yeast (Saccharomyces cerevisiae) cells: stress-protective molecules and genes involved in stress tolerance. Biotechnol Appl Biochem 53, 155–164.
- 124, & (2004) Reserve carbohydrates maintain the viability of Saccharomyces cerevisiae cells during chronological aging. Mech Ageing Dev 125, 229–235.
- 125, & (2010) Trehalose extends longevity in the nematode Caenorhabditis elegans. Aging cell 9, 558–569.
- 126& (2004) Role of trehalose phosphate synthase and trehalose during hypoxia: from flies to mammals. J Exp Biol 207, 3125–3129.
- 127, , , & (2002) Role of trehalose phosphate synthase in anoxia tolerance and development in Drosophila melanogaster. J Biol Chem 277, 3274–3279.
- 128, , , & (2003) Expression of Drosophila trehalose-phosphate synthase in HEK-293 cells increases hypoxia tolerance. J Biol Chem 278, 49113–49118.
- 129& (2006) Inhibition of germline proliferation during C. elegans dauer development requires PTEN, LKB1 and AMPK signalling. Development 133, 611–619.
- 130& (2006) Regulation of germline stem cell proliferation downstream of nutrient sensing. Cell Div 1, 29.
- 131, & (2006) Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5, 119–126.
- 132, & (2010) Trehalose extends longevity in the nematode Caenorhabditis elegans. Aging Cell 9, 558–569.

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