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First published online October 27, 2004
doi: 10.1242/10.1242/jcs.01540
Commentary |
Division of Molecular Physiology, Wellcome Trust Biocentre, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK
(e-mail: d.g.hardie{at}dundee.ac.uk)
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Summary |
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 Top Summary IntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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subunits of AMPK, and this is antagonized by high concentrations of ATP. AMP binding causes activation by a sensitive mechanism involving phosphorylation of AMPK by the tumour suppressor LKB1. Once activated, AMPK switches on catabolic pathways that generate ATP while switching off ATP-consuming processes. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of hormones and cytokines such as leptin, adiponectin and ghrelin. A particularly interesting downstream target recently identified is TSC2 (tuberin). The LKB1
AMPKTSC2 pathway negatively regulates the target of rapamycin (TOR), and this appears to be responsible for limiting protein synthesis and cell growth, and protecting against apoptosis, during cellular stresses such as glucose starvation.
Key words: AMP-activated protein kinase, LKB1, TSC2
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Introduction |
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TopSummaryIntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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One might expect that this system would respond to changes in the cellular ADP:ATP ratio. However, if the reaction catalysed by adenylate kinase (2ADP 
ATP + AMP) is maintained close to equilibrium (which appears to be the case in most eukaryotic cells), one can easily show that the AMP:ATP ratio varies as the square of the ADP:ATP ratio (Hardie and Hawley, 2001
). The former ratio is therefore a much more sensitive indicator of cellular energy status than the latter, and is the parameter that is monitored by the AMPK system (Fig. 1).
The AMPK field is developing very rapidly, and this Commentary cannot hope to be comprehensive. I therefore focus on recent developments, particularly the identification of new players acting upstream and downstream of AMPK. Readers who are particularly interested in aspects related to medicine or physiology should consult other recent reviews (Hardie, 2003; Hardie et al., 2003; Carling, 2004; Hardie, 2004a; Hardie, 2004b).
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Structure of the AMPK complex |
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TopSummaryIntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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subunit and regulatory ß and subunits (Hardie et al., 2003), each of which is encoded by two or three distinct genes (1, 2; ß1, ß2; 1, 2, 3) (Fig. 2). All possible combinations of isoforms appear to be able to form complexes and, along with splice variants and the use of alternative promoters, this leads to a diverse array of different AMPK complexes. Although the mammalian kinase is the only example that is well characterized at the biochemical level, genes encoding orthologues of the , ß and subunits are found in all eukaryotic species whose genome sequences have been determined. This even includes the primitive parasite Giardia lamblia (Hardie et al., 2003), which lacks mitochondria and, according to molecular phylogenies, is more than twice as distant from humans as is Saccharomyces cerevisiae (Adam, 2000). Thus, the existence of AMPK orthologues appears to be a fundamental feature of all eukaryotic cells.
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What are the functions of the three subunits? The 1 and 2 subunits contain a conventional kinase domain at the N-terminus (Fig. 2), and a phylogenetic tree of the >500 such domains encoded in the human genome (Manning et al., 2002) reveals that these lie on a distinct branch containing eleven others (Fig. 3) that we now refer to as the AMPK-related kinase family (Lizcano et al., 2004). The C-terminal regions of the subunits are required to form a complex with the ß and subunits (Crute et al., 1998). Comparison of ß subunit sequences from different species revealed that they contained two conserved regions originally termed the KIS and ASC domains (Jiang and Carlson, 1997). Recent work has shown that, in mammals, the ASC domain is sufficient for the formation of a complex with the and subunits, whereas the KIS domain is not (as previously thought) involved in subunit interactions but is in fact a glycogen-binding domain (GBD) (Hudson et al., 2003) (Fig. 2). According to the protein families (Pfam) database, the GBD is a member of the isoamylase-N domain family (see entry PF02922 at http://www.sanger.ac.uk/Software/Pfam/). These non-catalytic domains are usually found in enzymes that metabolize the 16 branch points in 14-linked glucans, such as glycogen and starch. Two lines of evidence confirmed that the GBD was indeed involved in glycogen binding. First, when the , ß and subunits are co-expressed in cultured human cells with a green fluorescent protein (GFP) tag on , fluorescence is associated with glycogen-containing granules in the cytoplasm, but this is abolished if the GBD is deleted from the ß subunit (Hudson et al., 2003). Second, the GBD from rat ß1 synthesized in bacteria binds to glycogen in cell-free assays (Polekhina et al., 2003).
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The exact function(s) of the GBD remains unclear, although there are several experimental findings linking AMPK with glycogen; however, these observations are currently difficult to synthesize into a single, all-encompassing hypothesis. The GBD does cause a partial localization of AMPK to glycogen particles, where one of its known downstream targets – glycogen synthase – resides (Hudson et al., 2003). There is also indirect evidence that glycogen regulates AMPK activity: in both rat (Wojtaszewski et al., 2002) and human (Wojtaszewski et al., 2003) skeletal muscle, a high content of glycogen represses activation of AMPK. This makes physiological sense because if muscle glycogen content is high it tends to be used preferentially as fuel and, although AMPK activation stimulates the usage by muscle of alternative fuels such as blood glucose and fatty acids, it is not required for glycogen breakdown or glycolysis. As yet, repression of AMPK activation by glycogen has not been reproduced in a cell-free system; so the molecular mechanism remains unclear. Given the ample evidence (discussed further below) that the AMPK system senses the immediate availability of cellular energy in the form of adenine nucleotides, an attractive hypothesis is that it can also sense longer-term reserves in the form of glycogen. Whatever its functions, the GBD is found universally in the ß subunit orthologues of all eukaryotes, which suggests that its function(s) are ancient and important.
Following their variable N-terminal regions, the subunits of AMPKs contain four tandem repeats of a sequence motif first identified by Bateman as a `CBS domain' (Bateman, 1997) (Fig. 2). These motifs contain about 60 residues and are found in various proteins in archaea, bacteria and eukaryotes: the acronym derives from the enzyme cystathionine ß-synthase, which has a pair of such motifs at the C-terminus. They invariably occur as tandem pairs, and the crystal structure of a bacterial inosine-5'-monophosphate (IMP) dehydrogenase (Zhang et al., 1999) shows that the repeats in a pair associate closely together through hydrophobic interactions. As it is now clear that the basic functional unit is a dimer, Kemp has suggested the term `Bateman domain' to refer to the structure formed by two tandem repeats (Kemp, 2004). Initially, the function(s) of Bateman domains was not known, but recent studies have revealed that Bateman domains in the subunits represent the regulatory AMP- and ATP-binding sites of the AMPK complex (Scott et al., 2004). The N-terminal and C-terminal Bateman domains from 2 can each bind one molecule of AMP or ATP in a mutually exclusive manner, whereas a construct containing both Bateman domains binds two molecules of AMP or ATP with strong positive cooperativity. The finding that there are two binding sites for AMP and ATP in a single ß complex had not been anticipated. Strong evidence that the Bateman domains are indeed the regulatory AMP- and ATP-binding sites came from studies of mutations in 2 that cause a human heart condition, Wolff-Parkinson-White syndrome. All five mutations caused both defective binding of AMP to the isolated Bateman domains (Scott et al., 2004) and defective activation of the intact ß complex by AMP (Daniel and Carling, 2002; Scott et al., 2004), and the order of severity of the individual mutations was the same for both parameters.
Bateman domains from other proteins bind other adenosine derivatives (Scott et al., 2004). Those of IMP dehydrogenase and CLC chloride channels bind ATP, whereas those of cystathionine ß-synthase bind S-adenosyl methionine, the common feature being the binding of an adenosine-containing ligand that activates protein function. Intriguingly, in all of these proteins, point mutations that interfere with ligand binding cause a variety of human hereditary diseases ranging from retinitis pigmentosa to epilepsy (Scott et al., 2004).
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Regulation of the AMPK complex |
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TopSummaryIntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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First, AMP binding causes allosteric activation of mammalian AMPK. The magnitude of this effect varies between AMPK isoforms but is typically fivefold or less. A puzzling finding is that, although the subunits of the yeast and plant orthologues contain two Bateman domains that are very similar to those of the mammalian enzyme, allosteric activation of the yeast and plant kinases has not been demonstrated. This might simply be due to technical problems: because adenylate kinase converts ADP formed in the kinase assay to AMP, one cannot demonstrate AMP activation unless adenylate kinase is completely removed. AMP does activate the AMPK orthologue from Drosophila (Pan and Hardie, 2002), which shows that this regulatory mechanism is at least conserved between mammals and insects.
Second, AMP binding makes AMPK a better substrate for the upstream kinase. The upstream kinase, recently identified as the tumour suppressor LKB1 (see below), activates the kinase by phosphorylation of the subunit at a specific threonine residue (Thr172) (Hawley et al., 1996) in the so-called activation loop, within which phosphorylation causes activation of many other protein kinases. As phosphorylation of Thr172 causes at least 50- to 100-fold activation, it is quantitatively much more important than the allosteric activation. Like the allosteric effect, activation by the upstream kinase is stimulated by AMP and inhibited by high concentrations of ATP (Hawley et al., 1996). AMP stimulation is only observed if the intact ß complex, and not the isolated kinase domain (which lacks the AMP-binding sites), is used as the substrate (Hawley et al., 2003). This shows that the effect is due to binding of AMP to the substrate, AMPK, and not to the upstream kinase. The critical threonine residue, and the sequence around it, is conserved in the subunit sequences of AMPK orthologues from all eukaryotes, and mutation of the equivalent threonine residue in the yeast subunit (Snf1p) causes a total loss of function in vivo (Estruch et al., 1992). Thus, although it is not yet clear whether the allosteric activation by AMP is conserved in all eukaryotes, the regulation by phosphorylation is certainly conserved.
Third, AMP binding to AMPK also inhibits dephosphorylation of Thr172 by protein phosphatases (Davies et al., 1995). Unlike the allosteric activation, this mechanism of regulation by AMP has also been reported to operate in higher plants (Sugden et al., 1999).
Why should AMP activate the system by three mechanisms, all of which probably involve binding to the same sites on the subunit? Computer simulations have revealed that this causes the system to be ultrasensitive; thus, a small change in the initial input (AMP) can produce a much larger relative change in the final output (Hardie et al., 1999). This is an example of multistep sensitivity, which arises when a signal molecule affects more than one step in a cascade (Chock and Stadtman, 1977). Sensitivity in the AMPK system also arises because the upstream kinase has a very low Km for AMPK (Hardie et al., 1999), a phenomenon referred to as zero-order ultrasensitivity (Goldbeter and Koshland, 1981). A factor that might increase the sensitivity of the AMPK system even further is the recent finding that the two Bateman domains on the subunits bind AMP cooperatively (see above). Overall, this exquisite sensitivity might be very important in the ability of AMPK to maintain the energy state of the cell within narrow limits.
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Mammalian AMPK is activated by stresses that cause ATP depletion |
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TopSummaryIntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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). Indeed, numerous studies now suggest that AMPK is an important mediator of the varied metabolic responses to exercise. For full coverage of this topic, the reader should refer to other reviews (Hardie, 2003; Hardie, 2004a; Hardie, 2004b). It is becoming clear that AMPK may be responsible for many of the health benefits of regular exercise, particularly with respect to prevention and treatment of obesity and Type 2 diabetes. Medical interest in the AMPK system was further stimulated by the finding that it is activated by two of the main classes of drugs currently used for treatment of Type 2 diabetes: biguanides and thiazolidinediones (Table 1). Both classes of drug inhibit complex I of the respiratory chain (Owen et al., 2000; Brunmair et al., 2004) and this might be how they activate AMPK, although in the case of metformin it has proved difficult to measure changes in cellular AMP:ATP ratios (Fryer et al., 2002; Hawley et al., 2002). With the possible exception of osmotic stress (Fryer et al., 2002), all of the stresses that activate AMPK are associated with changes in the cellular AMP:ATP ratio.
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Physiological roles of AMPK orthologues in yeast and plants |
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TopSummaryIntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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and subunits of the yeast SNF1 complex, and were originally identified by genetic screens for mutations that prevent growth on sucrose and non-fermentable carbon sources (Hardie et al., 1998). Growth on sucrose requires the expression of the enzyme that breaks it down (invertase), whereas growth on non-fermentable carbon sources requires expression of mitochondrial genes needed for oxidative metabolism. Expression of all of these genes is repressed by glucose, and the SNF1 and SNF4 genes are required for their derepression. One mechanism by which this is mediated is the phosphorylation of the repressor protein Mig1p by the SNF1 complex (Smith et al., 1999). Phosphorylation causes Mig1p to bind to a nuclear export protein that promotes its removal from the nucleus (DeVit and Johnston, 1999).
Thus, the primary role of the AMPK orthologue in yeast is in the response to glucose starvation. In cultured cells from mammals (Salt et al., 1998) and Drosophila (Pan and Hardie, 2002), AMPK is also activated by glucose deprivation; so this seems to have been an ancient role for the system. In green plants, darkness is the equivalent of starvation: plants synthesize carbohydrates by photosynthesis during light periods and then rely on breakdown of carbohydrate reserves (in the form of starch) during dark periods. The moss Physcomitrella patens has two genes encoding orthologues of the AMPK subunit. Disruption of both genes produces a complete failure to grow unless the plants are maintained under constant illumination (Thelander et al., 2004). Thus, the response to starvation also seems to be a fundamental role of AMPK orthologues in green plants.
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Regulation of whole body energy intake and expenditure |
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TopSummaryIntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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) and adiponectin (Tomas et al., 2002; Yamauchi et al., 2002). These two hormones are so-called adipokines secreted by adipocytes, and are thought to represent signals that body lipid stores are adequate. AMPK activation in muscle also increases glucose uptake (Merrill et al., 1997) and mitochondrial biogenesis (Zong et al., 2002), and leptin and adiponectin would therefore increase energy expenditure by stimulating oxidation of glucose as well as fatty acids in muscle. As well as its effects on muscle, high leptin levels in vivo can cause adipocytes to switch from net synthesis to net oxidation of fatty acids, and this is associated with AMPK activation in the cells (Orci et al., 2004). Thus, AMPK stimulates `burning' of fat when its storage is excessive (although why this fails in obese individuals remains unclear).
Remarkably, as well as increasing energy expenditure by stimulating fatty acid and glucose oxidation, AMPK also appears to regulate energy intake in mammals. In the regions of the hypothalamus involved in regulation of satiety and food intake, AMPK is inhibited in rodents by high levels of glucose, leptin and insulin, all of which repress food intake, whereas it is activated by ghrelin, a gut hormone that stimulates food intake (Andersson et al., 2004; Minokoshi et al., 2004). These changes in AMPK activity seem to trigger the subsequent changes in food intake, because direct injection of the AMPK activator 5-aminoimidazole 4-carboxamide (AICA) riboside into the hypothalamus increases food intake (Andersson et al., 2004), whereas expression of activated and dominant-negative inhibitory mutants of AMPK in the hypothalamus stimulates and inhibits food intake, respectively (Minokoshi et al., 2004). One interesting aspect of these findings is that leptin inhibits AMPK in the hypothalamus yet activates it in skeletal muscle, raising interesting questions about the mechanisms involved. It is also intriguing that the AMPK system appears to be involved in increasing food intake in response to lowered blood glucose levels in mammals, just as its orthologue in yeast, the SNF1 complex, is involved in the response to lowered glucose levels in the extracellular medium.
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Identification of the upstream kinase, LKB1-STRAD-MO25 |
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TopSummaryIntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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), its identity remained a mystery. However, recently, we (Sutherland et al., 2003) and others (Hong et al., 2003a) identified three closely related protein kinases (Elm1p, Tak1p, Tos3p) capable of acting upstream of the yeast SNF1 complex in vivo. One of the closest sequence matches to these in humans was the protein kinase LKB1, and compelling evidence now indicates that this is the key upstream kinase in mammalian cells (Hawley et al., 2003; Woods et al., 2003; Shaw et al., 2004). LKB1 forms a complex with two accessory subunits: STRAD and MO25 (Baas et al., 2003; Boudeau et al., 2003). The upstream kinase purified from rat liver is a complex between LKB1, STRAD and MO25, and all three subunits are required for full activity (Hawley et al., 2003).
LKB1 was first identified as the gene mutated in human Peutz-Jeghers syndrome (PJS) (Hemminki et al., 1998; Jenne et al., 1998). Subjects with PJS are heterozygous for a loss-of-function mutation in the LKB1 gene. They have unusual skin pigmentation and also suffer from numerous gastrointestinal polyps that are classed as hamartomas, benign tumours caused by abnormal cell growth, in which the normal differentiated state of the cells is maintained. Subjects with PJS also have an increased risk of developing malignant tumours, which led to LKB1 being designated as a tumour suppressor.
Heterozygous mice that lack one functional copy of the LKB1 gene develop extensive gastrointestinal polyps, as in the human syndrome; however, there are conflicting reports as to whether these are caused by loss of heterozygosity, i.e. loss of the remaining functional copy of the gene (Bardeesy et al., 2002; Miyoshi et al., 2002; Rossi et al., 2002). One strain of these mice has increased incidence of liver cancers, which is associated with loss of heterozygosity (Nakau et al., 2002). Homozygous LKB1-knockout mice die during embryonic development, but immortalized mouse embryo fibroblasts (MEFs) can be derived from the embryos, and have provided an important tool that proved that LKB1 is necessary for AMPK activation (Hawley et al., 2003; Shaw et al., 2004).
Are the tumour suppressor effects of LKB1 due to its ability to activate AMPK? This is certainly possible, because AMPK activation in HepG2 cells causes a cell-cycle arrest in G1 phase through stabilization of p53 (Imamura et al., 2001), and expression of LKB1 in HeLa or G361 cells (tumour cell lines that do not normally express the kinase) also causes a p53-dependent G1 arrest (Tiainen et al., 1999; Tiainen et al., 2002). However, LKB1 lies upstream of all of the AMPK-related kinases shown in Fig. 3 (Lizcano et al., 2004). Although the four MARKs appear to have functions in regulating cell polarity (Baas et al., 2004), the functions and downstream targets of the other AMPK-related kinases are not well understood. Thus, some of the tumour suppressor effects of LKB1 might be mediated by one or more of the AMPK-related kinases rather than AMPK itself.
Is the LKB1 complex itself regulated? Although this possibility cannot be excluded, recent results suggest that it is constitutively active. First, during stimulation of cultured muscle cells by several stress treatments that activate AMPK, LKB1 activity was constant (Woods et al., 2003). Second, during activation of AMPK in MEFs by the anti-diabetic drug phenformin, there was no change in LKB1 activity (Lizcano et al., 2004), despite the fact that activation requires the presence of LKB1 (Hawley et al., 2003). Third, during treatment of rat skeletal muscle with different AMPK-activating stimuli, the activities of LKB1, and several of the AMPK-related kinases downstream of LKB1, did not change (Sakamoto et al., 2004).
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Downstream targets of AMPK |
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TopSummaryIntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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; Hardie et al., 2003; Hardie, 2004a; Hardie, 2004b). Fig. 4 summarizes some of the well-established downstream targets, and a few of the more recently identified targets are discussed below. In general, activation of AMPK downregulates biosynthetic pathways such as fatty acid and cholesterol biosynthesis, yet switches on catabolic pathways that generate ATP, such as fatty acid oxidation, glucose uptake and glycolysis (Fig. 1). It achieves this not only through direct phosphorylation of metabolic enzymes, but also through effects on gene expression, such as upregulation of the glucose transporter GLUT4 and mitochondrial genes in muscle, and downregulation of genes encoding enzymes of fatty acid synthesis and gluconeogenesis in liver. Although in no single case do we completely understand the detailed mechanisms by which AMPK activation regulates the expression of a particular gene, it has many effects on individual transcription factors and coactivators. For example, it upregulates the expression of the co-activator PGC1 (Terada et al., 2002), which may be involved in the increased expression of mitochondrial genes in muscle (Zong et al., 2002), yet it downregulates the transcription factors SREBP-1c (Zhou et al., 2001) and HNF4 (Leclerc et al., 2001; Hong et al., 2003b), which may be involved in decreased expression of genes involved in lipogenesis, glucose uptake and glycolysis in liver. In muscle, it causes increased DNA binding by the transcription factors NRF1 (Bergeron et al., 2001) and MEF2 (Zheng et al., 2001), which may be involved in regulation of mitochondrial genes and GLUT4, respectively. Finally, it phosphorylates the ubiquitous co-activator p300 at a specific site (Ser89), reducing its ability to bind to nuclear hormone receptors and thus activate their target genes (Yang et al., 2001).
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Another mechanism by which AMPK activation affects the expression of proteins is through effects on mRNA stability. Through an undefined mechanism, AMPK activation reduces the cytoplasmic level of the RNA-binding protein HuR, which stabilizes specific mRNAs in the cytoplasm by binding to their 3'-untranslated regions (Wang et al., 2002). Target mRNAs for HuR include proteins that regulate the cell cycle, such as cyclin A, cyclin B1 and p21. The same group showed that activation of AMPK by an elevated AMP:ATP ratio in senescent fibroblasts in culture can explain many of the features of the senescent phenotype (Wang et al., 2003). Indeed, LKB1–/– MEF cells, in which AMPK cannot be activated by agents that elevate cellular AMP levels (phenformin) or that mimic the effects of AMP (AICA riboside) (Hawley et al., 2003), are resistant to passage-induced senescence (Bardeesy et al., 2002).
Another key biosynthetic pathway that is downregulated by AMPK is translation, which can account for around 20% of energy turnover in growing cells and is particularly sensitive to decreases in ATP synthesis (Buttgereit and Brand, 1995). Inhibition occurs by at least two mechanisms: (1) phosphorylation and activation of elongation factor-2 kinase (Horman et al., 2002; Browne et al., 2004), which switches off the elongation step in translation; and (2) inhibition of the target of rapamycin (TOR) pathway (Bolster et al., 2002; Krause et al., 2002; Kimura et al., 2003), which is a major positive stimulus for protein synthesis, cell growth and cell size. The TOR pathway is activated by growth factors and amino acids, and is thought to stimulate translation, and hence cell growth, by two mechanisms: (1) activation of ribosomal protein S6 kinase (S6K1); and (2) increased phosphorylation of elongation factor-4E binding protein 1 (4E-BP1), which stimulates the initiation step of translation (Carrera, 2004). Recent studies suggest that inhibition of the TOR pathway by AMPK might occur through phosphorylation of TSC2 (Inoki et al., 2003) (Fig. 5). TSC1 and TSC2 (also known as hamartin and tuberin) are partners that form a stable complex in the cell, and mutations in either leads to the human disease tuberous sclerosis complex. This is similar to PJS in that it is an autosomal dominant condition resulting in hamartomas, although they are not restricted to the intestine. Studies in Drosophila suggest that the TSC1-TSC2 complex negatively regulates cell growth, and acts upstream of TOR to cause its inhibition (Gao et al., 2002). AMPK phosphorylates TSC2 at two sites; by mutating these site, Guan and colleagues provided evidence that these phosphorylation events increase the ability of the TSC complex to inhibit the TOR pathway, and that phosphorylation of TSC2 by AMPK is involved in the mechanism by which the TSC complex inhibits cell growth and protects against apoptosis during glucose starvation (Inoki et al., 2003). Interestingly, Shaw et al. reported that LKB1–/– MEF cells are more susceptible to apoptosis in response to AMPK-activating stresses (Shaw et al., 2004). Given that the LKB1AMPKTSC2 pathway (Fig. 5) seems to limit cell growth and cell size by inhibiting TOR, the idea that the hamartomas caused by heterozygosity for mutations in LKB1 (which lies upstream of AMPK) are related to those caused by heterozygosity for mutations in TSC2 (which lies downstream of AMPK) is attractive, although why the lesions are restricted to the intestine in the case of LKB1 remains unclear. However, it is also possible that the lesions in PJS are caused in part by dysregulation of downstream kinases other than AMPK, such as the MARKs.
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Conclusions and perspectives |
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TopSummaryIntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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), that the AMPK system acts as an `energy checkpoint' that determines whether cellular energy status is sufficient before the cell commits to a programme of growth triggered by the TOR pathway. There are also indications that AMPK activation in response to low energy status inhibits cell division through effects on DNA replication and mitosis, although the detailed mechanisms remain to be elucidated. Finally, the AMPK system seems to have evolved in single-celled eukaryotes, where it might have had a primary role in orchestrating the response to glucose starvation. However, the recent findings that AMPK is regulated by cytokines such as leptin and adiponectin in mammals show that, during the evolution of multicellular organisms, it became involved in the regulation of energy intake and expenditure at the whole body level. |
Acknowledgments |
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References |
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TopSummaryIntroductionStructure of the AMPK...Regulation of the AMPK...Mammalian AMPK is activated...Physiological roles of AMPK...Regulation of whole body...Identification of the upstream...Downstream targets of AMPKConclusions and perspectivesReferences |
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 G. Marino, A. P. Ugalde, N. Salvador-Montoliu, I. Varela, P. M. Quiros, J. Cadinanos, I. van der Pluijm, J. M.P. Freije, and C. Lopez-Otin Premature aging in mice activates a systemic metabolic response involving autophagy induction Hum. Mol. Genet., July 15, 2008; 17(14): 2196 - 2211. [Abstract] [Full Text] [PDF]
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W. Jiang, Z. Zhu, and H. J. Thompson Dietary Energy Restriction Modulates the Activity of AMP-Activated Protein Kinase, Akt, and Mammalian Target of Rapamycin in Mammary Carcinomas, Mammary Gland, and Liver Cancer Res., July 1, 2008; 68(13): 5492 - 5499. [Abstract] [Full Text] [PDF]
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H. Lee, J. S. Cho, N. Lambacher, J. Lee, S.-J. Lee, T. H. Lee, A. Gartner, and H.-S. Koo The Caenorhabditis elegans AMP-activated Protein Kinase AAK-2 Is Phosphorylated by LKB1 and Is Required for Resistance to Oxidative Stress and for Normal Motility and Foraging Behavior J. Biol. Chem., May 30, 2008; 283(22): 14988 - 14993. [Abstract] [Full Text] [PDF]
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 A. S. Deshmukh, J. T. Treebak, Y. C. Long, B. Viollet, J. F. P. Wojtaszewski, and J. R. Zierath Role of Adenosine 5'-Monophosphate-Activated Protein Kinase Subunits in Skeletal Muscle Mammalian Target of Rapamycin Signaling Mol. Endocrinol., May 1, 2008; 22(5): 1105 - 1112. [Abstract] [Full Text] [PDF]
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L. A. Maile, B. E. Capps, E. C. Miller, L. B. Allen, U. Veluvolu, A. W. Aday, and D. R. Clemmons Glucose Regulation of Integrin-Associated Protein Cleavage Controls the Response of Vascular Smooth Muscle Cells to Insulin-Like Growth Factor-I Mol. Endocrinol., May 1, 2008; 22(5): 1226 - 1237. [Abstract] [Full Text] [PDF]
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S. Qin and G. W. De Vries {alpha}2 but Not {alpha}1 AMP-activated Protein Kinase Mediates Oxidative Stress-induced Inhibition of Retinal Pigment Epithelium Cell Phagocytosis of Photoreceptor Outer Segments J. Biol. Chem., March 14, 2008; 283(11): 6744 - 6751. [Abstract] [Full Text] [PDF]
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 J. W. Calvert, S. Gundewar, S. Jha, J. J.M. Greer, W. H. Bestermann, R. Tian, and D. J. Lefer Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS-Mediated Signaling Diabetes, March 1, 2008; 57(3): 696 - 705. [Abstract] [Full Text] [PDF]
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R. Okoshi, T. Ozaki, H. Yamamoto, K. Ando, N. Koida, S. Ono, T. Koda, T. Kamijo, A. Nakagawara, and H. Kizaki Activation of AMP-activated Protein Kinase Induces p53-dependent Apoptotic Cell Death in Response to Energetic Stress J. Biol. Chem., February 15, 2008; 283(7): 3979 - 3987. [Abstract] [Full Text] [PDF]
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M. Zhang, Y. Dong, J. Xu, Z. Xie, Y. Wu, P. Song, M. Guzman, J. Wu, and M.-H. Zou Thromboxane Receptor Activates the AMP-Activated Protein Kinase in Vascular Smooth Muscle Cells via Hydrogen Peroxide Circ. Res., February 15, 2008; 102(3): 328 - 337. [Abstract] [Full Text] [PDF]
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A. Riboulet-Chavey, F. Diraison, L. K. Siew, F. S. Wong, and G. A. Rutter Inhibition of AMP-Activated Protein Kinase Protects Pancreatic {beta}-Cells From Cytokine-Mediated Apoptosis and CD8+ T-Cell-Induced Cytotoxicity Diabetes, February 1, 2008; 57(2): 415 - 423. [Abstract] [Full Text] [PDF]
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M. Dixit, E. Bess, B. Fisslthaler, F. V. Hartel, T. Noll, R. Busse, and I. Fleming Shear stress-induced activation of the AMP-activated protein kinase regulates FoxO1a and angiopoietin-2 in endothelial cells Cardiovasc Res, January 1, 2008; 77(1): 160 - 168. [Abstract] [Full Text] [PDF]
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Q. Jin, L. Feng, C. Behrens, B. N. Bekele, I. I. Wistuba, W.-K. Hong, and H.-Y. Lee Implication of AMP-Activated Protein Kinase and Akt-Regulated Survivin in Lung Cancer Chemopreventive Activities of Deguelin Cancer Res., December 15, 2007; 67(24): 11630 - 11639. [Abstract] [Full Text] [PDF]
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J. D. Erusalimsky and S. Moncada Nitric Oxide and Mitochondrial Signaling: From Physiology to Pathophysiology Arterioscler. Thromb. Vasc. Biol., December 1, 2007; 27(12): 2524 - 2531. [Abstract] [Full Text] [PDF]
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R. J.O. Dowling, M. Zakikhani, I. G. Fantus, M. Pollak, and N. Sonenberg Metformin Inhibits Mammalian Target of Rapamycin Dependent Translation Initiation in Breast Cancer Cells Cancer Res., November 15, 2007; 67(22): 10804 - 10812. [Abstract] [Full Text] [PDF]
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P. P. Dzeja, P. Bast, D. Pucar, B. Wieringa, and A. Terzic Defective Metabolic Signaling in Adenylate Kinase AK1 Gene Knock-out Hearts Compromises Post-ischemic Coronary Reflow J. Biol. Chem., October 26, 2007; 282(43): 31366 - 31372. [Abstract] [Full Text] [PDF]
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 M. N. Galardo, M. F. Riera, E. H. Pellizzari, S. B. Cigorraga, and S. B. Meroni The AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-b-D-ribonucleoside, regulates lactate production in rat Sertoli cells J. Mol. Endocrinol., October 1, 2007; 39(4): 279 - 288. [Abstract] [Full Text] [PDF]
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 C. Forcet and M. Billaud Dialogue Between LKB1 and AMPK: A Hot Topic at the Cellular Pole Sci. Signal., September 18, 2007; 2007(404): pe51 - pe51. [Abstract] [Full Text] [PDF]
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 Y. Fukuyama, K. Ohta, R. Okoshi, M. Suehara, H. Kizaki, and K. Nakagawa Hypoxia Induces Expression and Activation of AMPK in Rat Dental Pulp Cells Journal of Dental Research, September 1, 2007; 86(9): 903 - 907. [Abstract] [Full Text] [PDF]
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 C. Chassin, M. Bens, J. de Barry, R. Courjaret, J. L. Bossu, F. Cluzeaud, S. Ben Mkaddem, M. Gibert, B. Poulain, M. R. Popoff, et al. Pore-forming epsilon toxin causes membrane permeabilization and rapid ATP depletion-mediated cell death in renal collecting duct cells Am J Physiol Renal Physiol, September 1, 2007; 293(3): F927 - F937. [Abstract] [Full Text] [PDF]
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 L. Tosca, S. Uzbekova, C. Chabrolle, and J. Dupont Possible Role of 5'AMP-Activated Protein Kinase in the Metformin-Mediated Arrest of Bovine Oocytes at the Germinal Vesicle Stage During In Vitro Maturation Biol Reprod, September 1, 2007; 77(3): 452 - 465. [Abstract] [Full Text] [PDF]
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J. Dominguez, P. Wu, C. S. Packer, C. Temm, and K. J. Kelly Lipotoxic and inflammatory phenotypes in rats with uncontrolled metabolic syndrome and nephropathy Am J Physiol Renal Physiol, September 1, 2007; 293(3): F670 - F679. [Abstract] [Full Text] [PDF]
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 J. A. Crowell, V. E. Steele, and J. R. Fay Targeting the AKT protein kinase for cancer chemoprevention Mol. Cancer Ther., August 1, 2007; 6(8): 2139 - 2148. [Abstract] [Full Text] [PDF]
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Y. Dagon, Y. Avraham, Y. Ilan, R. Mechoulam, and E. M. Berry Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase FASEB J, August 1, 2007; 21(10): 2431 - 2441. [Abstract] [Full Text] [PDF]
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 E. Pirinen, T. Kuulasmaa, M. Pietila, S. Heikkinen, M. Tusa, P. Itkonen, S. Boman, J. Skommer, A. Virkamaki, E. Hohtola, et al. Enhanced Polyamine Catabolism Alters Homeostatic Control of White Adipose Tissue Mass, Energy Expenditure, and Glucose Metabolism Mol. Cell. Biol., July 1, 2007; 27(13): 4953 - 4967. [Abstract] [Full Text] [PDF]
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 M. P. Richards and M. Proszkowiec-Weglarz Mechanisms Regulating Feed Intake, Energy Expenditure, and Body Weight in Poultry Poult. Sci., July 1, 2007; 86(7): 1478 - 1490. [Abstract] [Full Text] [PDF]
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 N. L. Spector, Y. Yarden, B. Smith, L. Lyass, P. Trusk, K. Pry, J. E. Hill, W. Xia, R. Seger, and S. S. Bacus Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells PNAS, June 19, 2007; 104(25): 10607 - 10612. [Abstract] [Full Text] [PDF]
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S.-P. Hong and M. Carlson Regulation of Snf1 Protein Kinase in Response to Environmental Stress J. Biol. Chem., June 8, 2007; 282(23): 16838 - 16845. [Abstract] [Full Text] [PDF]
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B. J. Krawiec, G. J. Nystrom, R. A. Frost, L. S. Jefferson, and C. H. Lang AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C2C12 cells Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1555 - E1567. [Abstract] [Full Text] [PDF]
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T. E. Jensen, A. J. Rose, S. B. Jorgensen, N. Brandt, P. Schjerling, J. F. P. Wojtaszewski, and E. A. Richter Possible CaMKK-dependent regulation of AMPK phosphorylation and glucose uptake at the onset of mild tetanic skeletal muscle contraction Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1308 - E1317. [Abstract] [Full Text] [PDF]
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 P. B. Bokko, L. Francione, E. Bandala-Sanchez, A. U. Ahmed, S. J. Annesley, X. Huang, T. Khurana, A. R. Kimmel, and P. R. Fisher Diverse Cytopathologies in Mitochondrial Disease Are Caused by AMP-activated Protein Kinase Signaling Mol. Biol. Cell, May 1, 2007; 18(5): 1874 - 1886. [Abstract] [Full Text] [PDF]
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M. A. Mayes, M. F. Laforest, C. Guillemette, R. B. Gilchrist, and F. J. Richard Adenosine 5'-Monophosphate Kinase-Activated Protein Kinase (PRKA) Activators Delay Meiotic Resumption in Porcine Oocytes Biol Reprod, April 1, 2007; 76(4): 589 - 597. [Abstract] [Full Text] [PDF]
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C. N. Wyatt, K. J. Mustard, S. A. Pearson, M. L Dallas, L. Atkinson, P. Kumar, C. Peers, D. G. Hardie, and A. M. Evans AMP-activated Protein Kinase Mediates Carotid Body Excitation by Hypoxia J. Biol. Chem., March 16, 2007; 282(11): 8092 - 8098. [Abstract] [Full Text] [PDF]
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B. Luo, G. J. Parker, R. C. Cooksey, Y. Soesanto, M. Evans, D. Jones, and D. A. McClain Chronic Hexosamine Flux Stimulates Fatty Acid Oxidation by Activating AMP-activated Protein Kinase in Adipocytes J. Biol. Chem., March 9, 2007; 282(10): 7172 - 7180. [Abstract] [Full Text] [PDF]
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 F. Cai, A. V Gyulkhandanyan, M. B Wheeler, and D. D Belsham Glucose regulates AMP-activated protein kinase activity and gene expression in clonal, hypothalamic neurons expressing proopiomelanocortin: additive effects of leptin or insulin J. Endocrinol., March 1, 2007; 192(3): 605 - 614. [Abstract] [Full Text] [PDF]
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L. Tosca, C. Chabrolle, S. Uzbekova, and J. Dupont Effects of Metformin on Bovine Granulosa Cells Steroidogenesis: Possible Involvement of Adenosine 5' Monophosphate-Activated Protein Kinase (AMPK) Biol Reprod, March 1, 2007; 76(3): 368 - 378. [Abstract] [Full Text] [PDF]
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C. Blume, P. M. Benz, U. Walter, J. Ha, B. E. Kemp, and T. Renne AMP-activated Protein Kinase Impairs Endothelial Actin Cytoskeleton Assembly by Phosphorylating Vasodilator-stimulated Phosphoprotein J. Biol. Chem., February 16, 2007; 282(7): 4601 - 4612. [Abstract] [Full Text] [PDF]
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M.-J. Lee, D. Feliers, M. M. Mariappan, K. Sataranatarajan, L. Mahimainathan, N. Musi, M. Foretz, B. Viollet, J. M. Weinberg, G. G. Choudhury, et al. A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy Am J Physiol Renal Physiol, February 1, 2007; 292(2): F617 - F627. [Abstract] [Full Text] [PDF]
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J.-S. Ju, M. A. Gitcho, C. A. Casmaer, P. B. Patil, D.-G. Han, S. A. Spencer, and J. S. Fisher Potentiation of insulin-stimulated glucose transport by the AMP-activated protein kinase Am J Physiol Cell Physiol, January 1, 2007; 292(1): C564 - C572. [Abstract] [Full Text] [PDF]
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 F. S. Gaskin, K. Kamada, M. Yusof, and R. J. Korthuis 5'-AMP-activated protein kinase activation prevents postischemic leukocyte-endothelial cell adhesive interactions Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H326 - H332. [Abstract] [Full Text] [PDF]
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 C. U. Niesler, K. H. Myburgh, and F. Moore Muscle: The changing AMPK expression profile in differentiating mouse skeletal muscle myoblast cells helps confer increasing resistance to apoptosis Exp Physiol, January 1, 2007; 92(1): 207 - 217. [Abstract] [Full Text] [PDF]
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 B. S. Kasinath, M. M. Mariappan, K. Sataranatarajan, M. J. Lee, and D. Feliers mRNA Translation: Unexplored Territory in Renal Science J. Am. Soc. Nephrol., December 1, 2006; 17(12): 3281 - 3292. [Abstract] [Full Text] [PDF]
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E. Zarrinpashneh, K. Carjaval, C. Beauloye, A. Ginion, P. Mateo, A.-C. Pouleur, S. Horman, S. Vaulont, J. Hoerter, B. Viollet, et al. Role of the {alpha}2-isoform of AMP-activated protein kinase in the metabolic response of the heart to no-flow ischemia Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2875 - H2883. [Abstract] [Full Text] [PDF]
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D. Meley, C. Bauvy, J. H. P. M. Houben-Weerts, P. F. Dubbelhuis, M. T. J. Helmond, P. Codogno, and A. J. Meijer AMP-activated Protein Kinase and the Regulation of Autophagic Proteolysis J. Biol. Chem., November 17, 2006; 281(46): 34870 - 34879. [Abstract] [Full Text] [PDF]
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L. Gissot, C. Polge, M. Jossier, T. Girin, J.-P. Bouly, M. Kreis, and M. Thomas AKINbeta{gamma} Contributes to SnRK1 Heterotrimeric Complexes and Interacts with Two Proteins Implicated in Plant Pathogen Resistance through Its KIS/GBD Sequence Plant Physiology, November 1, 2006; 142(3): 931 - 944. [Abstract] [Full Text] [PDF]
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 A. Tomiyama, S. Serizawa, K. Tachibana, K. Sakurada, H. Samejima, Y. Kuchino, and C. Kitanaka Critical role for mitochondrial oxidative phosphorylation in the activation of tumor suppressors bax and bak. J Natl Cancer Inst, October 18, 2006; 98(20): 1462 - 1473. [Abstract] [Full Text] [PDF]
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M. Baba, S.-B. Hong, N. Sharma, M. B. Warren, M. L. Nickerson, A. Iwamatsu, D. Esposito, W. K. Gillette, R. F. Hopkins III, J. L. Hartley, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling PNAS, October 17, 2006; 103(42): 15552 - 15557. [Abstract] [Full Text] [PDF]
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J.-T. Hwang, Y. M. Kim, Y.-J. Surh, H. W. Baik, S.-K. Lee, J. Ha, and O. J. Park Selenium Regulates Cyclooxygenase-2 and Extracellular Signal-Regulated Kinase Signaling Pathways by Activating AMP-Activated Protein Kinase in Colon Cancer Cells. Cancer Res., October 15, 2006; 66(20): 10057 - 10063. [Abstract] [Full Text] [PDF]
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S. P. Berasi, C. Huard, D. Li, H. H. Shih, Y. Sun, W. Zhong, J. E. Paulsen, E. L. Brown, R. E. Gimeno, and R. V. Martinez Inhibition of Gluconeogenesis through Transcriptional Activation of EGR1 and DUSP4 by AMP-activated Kinase J. Biol. Chem., September 15, 2006; 281(37): 27167 - 27177. [Abstract] [Full Text] [PDF]
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V. Bhalla, N. M. Oyster, A. C. Fitch, M. A. Wijngaarden, D. Neumann, U. Schlattner, D. Pearce, and K. R. Hallows AMP-activated Kinase Inhibits the Epithelial Na+ Channel through Functional Regulation of the Ubiquitin Ligase Nedd4-2 J. Biol. Chem., September 8, 2006; 281(36): 26159 - 26169. [Abstract] [Full Text] [PDF]
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K. Elbing, E. M. Rubenstein, R. R. McCartney, and M. C. Schmidt Subunits of the Snf1 Kinase Heterotrimer Show Interdependence for Association and Activity J. Biol. Chem., September 8, 2006; 281(36): 26170 - 26180. [Abstract] [Full Text] [PDF]
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S. Marshall Role of Insulin, Adipocyte Hormones, and Nutrient-Sensing Pathways in Regulating Fuel Metabolism and Energy Homeostasis: A Nutritional Perspective of Diabetes, Obesity, and Cancer Sci. Signal., August 1, 2006; 2006(346): re7 - re7. [Abstract] [Full Text] [PDF]
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 P. Tamas, S. A. Hawley, R. G. Clarke, K. J. Mustard, K. Green, D. G. Hardie, and D. A. Cantrell Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes J. Exp. Med., July 10, 2006; 203(7): 1665 - 1670. [Abstract] [Full Text] [PDF]
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D. L. Williamson, D. R. Bolster, S. R. Kimball, and L. S. Jefferson Time course changes in signaling pathways and protein synthesis in C2C12 myotubes following AMPK activation by AICAR. Am J Physiol Endocrinol Metab, July 1, 2006; 291(1): E80 - E89. [Abstract] [Full Text] [PDF]
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J. T. Treebak, S. Glund, A. Deshmukh, D. K. Klein, Y. C. Long, T. E. Jensen, S. B. Jorgensen, B. Viollet, L. Andersson, D. Neumann, et al. AMPK-Mediated AS160 Phosphorylation in Skeletal Muscle Is Dependent on AMPK Catalytic and Regulatory Subunits. Diabetes, July 1, 2006; 55(7): 2051 - 2058. [Abstract] [Full Text] [PDF]
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 H. Motoshima, B. J. Goldstein, M. Igata, and E. Araki AMPK and cell proliferation - AMPK as a therapeutic target for atherosclerosis and cancer J. Physiol., July 1, 2006; 574(1): 63 - 71. [Abstract] [Full Text] [PDF]
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B. Viollet, M. Foretz, B. Guigas, S. Horman, R. Dentin, L. Bertrand, L. Hue, and F. Andreelli Activation of AMP-activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders J. Physiol., July 1, 2006; 574(1): 41 - 53. [Abstract] [Full Text] [PDF]
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S. Ramamurthy and G. V. Ronnett Developing a head for energy sensing: AMP-activated protein kinase as a multifunctional metabolic sensor in the brain J. Physiol., July 1, 2006; 574(1): 85 - 93. [Abstract] [Full Text] [PDF]
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L. Bertrand, A. Ginion, C. Beauloye, A. D. Hebert, B. Guigas, L. Hue, and J.-L. Vanoverschelde AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H239 - H250. [Abstract] [Full Text] [PDF]
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R. J. McCrimmon, X. Fan, H. Cheng, E. McNay, O. Chan, M. Shaw, Y. Ding, W. Zhu, and R. S. Sherwin Activation of AMP-Activated Protein Kinase Within the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses in Rats With Defective Counterregulation Diabetes, June 1, 2006; 55(6): 1755 - 1760. [Abstract] [Full Text] [PDF]
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F. Andreelli, M. Foretz, C. Knauf, P. D. Cani, C. Perrin, M. A. Iglesias, B. Pillot, A. Bado, F. Tronche, G. Mithieux, et al. Liver Adenosine Monophosphate-Activated Kinase-{alpha}2 Catalytic Subunit Is a Key Target for the Control of Hepatic Glucose Production by Adiponectin and Leptin But Not Insulin Endocrinology, May 1, 2006; 147(5): 2432 - 2441. [Abstract] [Full Text] [PDF]
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K. Sakamoto, E. Zarrinpashneh, G. R. Budas, A.-C. Pouleur, A. Dutta, A. R. Prescott, J.-L. Vanoverschelde, A. Ashworth, A. Jovanovic, D. R. Alessi, et al. Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPK{alpha}2 but not AMPK{alpha}1 Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E780 - E788. [Abstract] [Full Text] [PDF]
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 L. Lin, M. Park, M. Hulver, and D. A. York Different metabolic responses to central and peripheral injection of enterostatin Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2006; 290(4): R909 - R915. [Abstract] [Full Text] [PDF]
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E. C. Nilsson, Y. C. Long, S. Martinsson, S. Glund, P. Garcia-Roves, L. T. Svensson, L. Andersson, J. R. Zierath, and M. Mahlapuu Opposite Transcriptional Regulation in Skeletal Muscle of AMP-activated Protein Kinase {gamma}3 R225Q Transgenic Versus Knock-out Mice J. Biol. Chem., March 17, 2006; 281(11): 7244 - 7252. [Abstract] [Full Text] [PDF]
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Z. Xie, Y. Dong, M. Zhang, M.-Z. Cui, R. A. Cohen, U. Riek, D. Neumann, U. Schlattner, and M.-H. Zou Activation of Protein Kinase C{zeta} by Peroxynitrite Regulates LKB1-dependent AMP-activated Protein Kinase in Cultured Endothelial Cells J. Biol. Chem., March 10, 2006; 281(10): 6366 - 6375. [Abstract] [Full Text] [PDF]
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D. S. Hutchinson and T. Bengtsson AMP-Activated Protein Kinase Activation by Adrenoceptors in L6 Skeletal Muscle Cells: Mediation by {alpha}1-Adrenoceptors Causing Glucose Uptake Diabetes, March 1, 2006; 55(3): 682 - 690. [Abstract] [Full Text] [PDF]
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K. R. Hallows, A. C. Fitch, C. A. Richardson, P. R. Reynolds, J. P. Clancy, P. C. Dagher, L. A. Witters, J. K. Kolls, and J. M. Pilewski Up-regulation of AMP-activated Kinase by Dysfunctional Cystic Fibrosis Transmembrane Conductance Regulator in Cystic Fibrosis Airway Epithelial Cells Mitigates Excessive Inflammation J. Biol. Chem., February 17, 2006; 281(7): 4231 - 4241. [Abstract] [Full Text] [PDF]
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T. M. Wagner, J. E. Mullally, and F. A. Fitzpatrick Reactive Lipid Species from Cyclooxygenase-2 Inactivate Tumor Suppressor LKB1/STK11: CYCLOPENTENONE PROSTAGLANDINS AND 4-HYDROXY-2-NONENAL COVALENTLY MODIFY AND INHIBIT THE AMP-KINASE KINASE THAT MODULATES CELLULAR ENERGY HOMEOSTASIS AND PROTEIN TRANSLATION J. Biol. Chem., February 3, 2006; 281(5): 2598 - 2604. [Abstract] [Full Text] [PDF]
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Y. Dagon, Y. Avraham, I. Magen, A. Gertler, T. Ben-Hur, and E. M. Berry Nutritional Status, Cognition, and Survival: A NEW ROLE FOR LEPTIN AND AMP KINASE J. Biol. Chem., December 23, 2005; 280(51): 42142 - 42148. [Abstract] [Full Text] [PDF]
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A. M. Evans, K. J. W. Mustard, C. N. Wyatt, C. Peers, M. Dipp, P. Kumar, N. P. Kinnear, and D. G. Hardie Does AMP-activated Protein Kinase Couple Inhibition of Mitochondrial Oxidative Phosphorylation by Hypoxia to Calcium Signaling in O2-sensing Cells? J. Biol. Chem., December 16, 2005; 280(50): 41504 - 41511. [Abstract] [Full Text] [PDF]
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 A. K. Al-Hakim, O. Goransson, M. Deak, R. Toth, D. G. Campbell, N. A. Morrice, A. R. Prescott, and D. R. Alessi 14-3-3 cooperates with LKB1 to regulate the activity and localization of QSK and SIK J. Cell Sci., December 1, 2005; 118(23): 5661 - 5673. [Abstract] [Full Text] [PDF]
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S. Foroutan, J. Brillault, B. Forbush, and M. E. O'Donnell Moderate-to-severe ischemic conditions increase activity and phosphorylation of the cerebral microvascular endothelial cell Na+-K+-Cl- cotransporter Am J Physiol Cell Physiol, December 1, 2005; 289(6): C1492 - C1501. [Abstract] [Full Text] [PDF]
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N. Fujii, M. F. Hirshman, E. M. Kane, R. C. Ho, L. E. Peter, M. M. Seifert, and L. J. Goodyear AMP-activated Protein Kinase {alpha}2 Activity Is Not Essential for Contraction- and Hyperosmolarity-induced Glucose Transport in Skeletal Muscle J. Biol. Chem., November 25, 2005; 280(47): 39033 - 39041. [Abstract] [Full Text] [PDF]
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M. Widmer, M. Uldry, and B. Thorens GLUT8 Subcellular Localization and Absence of Translocation to the Plasma Membrane in PC12 Cells and Hippocampal Neurons Endocrinology, November 1, 2005; 146(11): 4727 - 4736. [Abstract] [Full Text] [PDF]
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A. Sofer, K. Lei, C. M. Johannessen, and L. W. Ellisen Regulation of mTOR and Cell Growth in Response to Energy Stress by REDD1 Mol. Cell. Biol., July 15, 2005; 25(14): 5834 - 5845. [Abstract] [Full Text] [PDF]
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B. Kola, E. Hubina, S. A. Tucci, T. C. Kirkham, E. A. Garcia, S. E. Mitchell, L. M. Williams, S. A. Hawley, D. G. Hardie, A. B. Grossman, et al. Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase J. Biol. Chem., July 1, 2005; 280(26): 25196 - 25201. [Abstract] [Full Text] [PDF]
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S.-P. Hong, M. Momcilovic, and M. Carlson Function of Mammalian LKB1 and Ca2+/Calmodulin-dependent Protein Kinase Kinase {alpha} as Snf1-activating Kinases in Yeast J. Biol. Chem., June 10, 2005; 280(23): 21804 - 21809. [Abstract] [Full Text] [PDF]
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E. B. Taylor, W. J. Ellingson, J. D. Lamb, D. G. Chesser, and W. W. Winder Long-chain acyl-CoA esters inhibit phosphorylation of AMP-activated protein kinase at threonine-172 by LKB1/STRAD/MO25 Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1055 - E1061. [Abstract] [Full Text] [PDF]
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