Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.27 (AMPK)
 6,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucose homeostasis is regulated systemically by hormones such as insulin and glucagon, and at the cellular level by energy status. Glucagon enhances glucose output from the liver during fasting by stimulating the transcription of gluconeogenic genes via the cyclic AMP-inducible factor CREB (CRE binding protein). When cellular ATP levels are low, however, the energy-sensing kinase AMPK inhibits hepatic gluconeogenesis through an unknown mechanism. Here we show that hormonal and energy-sensing pathways converge on the coactivator TORC2 (transducer of regulated CREB activity 2) to modulate glucose output. Sequestered in the cytoplasm under feeding conditions, TORC2 is dephosphorylated and transported to the nucleus where it enhances CREB-dependent transcription in response to fasting stimuli. Conversely, signals that activate AMPK attenuate the gluconeogenic programme by promoting TORC2 phosphorylation and blocking its nuclear accumulation. Individuals with type 2 diabetes often exhibit fasting hyperglycaemia due to elevated gluconeogenesis; compounds that enhance TORC2 phosphorylation may offer therapeutic benefits in this setting.
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PMID:The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. 1614 43

Hormone-sensitive lipase (HSL) is important for the degradation of triacylglycerol in adipose and muscle tissue, but the tissue-specific regulation of this enzyme is not fully understood. We investigated the effects of adrenergic stimulation and AMPK activation in vitro and in circumstances where AMPK activity and catecholamines are physiologically elevated in humans in vivo (during physical exercise) on HSL activity and phosphorylation at Ser(563) and Ser(660), the PKA regulatory sites, and Ser(565), the AMPK regulatory site. In human experiments, skeletal muscle, subcutaneous adipose and venous blood samples were obtained before, at 15 and 90 min during, and 120 min after exercise. Skeletal muscle HSL activity was increased by approximately 80% at 15 min compared with rest and returned to resting rates at the cessation of and 120 min after exercise. Consistent with changes in plasma epinephrine, skeletal muscle HSL Ser(563) and Ser(660) phosphorylation were increased by 27% at 15 min (P < 0.05), remained elevated at 90 min, and returned to preexercise values postexercise. Skeletal muscle HSL Ser(565) phosphorylation and AMPK signaling were increased at 90 min during, and after, exercise. Phosphorylation of adipose tissue HSL paralleled changes in skeletal muscle in vivo, except HSL Ser(660) was elevated 80% in adipose compared with 35% in skeletal muscle during exercise. Studies in L6 myotubes and 3T3-L1 adipocytes revealed important tissue differences in the regulation of HSL. AMPK inhibited epinephrine-induced HSL activity in L6 myotubes and was associated with reduced HSL Ser(660) but not Ser(563) phosphorylation. HSL activity was reduced in L6 myotubes expressing constitutively active AMPK, confirming the inhibitory effects of AMPK on HSL activity. Conversely, in 3T3-L1 adipocytes, AMPK activation after epinephrine stimulation did not prevent HSL activity or glycerol release, which coincided with maintenance of HSL Ser(660) phosphorylation. Taken together, these data indicate that HSL activity is maintained in the face of AMPK activation as a result of elevated HSL Ser(660) phosphorylation in adipose tissue but not skeletal muscle.
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PMID:Regulation of HSL serine phosphorylation in skeletal muscle and adipose tissue. 1618 6

Members of the Snf1/AMPK family of protein kinases are activated by distinct upstream kinases that phosphorylate a conserved threonine residue in the Snf1/AMPK activation loop. Recently, the identities of the Snf1- and AMPK-activating kinases have been determined. Here we describe the purification and characterization of the three Snf1-activating kinases of Saccharomyces cerevisiae. The identities of proteins associated with the Snf1-activating kinases were determined by peptide mass fingerprinting. These kinases, Sak1, Tos3 and Elm2 do not appear to require the presence of additional subunits for activity. Sak1 and Snf1 co-purify and co-elute in size exclusion chromatography, demonstrating that these two proteins form a stable complex. The Snf1-activating kinases phosphorylate the activation loop threonine of Snf1 in vitro with great specificity and are able to do so in the absence of beta and gamma subunits of the Snf1 heterotrimer. Finally, we showed that the Snf1 kinase domain isolated from bacteria as a GST fusion protein can be activated in vitro and shows substrate specificity in the absence of its beta and gamma subunits.
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PMID:Purification and characterization of the three Snf1-activating kinases of Saccharomyces cerevisiae. 1620 71

Protein synthesis in skeletal muscle is known to decrease during contractions but the underlying regulatory mechanisms are unknown. Here, the effect of exercise on skeletal muscle eukaryotic elongation factor 2 (eEF2) phosphorylation, a key component in protein translation machinery, was examined. Eight healthy men exercised on a cycle ergometer at a workload eliciting approximately 67% peak pulmonary oxygen consumption (VO2 peak) with skeletal muscle biopsies taken from the vastus lateralis muscle at rest as well as after 1, 10, 30, 60 and 90 min of exercise. In response to exercise, there was a rapid (i.e. < 1 min) 5- to 7-fold increase in eEF2 phosphorylation at Thr56 that was sustained for 90 min of continuous exercise. The in vitro activity of skeletal muscle eEF2 kinase was not altered by exercise indicating that the increased activity of eEF2 kinase to eEF2 is not mediated by covalent mechanisms. In support of this, the increase in AMPK activity was temporally unrelated to eEF2 phosphorylation. However, skeletal muscle eEF2 kinase was potently activated by Ca(2)(+)-calmodulin in vitro, suggesting that the higher eEF2 phosphorylation in working skeletal muscle is mediated by allosteric activation of eEF2 kinase by Ca(2)(+) signalling via calmodulin. Given that eEF2 phosphorylation inhibits eEF2 activity and mRNA translation, these findings suggest that the inhibition of protein synthesis in contracting skeletal muscle is due to the Ca(2)(+)-induced stimulation of eEF2 kinase.
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PMID:Exercise rapidly increases eukaryotic elongation factor 2 phosphorylation in skeletal muscle of men. 1621 Mar 46

A portal venous 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion that results in hepatic 5-aminoimidazole-4-carboxamide-1-beta-D-ribosyl-5-monophosphate (ZMP) concentrations of approximately 4 micromol/g liver increases hepatic glycogenolysis and glucose output. ZMP is an AMP analog that mimics the regulatory actions of this nucleotide. The aim of this study was to measure hepatic AMP concentrations in response to increasing energy requirements to test the hypothesis that AMP achieves concentrations during exercise, consistent with a role in stimulation of hepatic glucose metabolism. Male C57BL/6J mice (27.4+/- 0.4 g) were subjected to 35 min of rest [sedentary (SED), n=8], underwent short-term (ST, 35 min) moderate (20 m/min, 5% grade) exercise (n=8), or underwent treadmill exercise under similar conditions but until exhaustion (EXH, n=8). Hepatic AMP concentrations were 0.82+/- 0.05, 1.17+/- 0.11, and 2.52+/- 0.16 micromol/g liver in SED, ST, and EXH mice, respectively (P< 0.05). Hepatic energy charge was 0.66+/- 0.01, 0.58+/- 0.02, and 0.33+/- 0.22 in SED, ST, and EXH mice, respectively (P< 0.05). Hepatic glycogen was 11.6+/- 1.0, 8.8+/- 2.2, and 0.0+/- 0.1 mg/g liver in SED, ST, and EXH mice, respectively (P< 0.05). Hepatic AMPK (Thr(172)) phosphorylation was 1.00+/- 0.14, 1.96+/- 0.16, and 7.44+/- 0.63 arbitrary units in SED, ST, and EXH mice, respectively (P< 0.05). Thus exercise increases hepatic AMP concentrations. These data suggest that the liver is highly sensitive to metabolic demands, as evidenced by dramatic changes in cellular energy indicators (AMP) and sensors thereof (AMP-activated protein kinase). In conclusion, AMP is sensitively regulated, consistent with it having an important role in hepatic metabolism.
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PMID:Energy state of the liver during short-term and exhaustive exercise in C57BL/6J mice. 1621 65

The mammalian TOR (mTOR) pathway is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human diseases, including cancer and diabetes. The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism. Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.
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PMID:Growing roles for the mTOR pathway. 1622 44

The mechanisms controlling fat depot-specific metabolism are poorly understood. During starvation of mice, downregulation of lipogenic genes, suppression of fatty acid synthesis, and increases in lipid oxidation were all more pronounced in epididymal than in subcutaneous fat. In epididymal fat, relatively strong upregulation of uncoupling protein 2 and phosphoenolpyruvate carboxykinase genes was found. In mice maintained both at 20 and 30 degrees C, AMP-activated protein kinase was activated in epididymal but did not change in subcutaneous fat. Our results suggest that AMPK may have a role in the different response of various fat depots to starvation.
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PMID:Involvement of AMP-activated protein kinase in fat depot-specific metabolic changes during starvation. 1622 40

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is characterized by benign tumors (hamartomas and hamartias) involving multiple organ systems, due to inactivating mutations in TSC1 or TSC2. Here, we review recent advances in our understanding of the growth and signaling functions of the TSC1 and TSC2 proteins. Led by seminal studies in Drosophila, the TSC1/TSC2 complex has been positioned in an ancestrally conserved signaling pathway that regulates cell growth. TSC1/TSC2 receives inputs from at least three major signaling pathways in the form of kinase-mediated phosphorylation events that regulate its function as a GTPase activating protein (GAP): the PI3K-Akt pathway, the ERK1/2-RSK1 pathway and the LKB1-AMPK pathway. TSC1/TSC2 functions as a GAP towards Rheb, which is a major regulator of the mammalian target of rapamycin (mTOR). In the absence of either TSC1 or TSC2, high levels of Rheb-GTP lead to constitutive activation of mTOR-raptor signaling, thereby leading to enhanced and deregulated protein synthesis and cell growth. As a specific inhibitor of mTOR, rapamycin has therapeutic potential for the treatment of TSC hamartomas.
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PMID:Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. 1624 23

Skeletal muscle from strength- and endurance-trained individuals represents diverse adaptive states. In this regard, AMPK-PGC-1alpha signaling mediates several adaptations to endurance training, while up-regulation of the Akt-TSC2-mTOR pathway may underlie increased protein synthesis after resistance exercise. We determined the effect of prior training history on signaling responses in seven strength-trained and six endurance-trained males who undertook 1 h cycling at 70% VO2peak or eight sets of five maximal repetitions of isokinetic leg extensions. Muscle biopsies were taken at rest, immediately and 3 h postexercise. AMPK phosphorylation increased after cycling in strength-trained (54%; P<0.05) but not endurance-trained subjects. Conversely, AMPK was elevated after resistance exercise in endurance- (114%; P<0.05), but not strength-trained subjects. Akt phosphorylation increased in endurance- (50%; P<0.05), but not strength-trained subjects after cycling but was unchanged in either group after resistance exercise. TSC2 phosphorylation was decreased (47%; P<0.05) in endurance-trained subjects following resistance exercise, but cycling had little effect on the phosphorylation state of this protein in either group. p70S6K phosphorylation increased in endurance- (118%; P<0.05), but not strength-trained subjects after resistance exercise, but was similar to rest in both groups after cycling. Similarly, phosphorylation of S6 protein, a substrate for p70 S6K, was increased immediately following resistance exercise in endurance- (129%; P<0.05), but not strength-trained subjects. In conclusion, a degree of "response plasticity" is conserved at opposite ends of the endurance-hypertrophic adaptation continuum. Moreover, prior training attenuates the exercise specific signaling responses involved in single mode adaptations to training.
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PMID:Early signaling responses to divergent exercise stimuli in skeletal muscle from well-trained humans. 1626 23

This study examined the effects of three different cellular stresses on oocyte maturation in meiotically arrested mouse oocytes. Cumulus-cell enclosed oocytes (CEO) or denuded oocytes (DO) from immature, eCG-primed mice were cultured for 17-18 h in dbcAMP-containing medium plus increasing concentrations of the metabolic poison, sodium arsenite, or the free radical-generating agent, menadione. Alternatively, oocytes were exposed to osmotic stress by pulsing with sorbitol and returned to control inhibitory conditions for the duration of culture. Arsenite and menadione each dose-dependently induced germinal vesicle breakdown (GVB) in both DO and CEO. DO, but not CEO, pulsed for 60 min with 500 mM sorbitol were stimulated to resume maturation. The lack of effect in CEO suggests that the cumulus cells may be playing a protective role in osmotic stress-induced GVB. The AMP-activated protein kinase (PRKA; formerly known as AMPK) inhibitors, compound C and araA, completely blocked the meiosis-stimulating effects of all the tested stresses. Western blots showed that acetyl-CoA carboxylase, an important substrate of PRKA, was phosphorylated before GVB, supporting a role for PRKA in stress-induced maturation. Together, these data show that a variety of stresses stimulate GVB in meiotically arrested mouse oocytes in vitro and suggest that this effect is mediated through activation of PRKA.
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PMID:Stress stimulates AMP-activated protein kinase and meiotic resumption in mouse oocytes. 1628 Apr 15


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