Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cAMP-dependent protein kinase (PKA) phosphorylates CREB327/341 at a single serine residue, Ser119/133, respectively. Phosphorylation at this site creates the sequence motif SXXXS(P), a consensus site of the glycogen synthase kinase-3 (GSK-3) enzyme (Fiol, C.J., Mahrenholz, A.M., Wang, Y., Roeske, R.W., and Roach, P.J. (1987) J. Biol. Chem. 262, 14042-14048). We examined the phosphorylation of CREB at the SXXXS(P) consensus site and its role in CREB transactivation to cAMP induction. Neither isoform of the GSK-3 enzyme (GSK-3 alpha or beta) utilizes CREB as its substrate unless CREB is already phosphorylated at Ser119/133. A 13-amino acid peptide containing the sequence surrounding Ser119/133 was phosphorylated by GSK-3, at Ser115/129, only after the primary phosphorylation of the peptide by PKA (at Ser119/133), suggesting that Ser115/129 is a GSK-3 phosphoacceptor site. Mutant CREB327/341 proteins containing Ser-->Ala substitutions confirmed Ser115/129 as the only GSK-3 phosphorylation site. Transfection assays of wild type and mutant Gal4-CREB fusion proteins in PC12 cells demonstrated that Ser-->Ala substitution of residue 129 of CREB341 impairs the transcriptional response to cAMP induction. Analogous mutation in CREB327 results in 70% decrease in its transactivation response to cAMP. In undifferentiated F9 cells, which are refractory to cAMP induction, transfected GSK-3 beta kinase induces a 60-fold increase in cyclic AMP response element-dependent transcription, mediated via the endogenous CREB protein. We propose that the hierarchical phosphorylation at the PKA and GSK-3 sites of CREB are essential for cAMP control of CREB.
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PMID:A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression. 779 17

Glycogen synthase kinase 3 (GSK-3) is involved in the regulation of several metabolic enzymes and transcription factors in response to extracellular signals. Here we report the use of a synthetic peptide derived from the sequence of the cyclic AMP responsive element binding protein (CREB) as a specific substrate for GSK-3 isoforms. The 13-amino acid peptide, KRREILSRRPSYR, was phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA) and purified on a C18 cartridge. Phosphorylation of the COOH-terminal serine of the peptide by PKA creates a phosphorylation site for GSK-3 since GSK-3 recognizes the consensus motif -S-X-X-X-S(P)-. Although the COOH-terminal serine of the peptide can be phosphorylated by PKA and several other kinases, the phospho-CREB peptide is specific for GSK-3 with Kms of 140 and 200 microM for GSK-3 alpha and GSK-3 beta isoforms, respectively. Using the phospho-CREB peptide, we have successfully purified GSK-3 activity from rabbit skeletal muscle and Escherichia coli cells transformed with a GSK-3 expression vector. The assay described provides a convenient and specific determination of GSK-3 activity.
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PMID:Use of a synthetic peptide as a selective substrate for glycogen synthase kinase 3. 797 84

During the last stage of Dictyostelium development a motile, cylindrical slug transforms into an immotile, stalked fruiting body and the constituent cells change from amoebae to either refractile spores or vacuolated stalk cells. Analysis of this process using genetics and simple culture techniques is becoming a powerful way of investigating a number of conserved signal transduction processes. A common pathway activating cAMP-dependent protein kinase (PKA) triggers the maturation of spore cells and those stalk cells forming the stalk. It uses a eukaryotic version of the 'bacterial' two-component phospho-relay system to control cAMP breakdown. A second pathway, inhibiting the GSK3 protein kinase, might control the maturation of a distinct set of stalk cells at the base of the fruiting body.
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PMID:Taking the plunge. Terminal differentiation in Dictyostelium. 1008 28

The TSC1/2 tumor-suppressor complex controls protein synthesis through the regulation of mTOR. In this issue of Cell, Inoki et al. (2006) report that the kinases GSK3 and AMPK cooperate in the activation of TSC2 to inhibit mTOR activity. Surprisingly, the phosphorylation of TSC2 by GSK3 is markedly suppressed by Wnt signaling. This suggests that components of the mTOR pathway may be therapeutic targets for diseases linked to hyperactive Wnt signaling.
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PMID:Mind the GAP: Wnt steps onto the mTORC1 train. 1695 74

Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.
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PMID:TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. 1695 61

The cardiac glycoside ouabain initiates a cascade of signaling events through Na+,K+-ATPase, leading to an increase in cell growth and proliferation in different cell types. We explored the effects of ouabain on glucose metabolism in skeletal muscle and clarified the mechanisms of ouabain signal transduction. In rat soleus muscle 200 microM ouabain decreased basal glucose uptake without effect on insulin-stimulated glucose uptake. Ouabain increased glycogen synthesis additively to insulin and this effect was abolished in the presence of a MEK1/2 inhibitor (PD98059) or a c-Src inhibitor (PP2). Ouabain exposure reduced glucose oxidation, and this effect was reversed in the presence of PP2. Incubation with ouabain did not affect intramuscular ATP and its metabolites; however acetyl-CoA carboxylase phosphorylation was reduced, with no effect on AMPK phosphorylation. Insulin-stimulated Akt phosphorylation was not affected by ouabain. Ouabain reduced basal and insulin-stimulated phosphorylation of PKC alpha/beta and delta isoforms, whereas phosphorylation of PKCzeta was unchanged. Ouabain exposure increased interaction of 1- and 2-subunits of Na-pump with c-Src, as assessed by co-immunoprecipitation with c-Src. Phosphorylation of ERK1/2, GSK 3 / and p90rsk activity was increased in response to ouabain, and these effects were prevented in the presence of PD98059 and PP2. In conclusion, the cardiac glycoside ouabain stimulates glycogen synthesis additively to insulin in rat skeletal muscle. This effect is mediated by activation of c-Src-, ERK1/2- p90rsk- and GSK3-dependent signaling pathway.
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PMID:Metabolic and signaling events mediated by cardiotonic steroid ouabain in rat skeletal muscle. 1753 36

Mutations in the tumor suppressor genes TSC1 and TSC2, encoding hamartin and tuberin, respectively, cause the tumor syndrome tuberous sclerosis with similar phenotypes. Until now, over 50 proteins have been demonstrated to interact with hamartin and/or tuberin. Besides tuberin, the proteins DOCK7, ezrin/radixin/moesin, FIP200, IKKbeta, Melted, Merlin, NADE(p75NTR), NF-L, Plk1 and TBC7 have been found to interact with hamartin. Whereas Plk1 and TBC7 have been demonstrated not to bind to tuberin, for all the other hamartin-interacting proteins the question, whether they can also bind to tuberin, has not been studied. Tuberin interacts with 14-3-3 beta,epsilon,gamma,eta,sigma,tau,zeta, Akt, AMPK, CaM, CRB3/PATJ, cyclin A, cyclins D1, D2, D3, Dsh, ERalpha, Erk, FoxO1, HERC1, HPV16 E6, HSCP-70, HSP70-1, MK2, NEK1, p27KIP1, Pam, PC1, PP2Ac, Rabaptin-5, Rheb, RxRalpha/VDR and SMAD2/3. 14-3-3 beta,epsilon,gamma,eta,sigma,tau,zeta, Akt, Dsh, FoxO1, HERC1, p27KIP1 and PP2Ac are known not to bind to hamartin. For the other tuberin-interacting proteins this question remains elusive. The proteins axin, Cdk1, cyclin B1, GADD34, GSK3, mTOR and RSK1 have been found to co-immunoprecipitate with both, hamartin and tuberin. The kinases Cdk1 and IKKbeta phosphorylate hamartin, Erk, Akt, MK2, AMPK and RSK1 phosphorylate tuberin, and GSK3 phosphorylates both, hamartin and tuberin. This detailed summary of protein interactions allows new insights into their relevance for the wide variety of different functions of hamartin and tuberin.
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PMID:The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners. 1829 11

In order to evaluate the role of insulin in chicken, an insulin immuno-neutralization was performed. Fed chickens received 1 or 3 i.v. injections of anti-insulin serum (2-h intervals), while fed or fasted controls received normal serum. Measurements included insulin signaling cascade (at 1 h in liver and muscle), metabolic or endocrine plasma parameters (at 1 and 5 h), and qRT-PCR analysis (at 5 h) of 23 genes involved in endocrine regulation, metabolisms, and transcription. Most plasma parameters and food intake were altered by insulin privation as early as 1 h and largely at 5 h. The initial steps of insulin signaling pathways including insulin receptor (IR), IR substrate-1 (IRS-1), and Src homology collagen and downstream elements: phosphatidylinositol 3-kinase (PI3K), Akt, GSK3, ERK2, and S6 ribosomal protein) were accordingly turned off in the liver. In the muscle, IR, IRS-1 tyrosine phosphorylation, and PI3K activity remained unchanged, whereas several subsequent steps were altered by insulin privation. In both tissues, AMPK was not altered. In the liver, insulin privation decreased Egr1, PPAR gamma, SREBP1, THRSP alpha (spot 14), D2-deiodinase, glucokinase (GK), and fatty acid synthase (whereas D3-deiodinase and IGF-binding protein 1 transcripts were up-regulated. Liver SREBP1 and GK and plasma IGFBP1 proteins were accordingly down- and up-regulated. In the muscle, PPAR beta delta and atrogin-1 mRNA increased and Egr1 mRNA decreased. Changes in messengers were partly mimicked by fasting. Thus, insulin signaling in muscle is peculiar in chicken and is strictly dependent on insulin in fed status. The 'diabetic' status induced by insulin immuno-neutralization is accompanied by impairments of glucagon secretion, thyroid axis, and expression of several genes involved in regulatory pathways or metabolisms, evidencing pleiotropic effects of insulin in fed chicken.
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PMID:Insulin immuno-neutralization in chicken: effects on insulin signaling and gene expression in liver and muscle. 1849 18

Excess energy intake via a palatable low-fat diet (cafeteria diet) is known to induce obesity and glucose intolerance in rats. However, the molecular mechanisms behind this adaptation are not known, and it is also not known whether exercise training can reverse it. Male Wistar rats were assigned to 12-wk intervention groups: chow-fed controls (CON), cafeteria diet (CAF), and cafeteria diet plus swimming exercise during the last 4 wk (CAF(TR)). CAF feeding led to increased body weight (16%, P < 0.01) and increased plasma glucose (P < 0.05) and insulin levels (P < 0.01) during an IVGTT, which was counteracted by training. In the perfused hindlimb, insulin-stimulated glucose transport in red gastrocnemius muscle was completely abolished in CAF and rescued by exercise training. Apart from a tendency toward an approximately 20% reduction in both basal and insulin-stimulated Akt Ser(473) phosphorylation (P = 0.051) in the CAF group, there were no differences in insulin signaling (IR Tyr(1150/1151), PI 3-kinase activity, Akt Thr(308), TBC1D4 Thr(642), GSK3-alpha/beta Ser(21/9)) or changes in AMPKalpha1 or -alpha2, GLUT4, Munc18c, or syntaxin 4 protein expression or in phosphorylation of AMPK Thr(172) among the groups. In conclusion, surplus energy intake of a palatable but low-fat cafeteria diet resulted in obesity and insulin resistance that was rescued by exercise training. Interestingly, insulin resistance was not accompanied by major defects in the insulin-signaling cascade or in altered AMPK expression or phosphorylation. Thus, compared with previous studies of high-fat feeding, where insulin signaling is significantly impaired, the mechanism by which CAF diet induces insulin resistance seems different.
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PMID:Cafeteria diet-induced insulin resistance is not associated with decreased insulin signaling or AMPK activity and is alleviated by physical training in rats. 2048 11

Apoptosis provoked by glucose shortage in dividing T cells is mediated via the BH3-only protein Noxa and inhibition of its binding partner Mcl-1. It is unknown how signals from cellular metabolism can affect the balance between Mcl-1 and Noxa and to what extent other Bcl-2 members are involved in this apoptosis cascade. Here, we defined the mechanism underlying apoptosis in relation to various types of metabolic stress. First, we established that the Noxa/Mcl-1 balance is regulated by glucose deprivation as well as by general metabolic stress, via changes in proteasome-mediated degradation of Mcl-1. Second, in contrast with cytokine-deprivation, no transcriptional modulation of Mcl-1, Puma, Bim or Noxa was observed during glucose deprivation. Third, no changes in PKB or GSK3 activity occurred and no clear role for AMPK was detected. Fourth, apoptosis triggered by nutrient deprivation was executed without signs of overt autophagy and independent of ROS production or p38 MAP kinase activity. Lastly, apoptosis under nutrient limitation could also be delayed by knock-down of Bim or overexpression of Bcl-2. In conclusion, Noxa functions in a specific apoptotic pathway that integrates overall nutrient stress, independent from attenuated PI3K/PKB signaling and without clear involvement of autophagy.
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PMID:Apoptosis induced by overall metabolic stress converges on the Bcl-2 family proteins Noxa and Mcl-1. 2151 46


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