EC:2.7.11.26 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: EC:2.7.11.26 (GSK)
6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6x10 repetitions of 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3- and 2.7-fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by approximately 2-fold and increased PGC-1alpha protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3beta at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E-BP1, eIF-2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK-PGC-1alpha signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB-TSC2-mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the "AMPK-PKB switch." We hypothesize that the AMPK-PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.
...
PMID:Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation. 1571 93

Obesity, a state of apparent "leptin resistance" is well known to be associated with insulin resistance. In diet-induced obesity (DIO), hepatic insulin signaling is impaired but the link between leptin and insulin signaling pathways is only incompletely defined. The aim of the present study was to evaluate the effects of DIO on leptin and insulin cross-signaling in the liver. Leptin receptor expression was measured by in situ hybridization with pan-leptin receptor probes and by immunoblotting. Furthermore, intracellular signaling was investigated in vivo under basal conditions and at 45 and 360 min after stimulation with a bolus of human recombinant leptin (hrec-leptin; 1 mg/kg body wt) or saline. At baseline, all forms of the leptin receptor were markedly to completely down-regulated in DIO rats. Hrec-leptin bolus injection stimulated leptin-dependent signaling with a fivefold increase in JAK-2pY in lean but not in DIO rats. Basal IRpY, IRS-1pY, IRS-1p85, IRS-2pY, IRSp85, and PKBpT308 levels were reduced (P<0.01) in DIO rats as compared with lean controls. Basal GSK-3beta serine phosphorylation (S9) was higher (P<0.01) in lean animals along with lower basal PEPCK activity compared with DIO rats consistent with the insulin and leptin resistance of the latter. Only in lean animals phosphorylation of PKB (T308) and GSK-3beta (S9) was acutely stimulated by leptin at 45 min followed by inhibition at 6 h after application. AMPKalpha protein levels as well as basal and leptin-stimulated total and alpha-specific AMPK activity were comparable in both groups. These data show that in a model of dietary-induced obesity 1) leptin receptors and subsequent signaling events are down-regulated, 2) basal insulin signaling is impaired, and 3) the cross-talk between leptin and insulin signaling is differentially regulated by the nutritional status, which is sensed by AMPK in rat liver. Thus, the liver seems to play a major role in the modulation of the leptin signal and insulin resistance in obesity.
...
PMID:Hepatic leptin signaling in obesity. 1578 47

Ischemic preconditioning confers powerful protection against myocardial infarction through pre-emptive activation of survival signaling pathways, but it remains difficult to apply to patients with ischemic heart disease, and its effects are transient. Promoting a sustained activation of preconditioning mechanisms in vivo would represent a novel approach of cardioprotection. We tested the role of the protein H11 kinase (H11K), which accumulates by 4- to 6-fold in myocardium of patients with chronic ischemic heart disease and in experimental models of ischemia. This increased expression was quantitatively reproduced in cardiac myocytes using a transgenic (TG) mouse model. After 45 minutes of coronary artery occlusion and reperfusion, hearts from TG mice showed an 82+/-5% reduction in infarct size compared with wild-type (WT), which was similar to the 84+/-4% reduction of infarct size observed in WT after a protocol of ischemic preconditioning. Hearts from TG mice showed significant activation of survival kinases participating in preconditioning, including Akt and the 5'AMP-activated protein kinase (AMPK). H11K directly binds to both Akt and AMPK and promotes their nuclear translocation and their association in a multiprotein complex, which results in a stimulation of survival mechanisms in cytosol and nucleus, including inhibition of proapoptotic effectors (glycogen synthase kinase-3beta, Bad, and Foxo), activation of antiapoptotic effectors (protein kinase Cepsilon, endothelial and inducible NO synthase isoforms, and heat shock protein 70), increased expression of the hypoxia-inducible factor-1alpha, and genomic switch to glucose utilization. Therefore, activation of survival pathways by H11K preemptively triggers the antiapoptotic and metabolic response to ischemia and is sufficient to confer cardioprotection in vivo equally potent to preconditioning.
...
PMID:H11 kinase prevents myocardial infarction by preemptive preconditioning of the heart. 1637 98

AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis and its activation during T cell receptor stimulation has recently been reported. In this study, we examined the role of AMPK in interleukin (IL)-2 production in T cells. Inhibition of AMPK by compound C, a specific inhibitor of AMPK or small interfering RNA of AMPKalpha1 suppressed IL-2 production in Jurkat T cells and peripheral blood lymphocytes stimulated with PMA plus ionomycin (PMA/Io) or with monoclonal anti-CD3 plus anti-CD28. We then showed that AMPK inhibition reduced PMA/Io-induced IL-2 mRNA expression and IL-2 promoter activation. Moreover, inhibition of AMPK suppressed transcriptional activation of NF-AT and AP-1, but not NF-kappaB, in PMA/Io-activated Jurkat cells. Finally, we found that compound C inhibited PMA/Io-induced phosphorylation of p38, JNK, and GSK-3beta but not of ERK. These results suggest that AMPK mediates IL-2 production by regulating NF-AT and AP-1activation during T cell stimulation.
...
PMID:Inhibition of AMP-activated protein kinase suppresses IL-2 expression through down-regulation of NF-AT and AP-1 activation in Jurkat T cells. 1709 50

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.
...
PMID:Metabolic and signaling events mediated by cardiotonic steroid ouabain in rat skeletal muscle. 1753 36

5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a commonly used pharmacological agent to study physiological effects which are similar to those of exercise. However, signal transduction pathways by which AICAR elicits downstream effects in liver are poorly understood. We report here that AICAR not only activated AMPK but also phosphorylated/deactivated glycogen synthase kinase-3 alpha/beta (GSK-3alpha/beta) and dephophorylated/activated glycogen synthase (GS) in a time-dependent manner in human hepatoma HepG2 cells. The signal connection between AICAR and GSK-3 is indirect and involves activation of Raf-1/MEK/p42/44(MAPK)/p90(RSK) signaling cascade as pharmacologic inhibition of MEK significantly reduced phosphorylation/deactivation of GSK-3 and consequent dephosphorylation/activation of GS. Moreover, silencing the expression of p90(RSK), a substrate of p42/44(MAPK), attenuated AICAR-dependent GSK-3 phosphorylation, implicating this kinase as a key mediator of AICAR signaling to GSK-3. Furthermore, consistent with the involvement of Raf-1 kinase cascade, AICAR-induced low-density lipoprotein (LDL) receptor expression in a p42/44(MAPK)-dependent manner. Finally, AICAR requires AMPK-alpha2-dependent and -independent pathways to activate Raf-1 kinase cascade as suppression of AMPKalpha2 activity, and not of AMPKalpha1, partially blocked AICAR-dependent p42/44(MAPK) activation and GSK-3 phosphorylation/deactivation. Collectively, these results highlight Raf-1 signaling cascade as the critical mediator of AICAR action on glucose and lipid metabolism in HepG2 cells.
...
PMID:AICAR positively regulate glycogen synthase activity and LDL receptor expression through Raf-1/MEK/p42/44MAPK/p90RSK/GSK-3 signaling cascade. 1794 90

Lithium has been shown to be neuroprotective against various insults including ethanol exposure. We previously reported that ethanol-induced apoptotic neurodegeneration in the postnatal day 7 (P7) mice is associated with decreases in phosphorylation levels of Akt, glycogen synthase kinase-3beta (GSK-3beta), and AMP-activated protein kinase (AMPK), and alteration in lipid profiles in the brain. Here, P7 mice were injected with ethanol and lithium, and the effects of lithium on ethanol-induced alterations in phosphorylation levels of protein kinases and lipid profiles in the brain were examined. Immunoblot and immunohistochemical analyses showed that lithium significantly blocked ethanol-induced caspase-3 activation and reduction in phosphorylation levels of Akt, GSK-3beta, and AMPK. Further, lithium inhibited accumulation of cholesterol ester (ChE) and N-acylphosphatidylethanolamine (NAPE) triggered by ethanol in the brain. These results suggest that Akt, GSK-3beta, and AMPK are involved in ethanol-induced neurodegeneration and the neuroprotective effects of lithium by modulating both apoptotic and survival pathways.
...
PMID:Lithium blocks ethanol-induced modulation of protein kinases in the developing brain. 1819 Jul 91

Although Na(+)-H(+) exchanger 1 (NHE-1) inhibition has been demonstrated to have anti-hypertrophic effect indirectly through mitochondria, the detailed cellular mechanisms mediating this effect remain elusive. In this study we sought to determine whether NHE-1 inhibition exerts an anti-hypertrophic effect by modulating the mitochondrial permeability transition pore (mPTP) opening through the AMP-activated protein kinase (AMPK)/glycogen synthase kinase 3beta (GSK-3beta) pathway during hypertrophy in cardiomyocytes. An in vivo model of hypertrophy was induced in male Sprague-Dawley rats by subjecting them to 3, 7 or 28 days of coronary artery ligation (CAL). To induce hypertrophy in vitro, cardiomyocytes isolated from hearts of neonatal (1-3 days) Sprague-Dawley rats were exposed to endothelin-1 (ET-1, 10 nM) in the presence or absence of various treatments. The results demonstrate that CAL affected both AMPKalpha and GSK-3beta phosphorylation in a time-dependent manner. In cultured cardiomyocytes, ET-1 increased phosphorylation of AMPKalpha(1)/alpha(2)(Ser485/Ser491) and GSK-3beta(Ser9) by 80% (P<0.05) and 225% (P<0.05) respectively, both of which were significantly blunted by the NHE-1 inhibitor AVE-4890 (5 microM). ET-1-induced phosphorylation of GSK-3beta(Ser9) was attenuated by inhibitors of phosphatidylinositol 3-kinase (LY294002), Akt (Akt inhibitor VIII), ERK1/2 (PD98059) and by the AMPK agonist 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). Prevention of GSK-3beta(Ser9) phosphorylation was also accompanied by suppression of ET-1-induced increases in cell surface area, ANP and alpha-skeletal actin gene expression. Co-immunoprecipitation studies revealed that GSK-3beta interacts with components of the mPTP, voltage-dependent anion channel (VDAC) and adenine nucleotide translocase. Furthermore, ET-1 reduced phosphorylation of VDAC, which was associated with both mPTP opening and mitochondrial membrane depolarization. These effects were mimicked by the GSK-3beta inhibitor SB216763, thus showing that modulation of mPTP formation is GSK-3beta-dependent. In conclusion, anti-hypertrophic effect of NHE-1 inhibition can be mediated through activation of GSK-3beta which in turn induces inhibition of mPTP opening due to VDAC phosphorylation.
...
PMID:Anti-hypertrophic effect of NHE-1 inhibition involves GSK-3beta-dependent attenuation of mitochondrial dysfunction. 1931 34

We have previously demonstrated that Leptin reduces extracellular amyloid beta (Abeta) protein both in vitro and in vivo, and intracellular tau phosphorylation in vitro. Further, we have shown that these effects are dependent on activation of AMP-activated protein kinase (AMPK) in vitro. Herein, we investigated downstream effectors of AMPK signaling directly linked to tau phosphorylation. One such target, of relevance to Alzheimer's disease (AD), may be GSK-3beta, which has been shown to be inactivated by Leptin. We therefore dissected the role of GSK-3beta in mediating Leptin's ability to reduce tau phosphorylation in neuronal cells. Our data suggest that Leptin regulates tau phosphorylation through a pathway involving both AMPK and GSK-3beta. This was based on the following: Leptin and the cell-permeable AMPK activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), reduced tau phosphorylation at AD-relevant sites similarly to the GSK-3beta inhibitor, lithium chloride (LiCl). Further, this reduction of tau phosphorylation was mimicked by the downregulation of GSK-3beta, achieved using siRNA technology and antagonized by the ectopic overexpression of GSK-3beta. These studies provide further insight into Leptin's mechanism of action in suppressing AD-related pathways.
...
PMID:Leptin inhibits glycogen synthase kinase-3beta to prevent tau phosphorylation in neuronal cells. 1942 19

5-[5-(2-Nitrophenyl) furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101) is a protease inhibitor which was reported to protect against ischaemic heart damage and apoptosis. This study evaluated the impact of UCF-101 on steptozotocin (STZ)-induced diabetic cardiomyocyte dysfunction. Adult FVB mice were made diabetic with a single injection of STZ (200 mg kg(1)). Two weeks after STZ injection, cardiomyocytes from control and STZ-treated mice were isolated and treated with UCF-101 (20 mum for 1 h). Cardiomyocyte contractile properties were analysed, including peak shortening (PS), maximal velocity of shortening/relengthening (+/-dL/dt), time to PS (TPS) and time to 90% relengthening (TR(90)). Steptozotocin-induced diabetes depressed PS and +/-dL/dt and prolonged TPS and TR(90) in cardiomyocytes, all of which were significantly alleviated by UCF-101. Immunoblotting analysis showed that UCF-101 significantly alleviated STZ-induced loss of phospholamban phosphorylation without affecting sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban. Steptozotocin reduced AMP-activated protein kinase (AMPK) phosphorylation at Thr172 of the catalytic subunit without affecting total AMPK expression, which was restored by UCF-101. Short-term exposure to UCF-101 did not change the expression of X-linked inhibitor of apoptosis protein (XIAP) and Omi stress-regulated endoprotease, high temperature requirement protein A2 (Omi/HtrA2), favouring an apoptosis-independent mechanism. Both the AMPK activator resveratrol and the antioxidant N-acetylcysteine mimicked the UCF-101-induced beneficial effect in STZ-induced diabetic cardiomyocytes. In addition, UCF-101 promoted the phosphorylation of p38 mitogen-activated protein kinases and c-Jun N-terminal kinase (JNK) after 15 min of incubation, while it failed to affect the phosphorylation of extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK-3beta) within 120 min in H9C2 myoblasts. Taken together, these results indicate that UCF-101 protects against STZ-induced cardiomyocyte contractile dysfunction, possibly via an AMPK-associated mechanism.
...
PMID:The protease inhibitor UCF-101 ameliorates streptozotocin-induced mouse cardiomyocyte contractile dysfunction in vitro: role of AMP-activated protein kinase. 2751 Jun 42

1 2 3 4 5 6 7 8 9 10 Next >>