Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperhomocysteinemia and insulin resistance are independent factors for cardiovascular disease. Most of the angiotoxic effects of homocysteine are related to the formation of homocysteine thiolactone and the consequent increase in oxidative stress. We have recently found that homocysteine thiolactone inhibits insulin receptor tyrosine kinase activity, which results in decreased phosphatidylinositol 3-kinase (PI3K) activity and inhibition of glycogen synthesis. Oxidative stress seemed to be the mechanism underlying these effects, since glutathione was able to restore the insulin signaling as well as the insulin-mediated glycogen synthesis. In the present work we have further investigated insulin receptor signaling studying mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3 (GSK-3) and p70 S6K phosphorylation. Again, homocysteine thiolactone (50 microM) prevented insulin-mediated MAPK, GSK-3 and p70 S6K phosphorylation and these effects were blocked by glutathione (250 microM). Since MAPK and PI3K pathways, including GSK3 and S6K, seem to mediate insulin-mediated growth and proliferation, we measured DNA and protein synthesis. We have found that homocysteine thiolactone (50 microM) inhibits insulin-mediated growth and proliferation, as previously shown for glycogen synthesis. Again, these effects seem to be mediated by oxidative stress, since 250 microM glutathione completely abolished the effects of homocysteine thiolactone on insulin-stimulated DNA and protein synthesis. In conclusion, these data suggest that homocysteine thiolactone impairs insulin signaling by a mechanism involving oxidative stress, leading to a defect in the action of insulin on growth and proliferation.
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PMID:Homocysteine thiolactone inhibits insulin-stimulated DNA and protein synthesis: possible role of mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3 (GSK-3) and p70 S6K phosphorylation. 1569 82

The molecular mechanisms underlying the pathogenesis of the malignant Hodgkin's/Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL) are largely unknown. This study investigates the contribution of phosphatidyl-inositide 3 kinase (PI3-kinase) and demonstrates that Akt, a substrate of PI3-kinase, is constitutively activated in HL-derived cell lines. Several downstream effectors of Akt signalling, including glycogen synthase kinase 3 (GSK-3) alpha and beta and mTOR substrates 4E-BP1 and p70 S6 kinase, were also phosphorylated in HL cells. The mTOR inhibitor, rapamycin, inhibited phosphorylation of these proteins. Furthermore, LY294002 inhibited phosphorylation of p70 S6 kinase and 4E-BP1, suggesting that the phosphorylation of p70 S6 kinase and 4E-BP1 in HL cells is PI3-kinase dependent. Importantly, HRS cells of primary tumour samples not only expressed high levels of activated Akt but also displayed phosphorylation of downstream targets of Akt activation including GSK-3, 4E-BP1, and p70 S6 Kinase. Inhibition of PI3-kinase and mTOR showed only modest effects on cell survival at the lower serum concentrations. However, rapamycin and doxorubicin acted synergistically to reduce HL cell survival. A combination of rapamycin and chemotherapy should be investigated in the treatment of HL.
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PMID:Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin's lymphoma cells through a mechanism involving Akt kinase and mTOR. 1571 59

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.
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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

We and others reported previously that IGF-I inhibits dexamethasone-induced proteolysis in cultured L6 myotubes. Recent evidence suggests that this effect of IGF-I at least in part reflects PI3K/Akt-mediated inhibition of Foxo transcription factors. The potential role of other mechanisms, downstream of PI3K/Akt, is not well understood. Here we tested the hypothesis that PI3K/Akt-mediated inactivation of GSK-3beta and activation of mTOR contribute to the anabolic effects of IGF-I in dexamethasone-treated myotubes. Cultured L6 myotubes were treated with 1 microM dexamethasone in the absence or presence of 0.1 microg/ml of IGF-I and inhibitors of GSK-3beta and mTOR. Protein degradation was measured by determining the release of trichloroacetic acid soluble radioactivity from myotubes that had been prelabeled with (3)H-tyrosine for 48 h. IGF-I reduced basal protein breakdown rates and completely abolished the dexamethasone-induced increase in myotube proteolysis. These effects of IGF-I were associated with increased phosphorylation of Akt, GSK-3beta, and the mTOR downstream targets p70(S6K) and 4E-BP1. The PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin reversed the anabolic effect of IGF-I in dexamethasone-treated myotubes. In addition, the GSK-3beta inhibitors LiCl and TDZD-8 reduced protein degradation in a similar fashion as IGF-I. Our results suggest that PI3K/Akt-mediated inactivation of GSK-3beta and activation of mTOR contribute to the anabolic effects of IGF-I in dexamethasone-treated myotubes.
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PMID:Insulin-like growth factor-I inhibits dexamethasone-induced proteolysis in cultured L6 myotubes through PI3K/Akt/GSK-3beta and PI3K/Akt/mTOR-dependent mechanisms. 1592 18

In this study we compared the content and phosphorylation levels of several molecules believed to regulate muscle hypertrophy and fiber type changes in the extensor digitorum longus (EDL), soleus, diaphragm, and heart of adult (6 months), aged (30 months), and very aged (36 months) Fischer 344 x Brown Norway rats. With aging, the mass of the EDL and soleus decreased significantly (approximately 38% and approximately 36%, respectively), the diaphragm's mass remained unchanged while the mass of the heart increased (approximately 35%). Western blotting demonstrated that calcineurin (CnA), the 70-kDa ribosomal S6 kinase (p70(S6k)), glycogen synthase kinase-3beta (GSK-3beta), and the phosphorylated forms of GSK-3beta and p70(S6k) (p-GSK-3beta(Ser9) and p-p70(S6kThr389)) were regulated differently with aging and between muscle types. Total p70(S6k), GSK-3beta, and p-GSK-3beta(Ser9) decreased in the aged-atrophic EDL and soleus while p-p70(S6kThr389) increased. Although total p70(S6k) content diminished in the continuously active diaphragm, phosphorylation of p70(S6k )remained unchanged. Conversely, the expression of GSK-3beta and p-GSK-3beta(Ser9) increased in the diaphragm. With aging, the amount of p-p70(S6kThr389) decreased approximately 56% in the heart while p-GSK-3beta( Ser9) increased approximately 193%. Interestingly, CnA content remained unchanged in the diaphragm, increased approximately 204% in the EDL, and decreased approximately 30% and approximately 65% with aging in the soleus and heart, respectively. These results indicate remarkable differences in the regulation of molecules thought to govern protein synthesis and changes in contractile protein expression.
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PMID:Regulation of p70S6k, GSK-3beta, and calcineurin in rat striated muscle during aging. 1604 21

The molecular mechanisms influencing muscle atrophy in humans are poorly understood. Atrogin-1 and MuRF1, two ubiquitin E3-ligases, mediate rodent and cell muscle atrophy and are suggested to be regulated by an Akt/Forkhead (FKHR) signaling pathway. Here we investigated the expression of atrogin-1, MuRF1, and the activity of Akt and its catabolic (FKHR and FKHRL1) and anabolic (p70(s6k) and GSK-3beta) targets in human skeletal muscle atrophy. The muscle atrophy model used was amyotrophic lateral sclerosis (ALS). All measurements were performed in biopsies from 22 ALS patients and 16 healthy controls as well as in G93A ALS mice. ALS patients had a significant increase in atrogin-1 mRNA and protein content, which was associated with a decrease in Akt activity. There was no difference in the mRNA and protein content of FKHR, FKHRL1, p70(s6k), and GSK-3beta. Similar observations were made in the G93A ALS mice. Human skeletal muscle atrophy, as seen in the ALS model, is associated with an increase in atrogin-1 and a decrease in Akt. The transcriptional regulation of human atrogin-1 may be controlled by an Akt-mediated transcription factor other than FKHR or via another signaling pathway.
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PMID:Human skeletal muscle atrophy in amyotrophic lateral sclerosis reveals a reduction in Akt and an increase in atrogin-1. 1650 68

Proliferation of activated hepatic stellate cells (HSC) is an important event in the development of hepatic fibrosis. Insulin-like growth factor-1 (IGF-1) has been shown to be mitogenic for HSC, but the intracellular signaling pathways involved have not been fully characterized. Thus, the aims of the current study were to examine the roles of the extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3-K) and p70-S6 kinase (p70-S6-K) signaling pathways in IGF-1- and platelet-derived growth factor (PDGF)-induced mitogenic signaling of HSC and to examine the potential crosstalk between these pathways. Both IGF-1 and PDGF increased ERK, PI3-K and p70-S6-K activity. When evaluating potential crosstalk between these signaling pathways, we observed that PI3-K is required for p70-S6-K activation by IGF-1 and PDGF, and is partially responsible for PDGF-induced ERK activation. PDGF and IGF-1 also increased the levels of cyclin D1 and phospho-glycogen synthase kinase-3beta. Coordinate activation of ERK, PI3-K and p70-S6-K is important for perpetuating the activated state of HSC during fibrogenesis.
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PMID:Coordinate activation of intracellular signaling pathways by insulin-like growth factor-1 and platelet-derived growth factor in rat hepatic stellate cells. 1669 71

Skeletal muscle size is tightly regulated by the synergy between anabolic and catabolic signalling pathways which, in humans, have not been well characterized. Akt has been suggested to play a pivotal role in the regulation of skeletal muscle hypertrophy and atrophy in rodents and cells. Here we measured the amount of phospho-Akt and several of its downstream anabolic targets (glycogen synthase kinase-3beta (GSK-3beta), mTOR, p70(s6k) and 4E-BP1) and catabolic targets (Foxo1, Foxo3, atrogin-1 and MuRF1). All measurements were performed in human quadriceps muscle biopsies taken after 8 weeks of both hypertrophy-stimulating resistance training and atrophy-stimulating de-training. Following resistance training a muscle hypertrophy ( approximately 10%) and an increase in phospho-Akt, phospho-GSK-3beta and phospho-mTOR protein content were observed. This was paralleled by a decrease in Foxo1 nuclear protein content. Following the de-training period a muscle atrophy (5%), relative to the post-training muscle size, a decrease in phospho-Akt and GSK-3beta and an increase in Foxo1 were observed. Atrogin-1 and MuRF1 increased after the hypertrophy and decreased after the atrophy phases. We demonstrate, for the first time in human skeletal muscle, that the regulation of Akt and its downstream signalling pathways GSK-3beta, mTOR and Foxo1 are associated with both the skeletal muscle hypertrophy and atrophy processes.
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PMID:Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy. 1691 7

Hormones and growth factors induce the activation of a number of protein kinases that belong to the AGC subfamily, including isoforms of PKA, protein kinase B (also known as Akt), PKC, S6K p70 (ribosomal S6 kinase), RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated protein kinase), which then mediate many of the physiological processes that are regulated by these extracellular agonists. It can be difficult to assess the individual functions of each AGC kinase because their substrate specificities are similar. Here we describe the small molecule BI-D1870, which inhibits RSK1, RSK2, RSK3 and RSK4 in vitro with an IC(50) of 10-30 nM, but does not signi-ficantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations. BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF (epidermal growth factor)-induced phosphoryl-ation of glycogen synthase kinase-3beta and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells. In contrast, BI-D1870 does not affect the agonist-triggered phosphorylation of substrates for six other AGC kinases. Moreover, BI-D1870 does not suppress the phorbol ester- or EGF-induced phosphorylation of CREB (cAMP-response-element-binding protein), consistent with the genetic evidence indicating that MSK, and not RSK, isoforms mediate the mitogen-induced phosphorylation of this transcription factor.
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PMID:BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. 1715 39

Fibroblast growth factor (FGF)-21 is a novel regulator of insulin-independent glucose transport in 3T3-L1 adipocytes and has glucose and triglyceride lowering effects in rodent models of diabetes. The precise mechanisms whereby FGF-21 regulates metabolism remain to be determined. Here we describe the early signaling events triggered by FGF-21 treatment of 3T3-L1 adipocytes and reveal a functional interplay between FGF-21 and peroxisome proliferator-activated receptor gamma (PPARgamma) pathways that leads to a marked stimulation of glucose transport. While the early actions of FGF-21 on 3T3-L1 adipocytes involve rapid accumulation of intracellular calcium and phosphorylation of Akt, GSK-3, p70(S6K), SHP-2, MEK1/2, and Stat3, continuous treatment for 72 h induces an increase in PPARgamma protein expression. Moreover, chronic activation of the PPARgamma pathway in 3T3-L1 adipocytes with the PPARgamma agonist and anti-diabetic agent, rosiglitazone (BRL 49653), enhances FGF-21 action to induce tyrosine phosphorylation of FGF receptor-2. Strikingly, treatment of cells with FGF-21 and rosiglitazone in combination leads to a pronounced increase in expression of the GLUT1 glucose transporter and a marked synergy in stimulation of glucose transport. Together these results reveal a novel synergy between two regulators of glucose homeostasis, FGF-21 and PPARgamma, and further define FGF-21 mechanism of action.
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PMID:Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling. 1706 60


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