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

Our experiments with the hIR protein have been designed to address a very general question of transmembrane receptor structure and function: What are the roles and interactions of the various deduced structural domains of such molecules in the initiation of the response of cells to extracellular signals? All of the evidence to date supports the previous hypothesis based on biochemical data that the IR requires ligand-activated TPK functions to initiate the insulin response by cells (for review, see Kahn 1985). Thus, mutations that compromise hIR TPK activity (site-directed point mutations or deletions) result in a concomitant decrease in at least one aspect of insulin action (glucose uptake; Ellis et al. 1986a). Other studies utilizing microinjection of antibodies to inhibit the receptor kinase have extended this conclusion to include a critical role for the receptor kinase in insulin's ability to stimulate ribosomal protein S6 phosphorylation in CHO cells, glycogen synthetase in hepatoma cells, glucose uptake in adipocytes (Morgan and Roth 1987), and frog oocyte maturation (Morgan et al. 1986). Second, analyses of cell lines that express experimentally truncated hIR TPKs demonstrate that, when membrane-anchored, this TPK domain is in fact capable of autonomous hormone-independent IR function: Such cells exhibit a constitutively elevated, insulin-independent uptake of 2-deoxyglucose (Ellis et al. 1987). Finally, by substitution of a homologous TPK for that of hIR, we find that although such a hybrid is capable of insulin-dependent transmembrane signaling (phosphorylation of the hybrid beta-subunit on tyrosine residues), the hybrid IR.ros molecule does not function as an IR in such cells: It mediates neither short-term (uptake of 2-deoxyglucose) nor long-term (incorporation of [3H]thymidine) effects of insulin (L. Ellis et al., in prep.). Together, these results suggest that (1) the hIR TPK domain conveys a substrate specificity for the insulin response and (2) that a functional hIR extracellular domain alone is not sufficient for generation of the insulin response (e.g., ligand-induced aggregation, or simple delivery of insulin into the cell). With the linking of the extracellular and cytoplasmic domains of the hIR molecule has evolved a cellular mechanism for the control of hIR TPK activity; the result is that cells which express the IR are now insulin responsive, and the physiological responses associated with the hormone are ligand-activated. Thus, the uncontrolled state of autonomous TPK activity, with the associated constitutive physiological response (e.g., as exhibited by the spBam hIR mutant), is circumvented.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of receptor-mediated transmembrane communication. 347 60

The role of the p90 ribosomal protein S6 kinase/mitogen-activated protein kinase (RSK/MAPK) signaling pathway in regulating glycogen synthase kinase-3 (GSK-3) activity was investigated. In vitro studies showed that GSK-3 was inactivated by 50% upon incubation with RSK purified from epidermal growth factor (EGF)-stimulated NIH/3T3 cells. Subsequently, the effect of EGF on GSK-3 activity was measured in NIH/3T3 cells that stably overexpressed mutated forms of MAPK kinase (MAPKK). The activation of RSK by EGF was markedly decreased in cell lines expressing the dominant negative MAPKK mutants S222A and K97A and was increased in cells expressing the S222E mutant as compared with control cell lines. EGF induced a rapid decrease in GSK-3 beta activity (50%) in control and S222E cells; however, only 25 and 10% inhibition in GSK-3 beta activity was observed in cell lines expressing the dominant negative mutants K97A and S222A, respectively, suggesting that inhibition of GSK-3 was partially blocked in these cells. Taken together, these results suggest that the action of EGF on GSK-3 inactivation is mediated by the RSK/MAPK signaling pathway in NIH/3T3 cells and provide evidence for a mechanism regulating GSK-3 activity in intact cells.
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PMID:Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. 783 18

Insulin and protein kinase B (or Akt) play critical roles in cardiomyocytic growth and survival. High concentrations of glucocorticoids antagonize insulin's action. To examine whether endogenous glucocorticoids modulate insulin's effect on Akt signaling in the protein and glycogen synthetic pathways in myocardium, we studied three groups of rats (n = 12 each) 4 d after either a bilateral adrenalectomy (ADX), ADX with physiological stress dose dexamethasone treatment (ADX + DEX), or a sham operation. Rats received either a saline infusion or a 3 mU/kg.min euglycemic insulin clamp for 3 h. ADX had no effect on myocardial Akt or GSK-3 [glycogen synthase (GS) kinase 3] phosphorylation, but it decreased the phosphorylation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1) and ribosomal protein S6 kinase (p70(S6K)) (P < 0.003 for both). Insulin enhanced the phosphorylation of Akt (P < 0.04), 4E-BP1 (P < 0.002), and p70(S6K) (P < 0.0001) in ADX, but not in sham rats. Dexamethasone restored the levels of 4E-BP1 and p70(S6K) phosphorylation and abrogated the insulin-stimulated Akt, 4E-BP1, and p70(S6K) phosphorylation. ADX rats had higher GS activity (P = 0.058) and lower glycogen content (P < 0.0001) than sham rats. GSK-3 phosphorylation after insulin infusion was greater in ADX rats. Insulin did not alter GS activity. Although insulin did not change the glycogen content in sham or ADX rats, it increased glycogen content by approximately 50% in ADX + DEX rats (P < 0.02). We conclude that endogenous glucocorticoids differentially modulate the regulation of Akt-4E-BP1/p70(S6K) and Akt-GSK-3-GS signaling pathways in heart by physiologic hyperinsulinemia over a range from deficiency to physiological stress concentrations.
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PMID:Glucocorticoids differentially modulate insulin-mediated protein and glycogen synthetic signaling downstream of protein kinase B in rat myocardium. 1463 Jul 10

Eccentric contractions (EC) are known to result in muscle hypertrophy, potentially through activation of the Akt-mammalian target of rapamycin-p70 S6 kinase (p70S6K) signaling pathway. Previous work has also demonstrated that EC result in the opening of stretch-activated channels (SAC), and inhibition of these channels resulted in an attenuation of EC-induced muscle hypertrophy. The purpose of this study was to test the hypothesis that a known intracellular pathway directly associated with muscle hypertrophy is coupled to the opening of SAC. Specifically, we measured the activation of the Akt, GSK-3beta, p70S6K, and ribosomal protein S6 following a single bout of EC in the rat tibialis anterior (TA) muscle. The TA muscles performed four sets of six repetitions of EC. In vivo blockade of SAC was performed by a continuous oral treatment with streptomycin in the drinking water (4 g/l) or by intravenous infusion of 80 micromol/kg gadolinium (Gd3+). EC increased the degree of Akt and p70S6K phosphorylation in the TA muscle, whereas in animals in which SAC had been inhibited, there was a reduced capacity for EC to induce Akt or p70S6K phosphorylation. Accompanying this reduced activation of Akt and p70S6K was a failure to phosphorylate GSK-3beta or S6 when SAC were inhibited. The results from these data indicate the necessity of functional SAC for the complete activation of Akt and p70S6K pathway in response to EC.
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PMID:Inhibition of stretch-activated channels during eccentric muscle contraction attenuates p70S6K activation. 1617 99

BCAAs (leucine, isoleucine, and valine), particularly leucine, have anabolic effects on protein metabolism by increasing the rate of protein synthesis and decreasing the rate of protein degradation in resting human muscle. Also, during recovery from endurance exercise, BCAAs were found to have anabolic effects in human muscle. These effects are likely to be mediated through changes in signaling pathways controlling protein synthesis. This involves phosphorylation of the mammalian target of rapamycin (mTOR) and sequential activation of 70-kD S6 protein kinase (p70 S6 kinase) and the eukaryotic initiation factor 4E-binding protein 1. Activation of p70 S6 kinase, and subsequent phopsphorylation of the ribosomal protein S6, is associated with enhanced translation of specific mRNAs. When BCAAs were supplied to subjects during and after one session of quadriceps muscle resistance exercise, an increase in mTOR, p70 S6 kinase, and S6 phosphorylation was found in the recovery period after the exercise with no effect of BCAAs on Akt or glycogen synthase kinase 3 (GSK-3) phosphorylation. Exercise without BCAA intake led to a partial phosphorylation of p70 S6 kinase without activating the enzyme, a decrease in Akt phosphorylation, and no change in GSK-3. It has previously been shown that leucine infusion increases p70 S6 kinase phosphorylation in an Akt-independent manner in resting subjects; however, a relation between mTOR and p70 S6 kinase has not been reported previously. The results suggest that BCAAs activate mTOR and p70 S6 kinase in human muscle in the recovery period after exercise and that GSK-3 is not involved in the anabolic action of BCAAs on human muscle.
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PMID:Branched-chain amino acids activate key enzymes in protein synthesis after physical exercise. 1636 96

We examined the effects of the adipose hormone leptin on the development of mouse cortical neurons. Treatment of neonatal and adult mice with intraperitoneal leptin (5 mg/kg) induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in pyriform and entorhinal cortex neurons. Stimulation of cultured embryonic cortical neurons with leptin evoked Janus kinase 2 and ERK1/2 phosphorylation and activated the downstream effector 90-kDa ribosomal protein S6 kinase. Moreover, leptin elicited the phosphorylation of the phosphatidylinositol 3-kinase effector Akt and evoked Ser-9 phosphorylation of glycogen synthase kinase-3beta (GSK3beta), an event inactivating this kinase. Leptin-mediated GSK3beta phosphorylation was prevented by the MEK/ERK inhibitor PD98059, the phosphatidylinositol 3-kinase inhibitor LY294002, or the protein kinase C inhibitor GF109203X. Exposure of cortical neurons to leptin also induced Ser-41 phosphorylation of the neuronal growth-associated protein GAP-43, an effect prevented by LY294002 and GF109203X but not by PD98059. Ser-41-GAP-43 phosphorylation is usually high in expanding axonal growth cones. Neurons exposed to 100 ng/ml leptin for 72 h displayed reduced rate of growth cone collapse, a shift of growth cone size distribution toward higher values, and a 4-fold increase in mean growth cone surface area compared with control cultures. The leptin-induced growth cone spreading was hampered in cortical neurons from Lepr(db/db) mice lacking functional leptin receptors; it was associated with localized Ser-9-GSK3beta phosphorylation and mimicked by the GSK3beta inhibitor SB216763. At concentrations preventing GSK3beta phosphorylation, PD98059, LY294002, or GF109203X reversed the leptin-induced growth cone surface enlargement. We concluded that the leptin-mediated regulation of growth cone morphogenesis in cortical neurons relies on upstream regulators of GSK3beta activity.
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PMID:Leptin increases axonal growth cone size in developing mouse cortical neurons by convergent signals inactivating glycogen synthase kinase-3beta. 1652 36

Prostaglandin F2alpha (PGF2alpha) increases reactive oxygen species (ROS) and induces vascular smooth muscle cell (VSMC) hypertrophy by largely unknown mechanism(s). To investigate the signaling events governing PGF2alpha-induced VSMC hypertrophy we examined the ability of the PGF2alpha analog, fluprostenol to elicit phosphorylation of Akt, the mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6k), glycogen synthase kinase-3beta (GSK-3beta), phosphatase and tensin homolog (PTEN), extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) in growth arrested A7r5 VSMC. Fluprostenol-induced hypertrophy was associated with increased ROS, mTOR translocation from the nucleus to the cytoplasm, along with Akt, mTOR, GSK-3beta, PTEN and ERK1/2 but not JNK phosphorylation. Whereas inhibition of phosphatidylinositol 3-kinase (PI3K) by LY-294002 blocked fluprostenol-induced changes in total protein content, pre-treatment with rapamycin or with the MEK1/2 inhibitor U0126 did not. Taken together, these findings suggest that fluprostenol-induced changes in A7r5 hypertrophy involve mTOR translocation and occur through PI3K-dependent mechanisms.
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PMID:PGF2alpha-associated vascular smooth muscle hypertrophy is ROS dependent and involves the activation of mTOR, p70S6k, and PTEN. 1816 Mar 24

We investigated the effect of resistance exercise and feeding on the activation of signaling proteins involved in translation initiation. Nine young men (23.7+/-0.41 yr; BMI=25.5+/-1.0 kg/m2; means+/-SE) were tested twice after they performed a strenuous bout of unilateral resistance exercise, such that their contralateral leg acted as a nonexercised comparator, in either the fasted and fed [1,000 kJ, each 90 min (3 doses): 10 g protein, 41 g carbohydrate, 4 g fat] states. Muscle biopsies were obtained 6 h postexercise from both legs, resulting in four experimental conditions: rest-fasted, rest-fed, exercise-fasted, and exercise-fed. Feeding increased PKB/Akt (Ser473) phosphorylation (P<0.05), while exercise increased the phosphorylation of Akt and the downstream 70 kDa S6 protein kinase (p70S6K1, Thr389) and ribosomal protein S6 (rpS6, Ser235/236, Ser240/244; all P<0.05). The combination of resistance exercise and feeding increased the phosphorylation of p70S6K1 (Thr389) and rpS6 (Ser240/244) above exercise alone (P<0.05). Exercise also reduced phosphorylation of the catalytic epsilon subunit of eukaryotic initiation factor 2B (eIF2Bepsilon, Ser540; P<0.05). Mammalian target of rapamycin (mTOR, Ser2448), glycogen synthase kinase-3beta (GSK-3beta, Ser9), and focal adhesion kinase (FAK, Tyr576/577) phosphorylation were unaffected by either feeding or resistance exercise (all P>0.14). In summary, feeding resulted in phosphorylation of Akt, while resistance exercise stimulated phosphorylation of Akt, p70S6K1, rpS6, and dephosphorylation eIF2Bepsilon with a synergistic effect of feeding and exercise on p70(S6K1) and its downstream target rpS6. We conclude that resistance exercise potentiates the effect of feeding on the phosphorylation and presumably activation of critical proteins involved in the regulation of muscle protein synthesis in young men.
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PMID:Resistance exercise decreases eIF2Bepsilon phosphorylation and potentiates the feeding-induced stimulation of p70S6K1 and rpS6 in young men. 1856 37

Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy, and although the genetic basis of this disease is well defined, the overall mechanisms that define its pathogenesis remain obscure. Alterations in individual signaling pathways have been described, but little information is available regarding their putative implications in Duchenne muscular dystrophy pathogenesis. Here, we studied the status of various major signaling pathways in the Golden Retriever muscular dystrophy dog that specifically reproduces the full spectrum of human pathology. Using antibody arrays, we found that Akt1, glycogen synthase kinase-3beta (GSK3beta), 70-kDa ribosomal protein S6 kinase (p70S6K), extracellular signal-regulated kinases 1/2, and p38delta and p38gamma kinases all exhibited decreased phosphorylation in muscle from a 4-month-old animal with Golden Retriever muscular dystrophy, revealing a deep alteration of the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase pathways. Immunohistochemistry analysis revealed the presence of muscle fibers exhibiting a cytosolic accumulation of Akt1, GSK3beta, and phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN), an enzyme counteracting PI3K-mediated Akt activation. Enzymatic assays established that these alterations in phosphorylation and expression levels were associated with decreased Akt and increased GSK3beta and PTEN activities. PTEN/GSK3beta-positive fibers were also observed in muscle sections from 3- and 36-month-old animals, indicating long-term PI3K/Akt pathway alteration. Collectively, our data suggest that increased PTEN expression and activity play a central role in PI3K/Akt/GSK3beta and p70S6K pathway modulation, which could exacerbate the consequences of dystrophin deficiency.
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PMID:PTEN contributes to profound PI3K/Akt signaling pathway deregulation in dystrophin-deficient dog muscle. 1926 9

This study is the first study to investigate the anticancer effect of 6-shogaol in human non-small cell lung cancer A549 cells. 6-Shogaol inhibited cell proliferation by inducing autophagic cell death, but not, predominantly, apoptosis. Pretreatment of cells with 3-methyladenine (3-MA), an autophagy inhibitor, suppressed 6-shogaol mediated antiproliferation activity, suggesting that induction of autophagy by 6-shogaol is conducive to cell death. We also found that 6-shogaol inhibited survival signaling through the AKT/mTOR signaling pathway by blocking the activation of AKT and downstream targets, including the mammalian target of rapamycin (mTOR), forkhead transcription factors (FKHR) and glycogen synthase kinase-3beta (GSK-3beta). Phosphorylation of both of mTOR's downstream targets, p70 ribosomal protein S6 kinase (p70S6 kinase) and 4E-BP1, was also diminished. Overexpression of AKT by AKT cDNA transfection decreased 6-shogaol mediated autophagic cell death, supporting inhibition of AKT beneficial to autophagy. Moreover, reduction of AKT expression by siRNA potentiated 6-shogaol's effect, also supporting inhibition of AKT beneficial to autophagy. Taken together, these findings suggest that 6-shogaol may be a promising chemopreventive agent against human non-small cell lung cancer.
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PMID:6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. 1979 25


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