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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deoxynivalenol (DNV) is the most frequently encountered trichothecene in grain-based foods, and is able to produce toxic effects resulting in various diseases in farm and laboratory animals. The molecular mechanisms that control this mycotoxin mediated effects in porcine endometrial cells are far from being completely understood. Recent results show that DNV inhibits protein synthesis in actively proliferating tissues. Therefore, the present study investigated the effects of this mycotoxin on a cellular level in an in vivo and in vitro system. The abundance and phosphorylation state (activity) of the cell cycle dependent kinases MAPk and Akt (PKB) and their potential targets eIF-4E (eukaryotic initiation factor 4E) and 4E-BP1 (4E binding protein, eIF4E repressor protein) were examined. In previous investigations it was found that these factors are involved in initiation of mRNA translation. The results show that DNV in vitro strongly reduce the abundance of p38 MAPk, protein kinase Akt and the alpha- and beta-4E-BP1 bands. The phosphorylation state of these proteins was obviously not modulated. In contrast, the eIF4E phosphorylation was strongly reduced in DNV treated cells. In summary, our in vitro results let assume that DNV potentially influences gene expression, but this work does not present a direct proof that DNV alters processes, which are involved in the initiation of mRNA translation. Surprisingly in vivo, an influence of DNV feeding on the investigated molecular events could not be demonstrated.
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PMID:In vitro and in vivo effects of deoxynivalenol (DNV) on regulators of cap dependent translation control in porcine endometrium. 1609 39

This study was conducted to investigate fasting-induced alterations in insulin signaling to the regulatory components of the translation machinery. Insulin (890 mIU/h) and IGF-I (40 nM/h) were infused into a chronically catheterized ovine fetus (0.85 gestation) for 7 h following a 5-d maternal fast. Amino acid and glucose concentrations were clamped to minimize the effects of alterations in circulating substrate concentrations. The IGF-I induced increase in 4E-BP1 phosphorylation (percentage in the gamma form) increased from 28% in control to 44% (NS). The insulin-induced increase in 4E-BP1 phosphorylation was more pronounced, and the gamma percentage was 56% on average in the insulin group. The insulin-induced increase in 4E-BP1 phosphorylation was lower than in fed animals and did not result in significant changes in eIF4E.4E-BP1 binding or eIF4E.eIF4G binding. Insulin increased PKB/Akt phosphorylation and p70S6K phosphorylation to a similar extent as in fed animals. We conclude that maternal fasting resulted in reduced insulin sensitivity of 4E-BP1 phosphorylation and eIF4F formation. This reduced insulin-induced 4E-BP1 phosphorylation was not due to a global defect in insulin signaling; the defects underlying the reduced basal phosphorylation and insulin-responsiveness of 4E-BP1 in fasted animals may be in signaling components other than, or downstream of, PKB/Akt. Selective inhibition of downstream components of insulin signaling allows fetuses to adapt to nutritional stress by decreasing the anabolic response to insulin and other growth factors, so that more amino acids can be used as oxidative substrate to compensate for shortage of energy due to reduced glucose supply.
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PMID:Changes in 4E-BP1 and p70S6K phosphorylation in skeletal muscle of the ovine fetus after prolonged maternal fasting: effects of insulin and IGF-I. 1618 12

Feeding promotes protein accretion in skeletal muscle through a stimulation of the mRNA translation initiation phase of protein synthesis either secondarily to nutrient-induced rises in insulin or owing to direct effects of nutrients themselves. The present set of experiments establishes the effects of meal feeding on potential signal transduction pathways that may be important in accelerating mRNA translation initiation. Gastrocnemius muscle from male Sprague-Dawley rats trained to consume a meal consisting of rat chow was sampled before, during, and after the meal. Meal feeding enhanced the assembly of the active eIF4G.eIF4E complex, which returned to basal levels within 3 h of removal of food. The increased assembly of the active eIF4G.eIF4E complex was associated with a marked 10-fold rise in phosphorylation of eIF4G(Ser(1108)) and a decreased assembly of inactive 4E-BP1.eIF4E complex. The reduced assembly of 4E-BP1.eIF4E complex was associated with a 75-fold increase in phosphorylation of 4E-BP1 in the gamma-form during feeding. Phosphorylation of S6K1 on Ser(789) was increased by meal feeding, although the extent of phosphorylation was greater at 0.5 h after feeding than after 1 h. Phosphorylation of mammalian target of rapamycin (mTOR) on Ser(2448) or Ser(2481), an upstream kinase responsible for phosphorylating both S6K1 and 4E-BP1, was increased at all times during meal feeding, although the extent of phosphorylation was greater at 0.5 h after feeding than after 1 h. Phosphorylation of PKB, an upstream kinase responsible for phosphorylating mTOR, was elevated only after 0.5 h of meal feeding for Thr(308), whereas phosphorylation Ser(473) was significantly elevated at only 0.5 and 1 h after initiation of feeding. We conclude from these studies that meal feeding stimulates two signal pathways in skeletal muscle that lead to elevated eIF4G.eIF4E complex assembly through increased phosphorylation of eIF4G and decreased association of 4E-BP1 with eIF4E.
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PMID:Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation. 1626 69

The present study examined the effects of an acute bout of treadmill exercise on signalling through the extracellular signal-regulated kinase (ERK)1/2 and mammalian target of rapamycin (mTOR) pathways to regulatory mechanisms involved in mRNA translation in mouse gastrocnemius muscle. Briefly, C57BL/6 male mice were run at 26 m min(-1) on a treadmill for periods of 10, 20 or 30 min, then the gastrocnemius was rapidly removed and analysed for phosphorylation and/or association of protein components of signalling pathways and mRNA translation regulatory mechanisms. Repression of global mRNA translation was suggested by disaggregation of polysomes into free ribosomes, which occurred by 10 min and was sustained throughout the time course. Exercise repressed the mTOR signalling pathway, as shown by dephosphorylation of the eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1), enhanced association of the regulatory-associated protein of mTOR with mTOR, and increased assembly of the tuberin-hamartin complex. In contrast, exercise caused no change in phosphorylation of either Akt/PKB or tuberin. Upstream of mTOR, exercise was associated with an increase in cAMP, protein kinase A activity, and AMP-activated protein kinase phosphorylation. Simultaneously, exercise caused a rapid and sustained activation of the MEK1/2-ERK1/2-p90RSK pathway, resulting in increased phosphorylation of downstream targets including eIF4E and the ribosomal protein (rp)S6 on S235/S236. Overall, the data are consistent with exercise-induced repression of mTOR signalling and global rates of mRNA translation, accompanied perhaps by up-regulated translation of selected mRNAs through regulatory mechanisms such as eIF4E and rpS6 phosphorylation, mediated by activation of the ERK1/2 pathway.
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PMID:Exercise-induced alterations in extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin (mTOR) signalling to regulatory mechanisms of mRNA translation in mouse muscle. 1660 Sep 96

Insulin rapidly activates protein synthesis by activating components of the translational machinery including eIFs (eukaryotic initiation factors) and eEFs (eukaryotic elongation factors). In the long term, insulin also increases the cellular content of ribosomes to augment the capacity for protein synthesis. The rapid activation of protein synthesis by insulin is mediated primarily through phosphoinositide 3-kinase. This involves the activation of PKB (protein kinase B). In one case, PKB acts to phosphorylate and inactivate glycogen synthase kinase 3, which in turn phosphorylates and inhibits eIF2B. Insulin elicits the dephosphorylation and activation of eIF2B. Since eIF2B is required for recycling of eIF2, a factor required for all cytoplasmic translation initiation events, this will contribute to overall activation of protein synthesis. PKB also phosphorylates the TSC1 (tuberous sclerosis complex 1)-TSC2 complex to relieve its inhibitory action on the mTOR (mammalian target of rapamycin). Inhibition of mTOR by rapamycin markedly impairs insulin-activated protein synthesis. mTOR controls translation initiation and elongation. The cap-binding factor eIF4E can be sequestered in inactive complexes by 4E-BP1 (eIF4E-binding protein 1). Insulin elicits phosphorylation of 4E-BP1 and its release from eIF4E, allowing eIF4E to form initiation factor complexes. Insulin induces dephosphorylation and activation of eEF2 to accelerate elongation. Both effects are blocked by rapamycin. Insulin inactivates eEF2 kinase by increasing its phosphorylation at several mTOR-regulated sites. Insulin also stimulates synthesis of ribosomal proteins by promoting recruitment of their mRNAs into polyribosomes. This is inhibited by rapamycin. Several key questions remain about, for example, the mechanisms by which mTOR controls 4E-BP1 and eEF2 kinase and the control of ribosomal protein translation.
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PMID:Regulation of protein synthesis by insulin. 1654 79

Protein expression in the heart is altered following periods of myocardial ischemia. The changes in protein expression are associated with increased cell size that can be maladaptive. There is little information regarding the regulation of protein expression through the process of mRNA translation during ischemia and reperfusion in the heart. Therefore, the purpose of this study was to identify changes in signaling pathways and downstream regulatory mechanisms of mRNA translation in an in vivo model of myocardial ischemia and reperfusion. Hearts were collected from rats whose left main coronary arteries had either been occluded for 25 min or reversibly occluded for 25 min and subsequently reperfused for 15 min. Following reperfusion, both the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways were activated, as evidenced by increased phosphorylation of Akt (PKB), extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase. Activation of Akt stimulated signaling through the protein kinase mammalian target of rapamycin, as evidenced by increased phosphorylation of two of its effectors, the ribosomal protein S6 kinase and the eukaryotic initiation factor eIF4E binding protein 1. Ischemia and reperfusion also resulted in increased phosphorylation of eIF2 and eIF2B. These changes in protein phosphorylation suggest that control of mRNA translation following ischemia and reperfusion is modulated through a number of signaling pathways and regulatory mechanisms.
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PMID:Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion. 1669 Jul 84

Patients with neurofibromatosis type 1 (NF1), resulting from neurofibromin gene mutations, frequently suffer from deficits in learning and spatial memory. Mice heterozygous for functional deletion of the NF1 gene (NF1(+/-) mice) also exhibit compromised spatial learning, and deficits in early-stage hippocampal long-term potentiation (LTP). Neurofibromin is a multifunctional protein which acts in part as an inhibitory constraint on Ras signalling, and the deficits in early-stage LTP and spatial learning have been linked to Ras hyperactivation. However, the downstream targets of Ras hyperactivation that lead to cognitive disruption are unknown. The levels of activity of signalling molecules potentially downstream of Ras were therefore studied in NF1(+/-) mice. Elevated phospho-ERK (pERK) levels were observed in the hippocampi from NF1(+/-) mice, while phospho-Akt/PKB (pAkt) and phospho-eIF4E (peIF4E) levels were unchanged relative to wild-type mice. Hippocampal levels of phospho-CREB (pCREB) were also increased, suggesting potential changes in late-phase LTP in NF1(+/-) mice. Indeed, LTP was found to be impaired for at least 4 h following induction in NF1(+/-) mice, linking neurofibromin function with the long-term maintenance of LTP. Remarkably, U0126, an inhibitor of ERK activation, at doses which reduced the hyperactive pERK levels in NF1(+/-) mice to the levels observed in control mice, caused a reduction in the deficits in early-phase LTP and completely rescued the long-term LTP deficits. In contrast to the abundant evidence that reductions in ERK activity lead to impaired plasticity, these data indicate that ERK hyperactivation in a partial model of type 1 neurofibromatosis leads to deficits in long-lasting hippocampal plasticity.
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PMID:Restored plasticity in a mouse model of neurofibromatosis type 1 via inhibition of hyperactive ERK and CREB. 1724 Dec 71

An important function of growth hormone (GH) is to promote cell and tissue growth, and a key component of these effects is the stimulation of protein synthesis. In this study, we demonstrate that, in H4IIE hepatoma cells, GH acutely activated protein synthesis through signaling via the mammalian target of rapamycin (mTOR) and specifically through the rapamycin-sensitive mTOR complex 1 (mTORC1). GH treatment enhanced the phosphorylation of two targets of mTOR signaling, 4E-BP1 and ribosomal protein S6. Phosphorylation of S6 and 4E-BP1 was maximal at 30-45 min and 10-20 min after GH stimulation, respectively. Both proteins modulate components of the translational machinery. The GH-induced phosphorylation of 4E-BP1 led to its dissociation from eIF4E and increased binding of eIF4E to eIF4G to form (active) eIF4F complexes. The ability of GH to stimulate the phosphorylation of S6 and 4E-BP1 was blocked by rapamycin. GH also led to the dephosphorylation of a third translational component linked to mTORC1, the elongation factor eEF2. Its regulation followed complex biphasic kinetics, both phases of which required mTOR signaling. GH rapidly activated both the MAP kinase (ERK) and PI 3-kinase pathways. Signaling through PI 3-kinase alone was, however, sufficient to activate the downstream mTORC1 pathway. Consistent with this, GH increased the phosphorylation of TSC2, an upstream regulator of mTORC1, at sites that are targets for Akt/PKB. Finally, the activation of overall protein synthesis by GH in H4IIE cells was essentially completely inhibited by wortmannin or rapamycin. These results demonstrate for the first time that mTORC1 plays a major role in the rapid activation of protein synthesis by GH.
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PMID:The rapid activation of protein synthesis by growth hormone requires signaling through mTOR. 1728 72

We previously reported a novel biological activity of Netrin-1 in translational stimulation of kappa opioid receptor (KOR). We now identify Grb7 as a new RNA-binding protein that serves as the molecular adaptor for transmitting Netrin-1 signals, through focal adhesion kinase (FAK), to the translation machinery. Grb7 binds specifically to the first stem loop of kor mRNA 5'-UTR through a new RNA-binding domain located in its amino terminus. Upon binding to its capped, target mRNA, Grb7 blocks the recruitment of eIF4E, rendering mRNA untranslatable. The RNA-binding and translation-repressive activity is reduced by FAK-mediated hyperphosphorylation on two tyrosine residues of its carboxyl terminus. This study reports an adaptor protein Grb7 that transmits the stimulating signals of Netrin-1 to the translational machinery to rapidly regulate mRNA translation.
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PMID:The adaptor Grb7 links netrin-1 signaling to regulation of mRNA translation. 1731 80

Previously we demonstrated that secondary products of plant mevalonate metabolism called isoprenoids attenuate 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA translational efficiency and cause tumor cell death. Here we compared effects of "pure" isoprenoids (perillyl alcohol and gamma-tocotrienol) and a "mixed" isoprenoid-genistein-on the PKB/Akt/mTOR pathway that controls mRNA translation and m(7)GpppX eIF4F cap binding complex formation. Effects were cell- and isoprenoid-specific. Perillyl alcohol and genistein suppressed 4E-BP1(Ser65) phosphorylation in prostate tumor cell lines, DU145 and PC-3, and in Caco2 adenocarcinoma cells. Suppressive effects were similar to or greater than that observed with a PI3 kinase inhibitor or rapamycin, an mTOR inhibitor. 4E-BP1(Thr37) phosphorylation was reduced by perillyl alcohol and genistein in DU145, but not in PC-3. Conversely, perillyl alcohol but not genistein decreased 4E-BP1(Thr37) phosphorylation in Caco2. PKB/Akt activation via Ser473 phosphorylation was enhanced in DU145 by perillyl alcohol and in PC-3 by gamma-tocotrienol, but was suppressed by genistein. Importantly, perillyl alcohol disrupted interactions between eIF4E and eIF4G, key components of eIF4F (m(7)GpppX) cap binding complex. These results demonstrate that "pure" isoprenoids and genistein differentially impact cap-dependent translation in tumor cell lines.
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PMID:Perillyl alcohol and genistein differentially regulate PKB/Akt and 4E-BP1 phosphorylation as well as eIF4E/eIF4G interactions in human tumor cells. 1760 86


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