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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Application of basic fibroblast growth factor (FGF-2) to the optic nerve after axotomy promotes the survival of retinal ganglion cells (RGCs) in the frog, Rana pipiens. Here we investigate the effects of FGF-2 treatment upon the synthesis of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine receptor kinase B (TrkB). Axotomy alone increased the amounts of BDNF and TrkB mRNA in RGCs after 1 week and 48 h, respectively; FGF-2 treatment to the nerve accelerated and increased this up-regulation of both. FGF-2 also increased the amounts of phosphorylated cAMP response element binding protein (pCREB) in the retina. Blocking extracellular-regulated kinase (ERK) activation with PD98059 or U0126 prevented the FGF-2-induced up-regulation of BDNF transcription but had no effect on TrkB. However, blocking protein kinase A (PKA) with H89 or Rp-8-Cl-cAMPS reduced the up-regulation of both BDNF and TrkB, and reduced pCREB. In addition, H89 inhibited ERK activation, indicating cross-talk between the pathways. Finally, axonal application of blocking antibody against the FGF receptor 1 (FGFR1) prevented the FGF-2-induced up-regulation of BDNF and TrkB. Our results suggest that FGF-2 acts on RGCs via FGFR1, activating the ERK pathway and CREB to increase BDNF synthesis, and PKA and CREB to increase TrkB synthesis.
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PMID:Fibroblast growth factor 2 applied to the optic nerve after axotomy up-regulates BDNF and TrkB in ganglion cells by activating the ERK and PKA signaling pathways. 1626 11

In diabetes (type 1 and type 2), increased flux of free fatty acids and glucose is associated with increased mitochondrial reactive oxygen species (ROS) production and, as a consequence, increased oxidative stress. ROS have been shown to activate various cellular stress-sensitive pathways, which can interfere with cellular signaling pathways. Exposure of different cell lines to micromolar concentrations of hydrogen peroxide leads to the activation of stress kinases such as c-Jun N-terminal kinase, p38, I kappaB kinase, and extracellular receptor kinase 1/2. This activation is accompanied by a down-regulation of the cellular response to insulin, leading to a reduced ability of insulin to promote glucose uptake, and glycogen and protein synthesis. The mechanisms leading to this down-regulation in oxidized cells are complicated, involving increased serine/threonine phosphorylation of insulin receptor substrate-1 (IRS1), impaired insulin-stimulated redistribution of IRS1 and phosphatidylinositol-kinase between cytosol and low-density microsomal fraction, followed by a reduced protein kinase-B phosphorylation and GLUT4 translocation to the plasma membrane. In addition, prolonged exposure to ROS affects transcription of glucose transporters: whereas the level of GLUT1 is increased, GLUT4 level is reduced. As can be expected, administration of antioxidants such as lipoic acid in oxidized cells, in animal models of diabetes, and in type 2 diabetes shows improved insulin sensitivity. Thus, oxidative stress is presently accepted as a likely causative factor in the development of insulin resistance.
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PMID:Proposed mechanisms for the induction of insulin resistance by oxidative stress. 1635 19

Membrane-recruitment of GRK2 (G-protein receptor kinase 2) provides a fundamental step in the desensitization process controlling GPCRs (G-protein-coupled receptors), such as the beta2AR (beta2-adrenergic receptor). In the present paper, we show that challenge of HEK-293beta2 [human embryonic kidney cells stably overexpressing the FLAG-tagged beta2AR-GFP (green fluorescent protein)] cells with the beta-adrenoceptor agonist, isoprenaline, causes GRK2 to become phosphorylated by PKA (cAMP-dependent protein kinase). This action is facilitated when cAMP-specific PDE4 (phosphodiesterase-4) activity is selectively inactivated, either chemically with rolipram or by siRNA (small interfering RNA)-mediated knockdown of PDE4B and PDE4D. PDE4-selective inhibition by rolipram facilitates the isoprenaline-induced membrane translocation of GRK2, phosphorylation of the beta2AR by GRK2, membrane translocation of beta-arrestin and internalization of beta2ARs. PDE4-selective inhibition also enhances the ability of isoprenaline to trigger the PKA phosphorylation of GRK2 in cardiac myocytes. In the absence of isoprenaline, rolipram-induced inhibition of PDE4 activity in HEK-293beta2 cells acts to stimulate PKA phosphorylation of GRK2, with consequential effects on GRK2 membrane recruitment and GRK2-mediated phosphorylation of the beta2AR. We propose that a key role for PDE4 enzymes is: (i) to gate the action of PKA on GRK2, influencing the rate of GRK2 phosphorylation of the beta2AR and consequential recruitment of beta-arrestin subsequent to beta-adrenoceptor agonist challenge, and (ii) to protect GRK2 from inappropriate membrane recruitment in unstimulated cells through its phosphorylation by PKA in response to fluctuations in basal levels of cAMP.
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PMID:Phosphodiesterase-4 influences the PKA phosphorylation status and membrane translocation of G-protein receptor kinase 2 (GRK2) in HEK-293beta2 cells and cardiac myocytes. 1635 65

In this study we have examined the interaction of CD44 (a major hyaluronan (HA) receptor) with a RhoA-specific guanine nucleotide exchange factor (leukemia-associated RhoGEF (LARG)) in human head and neck squamous carcinoma cells (HNSCC-HSC-3 cell line). Immunoprecipitation and immunoblot analyses indicate that CD44 and the LARG protein are expressed in HSC-3 cells and that these two proteins are physically associated as a complex. HA-CD44 binding induces LARG-specific RhoA signaling and phospholipase C epsilon (PLC epsilon) activity. In particular, the activation of RhoA-PLC epsilon by HA stimulates inositol 1,4,5-triphosphate production, intracellular Ca2+ mobilization, and the up-regulation of Ca2+/calmodulin-dependent kinase II (CaMKII), leading to phosphorylation of the cytoskeletal protein, filamin. The phosphorylation of filamin reduces its interaction with filamentous actin, promoting tumor cell migration. The CD44-LARG complex also interacts with the EGF receptor (EGFR). Most importantly, the binding of HA to the CD44-LARG-EGFR complex activates the EGFR receptor kinase, which in turn promotes Ras-mediated stimulation of a downstream kinase cascade including the Raf-1 and ERK pathways leading to HNSCC cell growth. Using a recombinant fragment of LARG (the LARG-PDZ domain) and a binding assay, we have determined that the LARG-PDZ domain serves as a direct linker between CD44 and EGFR. Transfection of the HSC-3 cells with LARG-PDZcDNA significantly reduces LARG association with CD44 and EGFR. Overexpression of the LARG-PDZ domain also functions as a dominant-negative mutant (similar to the PLC/Ca2+-calmodulin-dependent kinase II (CaMKII) and EGFR/MAPK inhibitor effects) to block HA/CD44-mediated signaling events (e.g. EGFR kinase activation, Ras/RhoA co-activation, Raf-ERK signaling, PLC epsilon-mediated inositol 1,4,5-triphosphate production, intracellular Ca2+ mobilization, CaMKII activity, filamin phosphorylation, and filamin-actin binding) and to abrogate tumor cell growth/migration. Taken together, our findings suggest that CD44 interaction with LARG and EGFR plays a pivotal role in Rho/Ras co-activation, PLC epsilon-Ca2+ signaling, and Raf/ERK up-regulation required for CaMKII-mediated cytoskeleton function and in head and neck squamous cell carcinoma progression.
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PMID:Hyaluronan-CD44 interaction with leukemia-associated RhoGEF and epidermal growth factor receptor promotes Rho/Ras co-activation, phospholipase C epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells. 1656 89

Brassinosteroids (BRs) are steroid hormones that control many aspects of plant growth and development. BRs bind to the plasma membrane receptor kinase BRI1, and act through a signalling pathway that involves a glycogen synthase kinase-3-like kinase (BIN2) and a serine/threonine phosphatase (BSU1). Previous models proposed that BIN2 negatively regulates BR signalling by controlling the stability and subcellular localization of the related transcription factors BES1 and BZR1 by phosphorylation, in a manner reminiscent of the canonical Wnt signalling pathway of metazoans. Here we present strong evidence for a different mode of regulation of BR signalling. We show that BES1 is localized constitutively to the nucleus, where its activity is modulated by nuclear-localized BIN2 kinase. BIN2-mediated phosphorylation of BES1 inhibits its DNA-binding activity on BR-responsive target promoters and its transcriptional activity through impaired multimerization. Our observations demonstrate that phosphorylation-dependent inhibition of DNA binding and trans-activation is the key primary mechanism of BES1 regulation.
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PMID:Downstream nuclear events in brassinosteroid signalling. 1667 72

The objective of this review is to identify a target or biomarker of altered neurochemical sensitivity that is common to the many animal models of human psychoses associated with street drugs, brain injury, steroid use, birth injury, and gene alterations. Psychosis in humans can be caused by amphetamine, phencyclidine, steroids, ethanol, and brain lesions such as hippocampal, cortical, and entorhinal lesions. Strikingly, all of these drugs and lesions in rats lead to dopamine supersensitivity and increase the high-affinity states of dopamine D2 receptors, or D2High, by 200-400% in striata. Similar supersensitivity and D2High elevations occur in rats born by Caesarian section and in rats treated with corticosterone or antipsychotics such as reserpine, risperidone, haloperidol, olanzapine, quetiapine, and clozapine, with the latter two inducing elevated D2High states less than that caused by haloperidol or olanzapine. Mice born with gene knockouts of some possible schizophrenia susceptibility genes are dopamine supersensitive, and their striata reveal markedly elevated D2High states; suchgenes include dopamine-beta-hydroxylase, dopamine D4 receptors, G protein receptor kinase 6, tyrosine hydroxylase, catechol-O-methyltransferase, the trace amine-1 receptor, regulator of G protein signaling RGS9, and the RIIbeta form of cAMP-dependent protein kinase (PKA). Striata from mice that are not dopamine supersensitive did not reveal elevated D2High states; these include mice with knockouts of adenosine A2A receptors, glycogen synthase kinase GSK3beta, metabotropic glutamate receptor 5, dopamine D1 or D3 receptors, histamine H1, H2, or H3 receptors, and rats treated with ketanserin or aD1 antagonist. The evidence suggests that there are multiple pathways that convergetoelevate the D2High state in brain regions and that this elevation may elicit psychosis. This proposition is supported by the dopamine supersensitivity that is a common feature of schizophrenia and that also occurs in many types of genetically altered, drug-altered, and lesion-altered animals. Dopamine supersensitivity, in turn, correlates with D2High states. The finding that all antipsychotics, traditional and recent ones, act on D2High dopamine receptors further supports the proposition.
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PMID:Psychosis pathways converge via D2high dopamine receptors. 1678 61

Protein phosphorylation is a key posttranslational modification mechanism controlling the conformation and activity of many proteins. Increasing evidence has implicated an essential role of phosphorylation by several major protein kinases in promoting and maintaining opioid tolerance. We review some of the most recent studies on protein kinase C (PKC), cyclic AMP dependent protein kinase A (PKA), calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase G (PKG), and G protein receptor kinase (GRK). These kinases act as the molecular switches to modulate opioid tolerance. Pharmacological interventions at one or more of the protein kinases and phosphatases may provide valuable strategies to improve opioid analgesia by attenuating tolerance to these drugs.
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PMID:Phosphorylation: a molecular switch in opioid tolerance. 1683 50

A comparative analysis on protein kinases encoded in the completely sequenced genomes of two plant species, namely Arabidopsis thaliana and Oryza sativa spp japonica cv. Nipponbare is reported in the current study. We have analysed 836 and 1386 kinases identified from A. thaliana and the O. sativa genomes respectively. Their classification into known subfamilies reveals selective expansions of the plant receptor kinase subfamily comprising of Ser/Thr receptor kinases. The presence of calcium dependent kinases, and potential absence of cyclic nucleotide-dependent protein kinase of the type found in other (non-plant) eukaryotes, are other notable features of the two plant kinomes described here. An analysis on domain organisation of each of the protein kinases encoded in the plant genome has been carried out. Uncommon composition of functional domains like nuclear translocation factor domain, redox sensor domain (PAS), ACT and lectin domains are observed in few protein kinases shared between the two plant species. Biochemical functions characteristic of the domains recruited in these protein kinase gene products suggest their mode of regulation by alternate cellular localisation, oxidation potential, amino acid flux and binding of carbohydrates. Occurrence of multi-functional kinases with diverse enzymatic modules, such as Transposases and peptidases, tethered to the kinase catalytic domain is another interesting feature of the protein kinase complement of the O. sativa genome. Co-occurrence of diverse nucleotide and carbohydrate binding domains with catalytic kinase domain containing gene products has also been observed. Putative homologues of protein kinases of A. thaliana that regulate plant-specific physiological processes like ethylene hormone response, somatic embryogenesis and pathogen defence have been identified in O. sativa genome as well.
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PMID:Genome-wide comparative analyses of domain organisation of repertoires of protein kinases of Arabidopsis thaliana and Oryza sativa. 1684 20

Challenge of the beta(2)Ar (beta(2)-adrenergic receptor) with isoprenaline in HEK-293beta(2) cells (human embryonic kidney cells stably overexpressing a FLAG- and green fluorescent protein-tagged beta(2)Ar) results in the PKA (cAMP-dependent protein kinase) phosphorylation of GRK2 (G-protein receptor kinase-2). This response was enhanced when PDE4 (phosphodiesterase-4) activity was attenuated using either rolipram, a PDE4-selective inhibitor, or with siRNA (small interfering RNA) knockdown of both PDE4B and PDE4D. Rolipram also facilitated GRK2 recruitment to the membrane and phosphorylation of the beta(2)Ar by GRK2 in response to isoprenaline challenge of cells. In resting cells, rolipram treatment alone is sufficient to promote PKA phosphorylation of GRK2, with consequential effects on GRK2 translocation and GRK2 phosphorylation of the beta(2)Ar. Similar effects are observed in cardiac myocytes. We propose that PDE4 activity protects GRK2 from inappropriate phosphorylation by PKA in resting cells that might have occurred through fluctuations in basal cAMP levels. Thus PDE4 gates the action of PKA to phosphorylate GRK2.
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PMID:Phosphodiesterase-4 gates the ability of protein kinase A to phosphorylate G-protein receptor kinase-2 and influence its translocation. 1685 36

The activation of extracellular receptor kinase (ERK) is one of the checkpoints to assess the activation of the classical Ras/mitogen-activated protein kinase (MAPK) cascade. Therefore, we tested more than 100 selenium-containing compounds for their ability to activate the MAPK signal pathway. Among them, we found that three selenazoles, 5-chloroacetyl-2-piperidino-1,3-selenazole (CS1), 5-chloroacetyl-2-morpholino-1,3-selenazole (CS2), and 5-chloroacetyl-2-dimethylamino-1,3-selenazole (CS3), induced the phosphorylation of ERK. These compounds also enhanced the phosphorylation of Akt, a signal transducing protein kinase for cell survival; and this phosphorylation was followed by suppression of cell death, thus suggesting that they had anti-apoptotic effects. Moreover, CSs 1-3 induced neurite outgrowth and facilitated the expression of neurofilament-M of PC12 cells, demonstrating that they induced neuronal differentiation of these cells. On the other hand, the CS-induced phosphorylation of MAPK was enhanced by buthionine sulfoximine (BSO), an activator of protein tyrosine phosphatases (PTPs), but inhibited by N-acetyl-l-cysteine (NAC), an inhibitor of receptor tyrosine kinase. These results imply that activation of some receptor tyrosine kinase(s) is involved in the mechanism of action of CSs 1-3. The activation of MAPK by CSs 1-3 was suppressed by U0126, a MEK inhibitor, but not by K252a, an inhibitor of TrkA; AG1478, an antagonist of epidermal growth factor receptor (EGFR); or by pertussis toxin. These results demonstrate that the CS-induced phosphorylation of Akt and MAP kinase (receptor tyrosine kinase(s)-MEK1/2-ERK1/2) cascades was responsible for suppression of apoptosis and facilitation of neuronal differentiation of PC12 cells, respectively. Our results suggest that CSs 1-3 are promising candidates as neuroprotective and/or neurotrophic agents for the treatment of various neurodegenerative neurological disorders.
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PMID:Selenazoles (selenium compounds) facilitate survival of cultured rat pheochromocytoma PC12 cells after serum-deprivation and stimulate their neuronal differentiation via activation of Akt and mitogen-activated protein kinase, respectively. 1712 95


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