Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion and to inhibition of histone deacetylase (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment.
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PMID:A common mechanism of action for three mood-stabilizing drugs. 1201 4

Growing axons during development are guided to their targets by the activity of their growth cones. Growth cones integrate positive and negative guidance cues in deciding the direction in which to extend. We demonstrated previously that treatment of embryonic retinal ganglion cells with brain-derived neurotrophic factor (BDNF) protects their growth cones from collapse induced by nitric oxide (NO). BDNF stabilizes growth-cone actin filaments against NO-induced depolymerization. In the present study, we examined the signaling mechanism involved in BDNF-mediated protection. We found that BDNF causes transient activation of protein kinase A (PKA) during the first 5 min of treatment. Treatment with PKA inhibitors before or in conjunction with BDNF treatment blocked the protective effects of BDNF. The effects of BDNF, however, were not blocked when addition of PKA inhibitors was delayed as little as 15 min after BDNF treatment. When cultures raised overnight in BDNF were treated with PKA inhibitors, BDNF-mediated protection did not end, demonstrating that the maintenance of the protective effects of BDNF is independent of PKA activity. The BDNF-induced activation of PKA was required for BDNF-mediated stabilization of growth-cone actin filaments against depolymerization by cytochalasin D. Finally, the initiation and maintenance of the protective effects of BDNF required protein synthesis. Collectively, these data demonstrate that PKA signaling is required only for an early phase of BDNF-mediated protection from NO-induced growth-cone collapse.
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PMID:Transient PKA activity is required for initiation but not maintenance of BDNF-mediated protection from nitric oxide-induced growth-cone collapse. 1207 97

To identify phosphoproteins that might play a role in naringin-sensitive hepatocellular cytoskeletal disruption and apoptosis induced by algal toxins, hepatocyte extracts were separated by gel electrophoresis and immunostained with a phosphothreonine-directed antibody. Use of dilute (5%) polyacrylamide gels containing 6 m urea allowed the resolution of one very large (approximately 500-kDa) okadaic acid- and naringin-sensitive phosphoprotein, identified by tryptic fingerprinting, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and immunostaining as the cytolinker protein, plectin. The naringin-sensitive phosphorylation induced by okadaic acid and microcystin-LR probably reflected inhibition of a type 2A protein phosphatase, whereas the naringin-resistant phosphorylation induced by calyculin A, tautomycin, and cantharidin probably involved a type 1 phosphatase. Okadaic acid caused a collapse of the plectin-immunostaining bile canalicular sheaths and the general cytoskeletal plectin network into numerous medium-sized plectin aggregates. Inhibitors of protein kinase C, cAMP-dependent protein kinase, or Ca(2+)/calmodulin-dependent kinase II had moderate or no protective effects on plectin network disruption, whereas naringin offered 86% protection. Okadaic acid induced a naringin-sensitive phosphorylation of AMP-activated protein kinase (AMPK), the stress-activated protein kinases SEK1 and JNK, and S6 kinase. The AMPK-activating kinase (AMPKK) is likely to be the target of inhibition by naringin, the other kinases serving as downstream components of an AMPKK-initiated signaling pathway.
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PMID:Naringin-sensitive phosphorylation of plectin, a cytoskeletal cross-linking protein, in isolated rat hepatocytes. 1209 91

Neurotrophins and semaphorin 3A are present along pathways and in targets of developing axons of dorsal root ganglion (DRG) sensory neurons. Growth cones of sensory axons are probably regulated by interaction of cytoplasmic signaling triggered coincidentally by both types of guidance molecules. We investigated the in vitro interactions of neurotrophins and semaphorin 3A (Sema3A) in modulating growth cone behaviors of axons extended from DRGs of embryonic day 7 chick embryos. Growth cones of DRGs raised in media containing 10(-9) m NGF or BDNF were more resistant to Sema3A-induced growth cone collapse than when DRGs were raised in 10(-11) m NGF. After overnight culture in 10(-11) m NGF, a 1 hr treatment with 10(-9) m NGF or BDNF was sufficient to increase growth cone resistance to Sema3A-induced collapse. This neurotrophin-mediated decrease in the collapse response of DRG growth cones was not associated with reduced expression on growth cones of the Sema3A-binding protein neuropilin-1. A series of pharmacological studies followed. Phosphatidylinositol 3 kinase activity is not required for these effects of NGF. The effects of inhibitors and activators of protein kinase A (PKA) indicate that PKA activity is involved in NGF modulation of Sema3A-induced growth cone collapse. The effects of inhibitors and activators of PKG indicate that PKG activity is involved in Sema3A-induced growth cone collapse. The effects of inhibitors also indicate that Rho-kinase activity is involved in Sema3A-induced growth cone collapse. These results are consistent with the idea that growth cone responses to an individual guidance cue depend on coincident signaling by other guidance cues and by other regulatory pathways.
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PMID:Nerve growth factor and semaphorin 3A signaling pathways interact in regulating sensory neuronal growth cone motility. 1215 45

Previous in vitro studies using cGMP or cAMP revealed a cross-talk between signaling mechanisms activated by axonal guidance receptors. However, the molecular elements modulated by cyclic nucleotides in growth cones are not well understood. cGMP is a second messenger with several distinct targets including cGMP-dependent protein kinase I (cGKI). Our studies indicated that the alpha isoform of cGKI is predominantly expressed by sensory axons during developmental stages, whereas most spinal cord neurons are negative for cGKI. Analysis of the trajectories of axons within the spinal cord showed a longitudinal guidance defect of sensory axons within the developing dorsal root entry zone in the absence of cGKI. Consequently, in cGKI-deficient mice, fewer axons grow within the dorsal funiculus of the spinal cord, and lamina-specific innervation, especially by nociceptive sensory neurons, is strongly reduced as deduced from anti-trkA staining. These axon guidance defects in cGKI-deficient mice lead to a substantial impairment in nociceptive flexion reflexes, shown using electrophysiology. In vitro studies revealed that activation of cGKI in embryonic dorsal root ganglia counteracts semaphorin 3A-induced growth cone collapse. Our studies therefore reveal that cGMP signaling is important for axonal growth in vivo and in vitro.
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PMID:cGMP-mediated signaling via cGKIalpha is required for the guidance and connectivity of sensory axons. 1241 79

Pulsed-field gradient (PFG) diffusion NMR spectroscopy studies were conducted with several helix-loop-helix regulatory Ca(2+)-binding proteins to characterize the conformational changes associated with Ca(2+)-saturation and/or binding targets. The calmodulin (CaM) system was used as a basis for evaluation, with similar hydrodynamic radii (R(h)) obtained for apo- and Ca(2+)-CaM, consistent with previously reported R(h) data. In addition, conformational changes associated with CaM binding to target peptides from myosin light chain kinase (MLCK), phosphodiesterase (PDE), and simian immunodeficiency virus (SIV) were accurately determined compared with small-angle X-ray scattering results. Both sets of data demonstrate the well-established collapse of the extended Ca(2+)-CaM molecule into a globular complex upon peptide binding. The R(h) of CaM complexes with target peptides from CaM-dependent protein kinase I (CaMKI) and an N-terminal portion of the SIV peptide (SIV-N), as well as the anticancer drug cisplatin were also determined. The CaMKI complex demonstrates a collapse analogous to that observed for MLCK, PDE, and SIV, while the SIV-N shows only a partial collapse. Interestingly, the covalent CaM-cisplatin complex shows a near complete collapse, not expected from previous studies. The method was extended to related calcium binding proteins to show that the R(h) of calcium and integrin binding protein (CIB), calbrain, and the calcium-binding region from soybean calcium-dependent protein kinase (CDPK) decrease on Ca(2+)-binding to various extents. Heteronuclear NMR spectroscopy suggests that for CIB and calbrain this is likely because of shifting the equilibrium from unfolded to folded conformations, with calbrain forming a dimer structure. These results demonstrate the utility of PFG-diffusion NMR to rapidly and accurately screen for molecular size changes on protein-ligand and protein-protein interactions for this class of proteins.
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PMID:Protein conformational changes studied by diffusion NMR spectroscopy: application to helix-loop-helix calcium binding proteins. 1253 86

Nerve growth factor (NGF) and semaphorin3A (Sema3A) are guidance cues found in pathways and targets of developing dorsal root ganglia (DRG) neurons. DRG growth cone motility is regulated by cytoplasmic signaling triggered by these molecules. We investigated interactions of NGF and Sema3A in modulating growth cone behaviors of axons extended from E7 chick embryo DRGs. Axons extending in collagen matrices were repelled by Sema3A released from transfected HEK293 cells. However, if an NGF-coated bead was placed adjacent to Sema3A-producing cells, axons converged at the NGF bead. Growth cones of DRGs raised in 10(-9) M NGF were more resistant to Sema3A-induced collapse than when DRGs were raised in 10(-11) M NGF. After overnight culture in 10(-11) M NGF, 1-hr treatment with 10(-9) M NGF also increased growth cone resistance to Sema3A. Pharmacological studies indicated that the activities of ROCK and PKG participate in the cytoskeletal alterations that lead to Sema3A-induced growth cone collapse, whereas PKA activity is required for NGF-mediated reduction of Sema3A-induced growth cone collapse. These results support the idea that growth cone responses to a guidance cue can be modulated by interactions involving coincident signaling by other guidance cues.
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PMID:Growth cones integrate signaling from multiple guidance cues. 1264 22

We previously showed that an overproduction of nitric oxide (NO) by macrophages was responsible for the collapse of lymphoproliferative responses after burn injury in rats. First, we demonstrate here that 10 days post-burn, the inhibition of splenocyte response to concanavalin-A results from cytostatic, apoptotic, and necrotic effects of NO on activated T cells. This was evidenced by various criteria at the levels of DNA, mitochondria, and plasma membrane. Inhibition of NO synthase by S-methylisothiourea (10 microM) normalized all the parameters. Second, we show that two soluble guanylate cyclase (sGC) inhibitors, LY83583 and ODQ, restored the proliferative response in a concentration-dependent manner. LY83583 (0.5 microM) rescued T cells from apoptosis. Similar results were obtained with KT5823 (5 microM) a specific inhibitor of protein kinase G (PKG). In contrast, neither LY83583 nor KT5823 inhibited NO-induced necrosis. These results suggest that NO blocked T cells in the G1 phase and induced apoptosis through a sGC-PKG-dependent pathway and necrosis through an independent one.
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PMID:Nitric oxide inhibits spleen cell proliferative response after burn injury by inducing cytostasis, apoptosis, and necrosis of activated T lymphocytes: role of the guanylate cyclase. 1274 82

Signaling through the B cell antigen receptor (BCR) is a key determinant in the regulation of B cell physiology. Depending on additional factors, such as microenvironment and developmental stage, ligation of the BCR can trigger B lymphocyte activation, proliferation, or apoptosis. The regulatory mechanisms determining B cell apoptosis and survival are not completely known. Using the murine B lymphoma cell line WEHI-231 as a model system, we investigated the role of Bad phosphorylation, a pro-apoptotic member of the Bcl-2 family, in anti-IgM mediated apoptosis. For apoptotic analysis we focused in particular on the mitochondrial potential (deltapsi(m)) collapse which has been reported as a rate-limiting step in the BCR-induced cell death of immature B lymphocytes. Bad phosphorylation at serine 112, 136 and 155 was found in WEHI-231 cell control cultures and its hypophosphorylation on the three sites correlated with the appearance of apoptosis when cross-linking surface IgM. Furthermore, treatment of cells with specific PK inhibitors known to be involved in serine phosphorylation of Bad (LY294002 for PI3K and H-89 for PKA) mimiced or enhanced BCR-induced cell death. These results strongly suggest that regulation of Bad phosphorylation plays an active role in mediating anti-IgM-induced apoptosis of immature B cells.
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PMID:Changes in bad phosphorylation are correlated with BCR-induced apoptosis of WEHI-231 immature B cells. 1458 39

Ephrin-As are repulsive axonal guidance cues that regulate retinotectal projection. EphA tyrosine kinases, which are the receptors of ephrin-As, activate signaling cascades leading to cytosckeleton reorganization. Here, we address the role of cyclin-dependent kinase (Cdk) 5 in Eph receptor signaling induced by ephrin-A5. Ephrin-A5 induced a cell morphological response in PC-3M cells that endogenously express Cdk5 and EphA2, a receptor for ephrin-A5. This response was augmented by the transfection of p35, which is a neuronal regulator of Cdk5. While the morphological response of native PC-3M cells was not affected by olomoucine, an inhibitor of Cdk, the response was inhibited in the p35-transfected cells. In retinal ganglion cells, either olomoucine at 20 microM or Y-27632 at 10 microM, an inhibitor of Rho-kinase/ROKalpha/ROCKII, showed maximum inhibitory effect against ephrin-A5 (10 microg/ml)-induced growth cone collapse. Combined application of olomoucine and Y-27632 further suppressed the ephrin-A5-induced response. Ephrin-A5 evoked phosphorylation of Cdk5 at Tyr15 and tau, a substrate of Cdk5 in retinal growth cones. Recombinant herpes simplex virus expressing Cdk5 mutant (kinase-negative or Tyr15 to Ala) showed a dominant-negative effect on the ephrin-A5-induced growth cone collapse. These findings demonstrate that both Cdk5 and the Rho kinase pathway independently contribute to the downstream of ephrin-A-induced signaling in retinal ganglion cells.
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PMID:Cdk5/p35 and Rho-kinase mediate ephrin-A5-induced signaling in retinal ganglion cells. 1466 14


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