scholarly journals An optimized and versatile synthesis to pyridinylimidazole-type p38α mitogen activated protein kinase inhibitors

2015 ◽  
Vol 13 (43) ◽  
pp. 10699-10704 ◽  
Author(s):  
Ahmed El-Gokha ◽  
Stefan A. Laufer ◽  
Pierre Koch
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Synthetic Approach ◽  
Mitogen Activated Protein ◽  
P38α Map Kinase

An optimized and diverse synthetic approach for the preparation of potent pyridinylimidazole-based p38α MAP kinase inhibitors is reported.

Involvement of Ras/MAP Kinase in the Regulation of Ca2+ Channels in Adult Bullfrog Sympathetic Neurons by Nerve Growth Factor

1998 ◽  
Vol 80 (3) ◽  
pp. 1352-1361 ◽  
Author(s):  
Saobo Lei ◽  
William F. Dryden ◽  
Peter A. Smith
Keyword(s):  
Nerve Growth Factor ◽  
Growth Factor ◽  
Protein Kinase ◽  
Map Kinase ◽  
Kinase Inhibitors ◽  
Sympathetic Neurons ◽  
Mitogen Activated Protein Kinase ◽  
Nerve Growth ◽  
Channel Current ◽  
Mitogen Activated Protein

Lei, Saobo, William F. Dryden, and Peter A. Smith. Involvement of Ras/MAP kinase in the regulation of Ca2+ channels in adult bullfrog sympathetic neurons by nerve growth factor. J. Neurophysiol. 80: 1352–1361, 1998. The cellular mechanisms that underlie nerve growth factor (NGF) induced increase in Ca2+-channel current in adult bullfrog sympathetic B-neurons were examined by whole cell recording techniques. Cells were maintained at low density in neuron-enriched, defined-medium, serum-free tissue culture for 6 days in the presence or absence of NGF (200 ng/ml). The increase in Ba2+ current ( I Ba) density induced by NGF was attenuated by the RNA synthesis inhibitor cordycepin (20 μM), by the DNA transcription inhibitor actinomycin D (0.01 μg/ml), by inhibitors of Ras isoprenylation (perillic acid 0.1–1.0 mM or α-hydroxyfarnesylphosphonic acid 10–100 μM), by tyrosine kinase inhibitors genistein (20 μM) or lavendustin A (1 μM), and by PD98059 (10–100 μM), an inhibitor of mitogen-activated protein kinase kinase. Inhibitors of the phosphatidylinositol 3-kinase (PI3K) pathway (wortmannin, 100 nM, or LY29400, 100 μM) were ineffective as were inhibitors of phospholipase Cγ (U73122 or neomycin, both 100 μM). The effect of NGF persisted in Ca2+-free medium that contained 1.8 mM Mg2+ and 2 mM ethylene glycol-bis(β-aminoethyl ether)- N, N, N′, N′-tetraacetic acid. It was mimicked by a Trk antibody that was capable of inducing neurite outgrowth in explant cultures of bullfrog sympathetic ganglion. Antibodies raised against the low-affinity p75 neurotrophin receptor were ineffective in blocking the effect of NGF on I Ba. These results suggest that NGF-induced increase in Ca2+ channel current in adult sympathetic neurons results, at least in part, from new channel synthesis after Trk activation of Ras and mitogen activated protein kinase by a mechanism that is independent of extracellular Ca2+.

scholarly journals Mitogen-activated protein kinase-mediated phosphorylation of peroxiredoxin 6 regulates its phospholipase A2 activity

2009 ◽  
Vol 419 (3) ◽  
pp. 669-679 ◽  
Author(s):  
Yongzheng Wu ◽  
Sheldon I. Feinstein ◽  
Yefim Manevich ◽  
Ibrul Chowdhury ◽  
Jhang Ho Pak ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Phospholipase A2 ◽  
Kinase Inhibitors ◽  
Phosphorylation Site ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Alveolar Type ◽  
Peroxiredoxin 6 ◽  
Mitogen Activated Protein

Prdx6 (peroxiredoxin 6), a bifunctional protein with both GSH peroxidase and PLA2 (phospholipase A2) [aiPLA2 (acidic calcium-independent PLA2)] activities, is responsible for the metabolism of lung surfactant phospholipids. We propose that the aiPLA2 activity of the enzyme is regulated through phosphorylation. Incubation of isolated rat alveolar type II cells (AECII) with PMA, a PKC (protein kinase C) agonist, had no effect on Prdx6 expression but led to ∼75% increase in aiPLA2 activity that was abolished by pretreatment of cells with the MAPK (mitogen-activated protein kinase) inhibitors, SB202190 or PD98059. Prdx6 phosphorylation after incubation of AECII with PMA was demonstrated by autoradiography after immunoprecipitation with either anti-phosphothreonine o-phosphoserine antibodies. in vitro, several active isoforms of ERK (extracellular-signal-regulated kinase) and p38 phosphorylated Prdx6, resulting in an 11-fold increase in aiPLA2 activity. The increased activity was calcium-independent and was abolished by the aiPLA2 inhibitors, surfactant protein A and hexadecyl-3-trifluorethylglycero-sn-2-phospho-methanol (MJ33). The peroxidase activity of Prdx6 was unaffected by phosphorylation. Mass spectroscopic analysis of in vitro phosphorylated Prdx6 showed a unique phosphorylation site at Thr-177 and mutation of this residue abolished protein phosphorylation and the increase in MAPK-mediated activity. These results show that the MAPKs can mediate phosphorylation of Prdx6 at Thr-177 with a consequent marked increase in its aiPLA2 activity.

scholarly journals Genetic Complementation Screen Identifies a Mitogen-activated Protein Kinase Phosphatase, MKP3, as a Regulator of Dopamine Transporter Trafficking

2008 ◽  
Vol 19 (7) ◽  
pp. 2818-2829 ◽  
Author(s):  
Ole Valente Mortensen ◽  
Mads Breum Larsen ◽  
Balakrishna M. Prasad ◽  
Susan G. Amara
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Dopamine Transporter ◽  
Map Kinases ◽  
Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Genetic Complementation ◽  
Monoamine Transporters ◽  
Map Kinase Phosphatase ◽  
Mitogen Activated Protein

The antidepressant and cocaine sensitive plasma membrane monoamine transporters are the primary mechanism for clearance of their respective neurotransmitters and serve a pivotal role in limiting monoamine neurotransmission. To identify molecules in pathways that regulate dopamine transporter (DAT) internalization, we used a genetic complementation screen in Xenopus oocytes to identify a mitogen-activated protein (MAP) kinase phosphatase, MKP3/Pyst1/DUSP6, as a molecule that inhibits protein kinase C–induced (PKC) internalization of transporters, resulting in enhanced DAT activity. The involvement of MKP3 in DAT internalization was verified using both overexpression and shRNA knockdown strategies in mammalian cell models including a dopaminergic cell line. Although the isolation of MKP3 implies a role for MAP kinases in DAT internalization, MAP kinase inhibitors have no effect on internalization. Moreover, PKC-dependent down-regulation of DAT does not correlate with the phosphorylation state of several well-studied MAP kinases (ERK1/2, p38, and SAPK/JNK). We also show that MKP3 does not regulate PKC-induced ubiquitylation of DAT but acts at a more downstream step to stabilize DAT at the cell surface by blocking dynamin-dependent internalization and delaying the targeting of DAT for degradation. These results indicate that MKP3 can act to enhance DAT function and identifies MKP3 as a phosphatase involved in regulating dynamin-dependent endocytosis.

scholarly journals Ocular Toxicity of Mitogen-Activated Protein Kinase Inhibitors

JAMA Oncology ◽  
2017 ◽  
Vol 3 (2) ◽  
pp. 275 ◽  
Author(s):  
Robert M. J. Purbrick ◽  
Olaoluwakitan A. Osunkunle ◽  
Denis C. Talbot ◽  
Susan M. Downes
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Ocular Toxicity ◽  
Mitogen Activated Protein
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