The Activation State of p38 Mitogen-Activated Protein Kinase Determines the Efficiency of ATP Competition for Pyridinylimidazole Inhibitor Binding

Frantz, Betsy; Klatt, Tracey; Pang, Margaret; Parsons, Janey N.; Rolando, Anna M.; Williams, Hollis R.; Tocci, Michael J.; O’Keefe, Stephen J.; O’Neill, Edward A.

doi:10.1021/bi980832y

Cited by 196 publications

(139 citation statements)

References 29 publications

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“…It has been shown that PD98059 prevents ERKs phosphorylation/activation by inhibiting mitogen-activated protein kinase/extracellular signal-regulated kinase kinase activity (30). SB203580 was first described as an inhibitor of p38 MAPK activity by competing with ATP for binding (31), but it was later demonstrated that the drug also prevents p38 MAPK phosphorylation/activation (32). We observed that treatment of U-937 cells with 30 M PD98059 totally abolished ERK phosphorylation, whereas treatment with 5-20 M SB203580 (because higher concentrations were toxic) only partially inhibited p38 MAPK phosphorylation (Fig.…”

Section: Effect Of Kinase Inhibitors On Apoptosis-the Rapid Increase mentioning

confidence: 99%

Stimulation of p38 Mitogen-activated Protein Kinase Is an Early Regulatory Event for the Cadmium-induced Apoptosis in Human Promonocytic Cells

Galán¹,

García‐Bermejo²,

Troyano³

et al. 2000

Journal of Biological Chemistry

167

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Pulse treatment of U-937 promonocytic cells with cadmium chloride (2 h at 200 M) provoked apoptosis and induced a rapid phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK ) as well as a late phosphorylation of extracellular signal-regulated protein kinases (ERK1/2). However, although the p38 MAPK -specific inhibitor SB203580 attenuated apoptosis, the process was not affected by the ERK-specific inhibitor PD98059. The attenuation of the cadmium-provoked apoptosis by SB203580 was a highly specific effect. In fact, the kinase inhibitor did not prevent the generation of apoptosis by heat shock and camptothecin, nor the generation of necrosis by cadmium treatment of glutathione-depleted cells, nor the cadmium-provoked activation of the stress response. The generation of apoptosis was preceded by intracellular H 2 O 2 accumulation and was accompanied by the disruption of mitochondrial transmembrane potential, both of which were inhibited by SB203580. On the other hand, the antioxidant agent butylated hydroxyanisole-inhibited apoptosis but did not prevent p38 MAPK phosphorylation. In a similar manner, p38 MAPK phosphorylation was not affected by the caspase inhibitors Z-VAD and DEVD-CHO, which nevertheless prevented apoptosis. These results indicate that p38 MAPK activation is an early and specific regulatory event for the cadmium-provoked apoptosis in promonocytic cells.Cadmium and other heavy metals are frequent environmental contaminants with well known mutagenic, carcinogenic, and teratogenic effects (1). Another property of heavy metals (and of other physical and chemical agents, such as heat and inhibitors of energy metabolism) is the capacity to induce the stress response, characterized by the synthesis and accumulation of heat-shock proteins (HSPs)

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Section: Effect Of Kinase Inhibitors On Apoptosis-the Rapid Increase mentioning

confidence: 99%

Stimulation of p38 Mitogen-activated Protein Kinase Is an Early Regulatory Event for the Cadmium-induced Apoptosis in Human Promonocytic Cells

Galán¹,

García‐Bermejo²,

Troyano³

et al. 2000

Journal of Biological Chemistry

167

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“…In these cells, T-cell receptor (TCR) ligation results in activation of the Zap70 pathway, which subsequently results in the phosphorylation of Tyr323 on P38 and induction of the intramolecular P38 activity (Salvador et al, 2005). The dual phosphorylation of P38 mediated via MKKs is insensitive to inhibition of P38 by SB203580, which action lies in occupation of the ATP-binding pocket within the P38 kinase domain (Lee et al, 2000;Kumar et al, 1999;Gum et al, 1998;Frantz et al, 1998). However, P38 phosphorylation under conditions of TAB1 association or Tyr323 phosphorylation is sensitive to SB203580 (Ge et al, 2002;Salvador et al, 2005;Kim et al, 2005) indicating that this phosphorylation of P38 occurs via P38 mediated autophosphorylation.…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of TNFα and GM-CSF induced activation of P38 MAPK in neutrophils and eosinophils

Hove

Houben

Raaijmakers

et al. 2007

Molecular Immunology

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P38 MAPK is a central mediator in cytokine signalling in human leukocytes. P38 MAPK is activated by phosphorylation of a conserved Thr180-X-Tyr182 motif by dual phosphorylation via the upstream kinases MKK3 and MKK6. Alternatively, P38 MAPK can be activated via autophosphorylation when associated with TAB1. In this study P38 MAPK phosphorylation and activation (measured via phosphorylation of P38 MAPK downstream target MK2) were investigated upon engagement of the GM-CSF-and TNF␣-receptors expressed on both eosinophils and neutrophils. The MKK3/MKK6 pathway mediated neutrophil P38 MAPK activation after stimulation with TNF␣ (100 U/ml) or GM-CSF (10 −10 M). Under these conditions the activation but not phosphorylation of P38 MAPK could be inhibited by SB203580 (10 −5 M or 10 −6 M). In eosinophils SB203580 (10 −6 M) inhibited both the phosphorylation and activation of P38 MAPK after stimulation with several doses of TNF␣ (10-10000 U/ml) or GM-CSF (10 −11 to 10 −9 M), indicating that P38 MAPK activation is mediated via autophosphorylation in eosinophils. This hypothesis was supported by the finding that in marked contrast to neutrophils, MKK3/MKK6 did not show enhanced phosphorylation in eosinophils after cytokine stimulation, but were constitutively phosphorylated. Therefore, the involvement of TAB1 was investigated with regard to this cytokine-induced autophosphorylation. Co-immunoprecipitation experiments showed that TAB1 was constitutively associated with P38 MAPK in eosinophils and neutrophils and that cytokine-induced autophosphorylated P38 MAPK was co-precipitated with TAB1. These findings are consistent with the hypothesis that cytokine-induced autophosphorylation of P38 MAPK in primary granulocytes depends on the interaction with TAB1.

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“…Wie Abbildung 3 zeigt, bindet p38a den Inhibitor SB202190 (331 Da) mit K D = (48 AE 21) nm, was den Literaturwert von 37 nm wiedergibt. [21] Die Obergrenzen der Affinität zu PD169316 (360 Da) und SB239063 (368 Da) wurden zu 33 nm bzw. 20 nm bestimmt.…”

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“…Diese Ergebnisse stimmen gut mit den Literaturwerten überein. [21][22][23] Hitzedenaturierte p38a zeigte keine Bindung (Kontrolle).…”

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Markierungsfreie “Microscale Thermophoresis” zur Bestimmung von Bindestellen und Affinitäten bei Protein‐Liganden‐Wechselwirkungen

et al. 2012

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Kleine Mengen, keine Marker: Die Titelmethode nutzt die intrinsische Fluoreszenz von Proteinen, um die Bindungsaffinität von Liganden zu messen und deren Bindungsstelle zu bestimmen. Mit dieser Methode gelingt es, Wechselwirkungen mit sehr geringen Proteinmengen in Lösung zu studieren. Die Bindungen von Liganden an iGluR‐Membranrezeptoren, niedermolekularen Inhibitoren an p38‐Kinase, Aptameren an Thrombin und Ca2+‐Ionen an Synaptotagmin wurden so quantifiziert.

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The Activation State of p38 Mitogen-Activated Protein Kinase Determines the Efficiency of ATP Competition for Pyridinylimidazole Inhibitor Binding

Cited by 196 publications

References 29 publications

Stimulation of p38 Mitogen-activated Protein Kinase Is an Early Regulatory Event for the Cadmium-induced Apoptosis in Human Promonocytic Cells

Stimulation of p38 Mitogen-activated Protein Kinase Is an Early Regulatory Event for the Cadmium-induced Apoptosis in Human Promonocytic Cells

Differential regulation of TNFα and GM-CSF induced activation of P38 MAPK in neutrophils and eosinophils

Markierungsfreie “Microscale Thermophoresis” zur Bestimmung von Bindestellen und Affinitäten bei Protein‐Liganden‐Wechselwirkungen

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