Regulation of Apoptosis Signal-regulating Kinase 1 (ASK1) by PolyamineLevels via Protein Phosphatase5
| Autor: | Tatyana A. Voyno-Yasenetskaya, Mikhail A. Kutuzov, Alexandra V. Andreeva |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Phosphatase
Spermine Apoptosis Biology MAP Kinase Kinase Kinase 5 Biochemistry Article Substrate Specificity Dephosphorylation chemistry.chemical_compound Chlorocebus aethiops Phosphoprotein Phosphatases Animals ASK1 Phosphorylation RNA Small Interfering Molecular Biology Kinase Nuclear Proteins Cell Biology Cell biology Enzyme Activation Oxidative Stress chemistry COS Cells Second messenger system Polyamine Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 280:25388-25395 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m413202200 |
| Popis: | Recent evidence has implicated the protein phosphatase PP5 in a variety of signaling pathways. Whereas several proteins have been identified that interact with PP5 and regulate its activity, a possibility of its regulation by second messengers remains speculative. Activation of PP5 in vitro by polyunsaturated fatty acids (e.g. arachidonic acid) and fatty acyl-CoA esters (e.g. arachidonoyl-CoA) has been reported. We report here that PP5 is strongly inhibited by micromolar concentrations of a natural polyamine spermine. This inhibition was observed both in assays with a low molecular weight substrate p-nitrophenyl phosphate as well as phosphocasein and apoptosis signal-regulating kinase 1 (ASK1), thought to be a physiological substrate of PP5. Furthermore, a decrease in polyamine levels in COS-7 cells induced by alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, led to accelerated dephosphorylation of oxidative stress-activated ASK1. This effect was suppressed by okadaic acid and by siRNA-mediated PP5 depletion, indicating that the effect of polyamine levels on ASK1 dephosphorylation was mediated by PP5. In line with the decreased ASK1 activation, polyamine depletion in COS-7 cells abrogated oxidative stress-induced activation of caspase-3, which executes ASK1-induced apoptosis, as well as caspase-3 activation induced by ASK1 overexpression, but had no effect on basal caspase-3 activity. These results implicate polyamines, emerging intracellular signaling molecules, as potential physiological regulators of PP5. Our findings also suggest a novel mechanism of the anti-apoptotic action of a decrease in polyamine levels via de-inhibition of PP5 and accelerated dephosphorylation and deactivation of ASK1. |
| Databáze: | OpenAIRE |
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