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首页> 外文期刊>Cellular Signalling >Nuclear Dbf2-related protein kinases (NDRs) in isolated cardiac myocytes and the myocardium: Activation by cellular stresses and by phosphoprotein serine-/threonine-phosphatase inhibitors
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Nuclear Dbf2-related protein kinases (NDRs) in isolated cardiac myocytes and the myocardium: Activation by cellular stresses and by phosphoprotein serine-/threonine-phosphatase inhibitors

机译：核DBF2相关蛋白激酶（NDR）在孤立的心肌细胞和心肌中：通过细胞应激和磷蛋白丝氨酸 - /苏氨酸 - 磷酸酶抑制剂活化

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摘要

The nuclear Dbf2-related protein kinases 1 and 2 (NDR1/2) are closely-related AGC family kinases that are strongly conserved through evolution. In mammals, they are activated inter alia by phosphorylation of an hydrophobic domain threonine-residue [NDR1(Thr-444)/NDR2(Thr-442)] by an extrinsic protein kinase followed by autophosphorylation of a catalytic domain serine-residue [NDR1(Ser-281)/NDR2(Ser-282)]. We examined NDR1/2 expression and regulation in primary cultures of neonatal rat cardiac myocytes and in perfused adult rat hearts. In myocytes, transcripts for NDR2, but not NDR1, were induced by the hypertrophic agonist, endothelin-1. NDR1(Thr-444) and NDR2(Thr-442) were rapidly phosphorylated (maximal in 15-30 min) in myocytes exposed to some phosphoprotein Ser-/Thr-phosphatase 1/2 inhibitors (calyculin A, okadaic acid) and, to a lesser extent, by hyperosmotic shock, low concentrations of H2O2, or chelerythrine. In myrocytes adenovirally-transduced to express FLAG-NDR2 (which exhibited a mainly-cytoplasmic localisation), the same agents increased FLAG-NDR2 activity as assessed by in vitro protein kinase assays, indicative of FLAG-NDR2(Ser-282/Thr-442) phosphorylation. Calyculin A-induced phosphorylation of NDR1(Thr-444)/NDR2(Thr-442) and activation of FLAG-NDR2 were inhibited by staurosporine, but not by other protein kinase inhibitors tested. In ex vivo rat hearts, NDR1 (Thr-444)/NDR2(Thr-442) were phosphorylated in response to ischaemia-reperfusion or calyculin A. From a pathological viewpoint, we conclude that activities of NDR1 and NDR2 are responsive to cytotoxic stresses in heart preparations and this may represent a previously-unidentified response to myocardial ischaemia in vivo. (c) 2008 Elsevier Inc. All rights reserved.
机译：核DBF2相关蛋白激酶1和2（NDR1 / 2）是密切相关的AGC系列激酶，通过演变而受到强烈保守。在哺乳动物中，通过通过外本蛋白激酶进行疏水结构域苏氨酸苏氨酸 - 残基[NDR1（Thr-444）/ NDR2（Thr-442）的磷酸化，然后通过催化结构域丝氨酸 - 残基的自磷酸化[NDR1（ SER-281）/ NDR2（SER-282）]。我们在新生大鼠心肌细胞和灌注成年大鼠心脏中检查了NDR1 / 2表达和调节。在肌细胞中，通过肥大激动剂，内皮蛋白-1诱导NDR2，但不是NDR1的转录物。 NDR1（Thr-444）和NDR2（Thr-442）在暴露于一些磷蛋白Ser-/ Thr-磷酸酶1/2抑制剂（Calyculin A，Okadaic acid）和较小程度，通过高骨休克，低浓度的H 2 O 2或Chelerythrine。在腺瘤腺瘤的腺瘤中，以表达主要 - 细胞质定位的标志-NDR2（其出现主要 - 细胞质定位），相同的药剂增加了由体外蛋白激酶测定评估的标志-ND2活性，这表明Flag-NDR2（Ser-282 / Thr-442 ）磷酸化。 Calyculin A诱导的NDR1（Thr-444）/ NDR2（Thr-442）的磷酸化并通过Staurosporine抑制Flag-NDR2的活化，但不是由其他蛋白激酶抑制剂测试的。在离体大鼠心中，NDR1（Thr-444）/ NDR2（Thr-442）响应于缺血再灌注或钙霉素A磷酸化。从病理观点来看，我们得出结论，NDR1和NDR2的活性对细胞毒性应力敏感心脏制剂和这可能代表体内对心肌缺血的先前身份不明的反应。 （c）2008年elestvier Inc.保留所有权利。

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