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首页> 外文期刊>Cellular Signalling >p38 alpha- and DYRK1A-dependent phosphorylation of caspase-9 at an inhibitory site in response to hyperosmotic stress
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p38 alpha- and DYRK1A-dependent phosphorylation of caspase-9 at an inhibitory site in response to hyperosmotic stress

机译:对高渗胁迫的抑制位点上caspase-9的p38α和DYRK1A依赖性磷酸化

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摘要

The cysteine aspartyl protease caspase-9 is a critical component of the intrinsic apoptotic pathway. Activation of caspase-9 is inhibited by phosphorylation at Thr125, which is catalysed by the mitogen-activated protein kinases (MAPKs) ERK1/2 in response to growth factors, by the cyclin-dependent protein kinase CDK1-cyclin B1 during mitosis, and at a basal level by the dual-specificity tyrosine-phosphorylation regulated protein kinase DYRK1A. Here we show that inhibitory phosphorylation of caspase-9 at Thr125 is induced in mammalian cells by hyperosmotic stress. This response does not require ERK1/2 or ERK5, but it is diminished by ablation of DYRK1A expression by siRNA or chemical inhibition of DYRK1A by harmine. Phosphorylation of Thr125 in response to hyperosmotic stress is also reduced by chemical inhibition of p38 MAPK and is abolished in p38 alpha(-/-) mouse embryonic fibroblasts. These results show that both DYRK1A and p38 alpha play roles in the inhibitory phosphorylation of caspase-9 following hyperosmotic stress and suggest a functional interaction between these protein kinases. Phosphorylation of caspase-9 at Thr125 may restrain apoptosis during the acute response to hyperosmotic stress.
机译:半胱氨酸天冬氨酰蛋白酶caspase-9是内在凋亡途径的关键组成部分。 caspase-9的激活受到Thr125磷酸化的抑制,Thr125的磷酸化被有丝分裂原激活的蛋白激酶(MAPKs)ERK1 / 2响应生长因子催化,细胞周期蛋白依赖性蛋白激酶CDK1-cyclin B1则在有丝分裂期间以及通过双特异性酪氨酸磷酸化调节的蛋白激酶DYRK1A达到基础水平。在这里,我们显示高渗胁迫在哺乳动物细胞中诱导了在Thr125处caspase-9的抑制性磷酸化。此反应不需要ERK1 / 2或ERK5,但是通过siRNA消除DYRK1A的表达或通过harmine对DYRK1A的化学抑制而减弱。通过对p38 MAPK的化学抑制作用,还可以降低Thr125响应高渗胁迫的磷酸化,并在p38 alpha(-/-)小鼠胚胎成纤维细胞中被废除。这些结果表明,DYRK1A和p38α都在高渗胁迫后在caspase-9的抑制性磷酸化中起作用,并暗示这些蛋白激酶之间的功能相互作用。 caspase-9在Thr125处的磷酸化可能会在对高渗应激的急性反应中抑制细胞凋亡。

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