Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia
Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia
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DOI：
10.1111/j.1460-9568.2008.06209.x
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发表时间：
2008-05-01
影响因子：
3.4
通讯作者：
Shamloo, Mehrdad
中科院分区：
文献类型：
--
作者：
Braithwaite, Steven P.;Xu, Jian;Shamloo, Mehrdad
纹状体富集蛋白酪氨酸磷酸酶（STEP）在中枢神经系统中起作用，使许多参与突触功能的重要蛋白质（包括ERK和NMDA受体亚基）去磷酸化。这些蛋白质也与中风有关，中风时脑缺血会引发一系列复杂的事件。在这里，我们表明，STEP的调节在转录和转录后水平在大鼠脑缺血模型，它的调节可能发挥作用，在缺血性损伤的结果。短暂性大脑中动脉闭塞后，STEP mRNA水平显著降低，而在全脑缺血时，STEP mRNA在易受缺血性损伤的区域选择性下调。在神经保护性预处理范例中，并且在相对抵抗缺血性损伤的脑区域中，STEP mRNA水平增加。此外，有一个显着的处理后，缺血的STEP产生一种新的物种，STEP33，导致STEP的重新分配从膜结合的可溶性隔室。伴随着STEP成熟形式的裂解，ERK的磷酸化状态发生变化。我们表明，STEP的裂解导致催化活性形式，但这种裂解形式不再结合到其底物pERK并使其去磷酸化。因此，响应于缺血性损伤，STEP的量和活性、其定位以及其关键底物之一pERK的活性均显著降低。STEP的这些变化可能反映了缺血性脑损伤结局中的关键作用。
Striatal enriched protein tyrosine phosphatase (STEP) acts in the central nervous system to dephosphorylate a number of important proteins involved in synaptic function including ERK and NMDA receptor subunits. These proteins are also linked to stroke, in which cerebral ischemia triggers a complex cascade of events. Here we demonstrate that STEP is regulated at both the transcriptional and the post-transcriptional levels in rat models of cerebral ischemia and that its regulation may play a role in the outcome of ischemic insults. After transient middle cerebral artery occlusion, there are profound decreases in the levels of STEP mRNA, whilst in global ischemia STEP mRNA is selectively down-regulated in areas susceptible to ischemic damage. In a neuroprotective preconditioning paradigm, and in regions of the brain that are relatively resistant to ischemic damage, STEP mRNA levels are increased. Furthermore, there is a significant processing of STEP after ischemia to generate a novel species, STEP33, resulting in a redistribution of STEP from membrane-bound to soluble compartments. Concomitant with the cleavage of mature forms of STEP, there are changes in the phosphorylation state of ERK. We show that the cleavage of STEP leads to a catalytically active form, but this cleaved form no longer binds to and dephosphorylates its substrate pERK. Therefore, in response to ischemic insults, there are profound reductions in both the amount and the activity of STEP, its localization, as well as the activity of one of its key substrates, pERK. These changes in STEP may reflect a critical role in the outcomes of ischemic brain injury.