Sustained activation of Src-family tyrosine kinases by ischemia: A potential mechanism mediating extracellular signal-regulated kinase cascades in hippocampal dentate gyrus
Sustained activation of Src-family tyrosine kinases by ischemia: A potential mechanism mediating extracellular signal-regulated kinase cascades in hippocampal dentate gyrus
复制标题
缺血引起的 Src 家族酪氨酸激酶持续激活：介导海马齿状回细胞外信号调节激酶级联的潜在机制
DOI：
10.1016/j.neuroscience.2006.08.031
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发表时间：
2006-12-13
期刊：
影响因子：
3.3
通讯作者：
Sun, Y. J.
中科院分区：
文献类型：
--
作者：
Guo, J.;Wu, H. W.;Sun, Y. J.
在本报告中，我们研究了持续激活的Src家族酪氨酸激酶（主要是Src激酶）与缺血诱导的细胞外信号调节激酶（ERK）的双相磷酸化之间的关联在大鼠海马CA 3/齿状回亚区。缺血再灌注后ERK磷酸化呈Ras依赖性;氯胺酮或4-氨基-5-甲基-N-甲基-D-天冬氨酸受体或Src家族蛋白激酶的下调（4-氯苯基）-7-（叔丁基）吡唑并[3，4-d]嘧啶（PP 2）能有效地拮抗ERK的激活，表明NMDA受体和Src家族酪氨酸激酶对于缺血刺激后ERK活性的上调至关重要。此外，缺血诱导的RKIP和Raf-1之间的关联通过抑制Src介导的Raf-1在Tyr 340/341残基的磷酸化而导致ERK信号级联的抑制。这种缺血诱导的ERK抑制与蛋白激酶B（Akt）引起的Raf-1丝氨酸259磷酸化的其他下游途径无关。通过24小时再灌注或（4S）-3-[（E）-丁-2-烯酰基]-4-苄基-2-恶唑烷酮（locostatin）使Raf-1从RKIP解离影响Src-Raf盒引起的ERK激活的第二阶段。我们建议，缺血后，Src家族酪氨酸激酶是至关重要的Ras/Raf/MEK/ERK级联，其中RKIP参与ERK的双相磷酸化通过阻断Src-Raf级联的调制。(c)2006年IBRO。由Elsevier Ltd.出版。保留所有权利。
In the present report, we investigated the association between the sustained activation of Src family tyrosine kinases (primarily Src kinase) with the biphasic phosphorylation of extracellular signal-regulated kinase (ERK) induced by ischemia in the rat hippocampal CA3/dentate gyrus sub-field. Post-ischemia reperfusion resulted in the phosphorylation of ERK in a Ras-dependent manner; down-regulation of NMDA receptors or Src family protein kinases by ketamine or 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP2) potently antagonized the activation of ERK, indicating that NMDA receptors and Src family tyrosine kinases are essential for the up-regulation of ERK activity following ischemic stimuli. Additionally, an ischemia-induced association between RKIP and Raf-1 resulted in the inhibition of the ERK signaling cascade through an inhibition of Src-mediated Raf-1 phosphorylation at Tyr340/341 residues. This ischemia-induced inhibition of ERK was not associated with other downstream pathways involving Raf-1 phosphorylation at Ser 259 elicited by protein kinase B (Akt). Dissociation of Raf-1 from RKIP by 24 h reperfusion or (4S)-3-[(E)-but-2-enoyl]-4-benzyl-2-oxazolidinone (locostatin) influenced the second phase of ERK activation elicited by the Src-Raf cassette. We propose that, following ischemia, the Src family tyrosine kinases are critical for modulation of the Ras/Raf/MEK/ERK cascade, in which RKIP is involved in biphasic phosphorylation of ERK via a blockade of Src-Raf cascades. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.