...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways
【24h】

Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways

机译：细胞周期蛋白依赖性激酶（CDK）磷酸化通过多种途径破坏体细胞Wee1

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

At the onset of M phase, the activity of somatic Wee1 (Wee1 A), the inhibitory kinase for cyclin-dependent kinase (CDK), is down-regulated primarily through proteasome-dependent degradation after ubiquitination by the E3 ubiquitin ligase SCPbeta-TrcP. The F-box protein beta-TrCP (beta-transducin repeat-containing protein), the substrate recognition component of the ubiquitin ligase, binds to its substrates through a conserved binding motif (phosphodegron) containing two phosphoserines, DpSGXXpS. Although Wee1A lacks this motif, phosphorylation of serines 53 and 123 (S53 and S123) of Wee1A by polo-like kinase 1 (Plk1) and CDK, respectively, are required for binding to beta-TrCP. The sequence surrounding phosphorylated S53 (DpSAFQE) is similar to the conserved beta-TrCP-binding motif; however, the role of S123 phosphorylation (EEGFGSSpSPVK) in beta-TrCP binding was not elucidated. in the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to beta-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of beta-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2), to create two phosphodegrons on Wee1A. In the case of Plk1, S123 phosphorylation created a polo box domain-binding motif (SpSP) on Wee1A to accelerate phosphorylation of S53 by Plk1. CK2 could phosphorylate S121, but only if S123 was phosphorylated first, thereby generating the second)beta-TrCP-binding site (EEGFGpS121). Using a specific inhibitor of CK2, we showed that the phosphorylation-dependent degradation of Wee1A is important for the proper onset of mitosis.
机译：在M期开始时，E3泛素连接酶SCPbeta-TrcP泛素化后，主要通过蛋白酶体依赖性降解来下调细胞周期蛋白Wee1（Wee1 A）的活性，这是细胞周期蛋白依赖性激酶（CDK）的抑制激酶。 F-box蛋白β-TrCP（含β-转导蛋白重复序列​​的蛋白质）是泛素连接酶的底物识别成分，通过包含两个磷酸丝氨酸DpSGXXpS的保守结合基序（磷极）来与其底物结合。尽管Wee1A缺少此基序，但与β-TrCP结合时，分别需要polo样激酶1（Plk1）和CDK使Wee1A的丝氨酸53和123（S53和S123）磷酸化。磷酸化的S53（DpSAFQE）周围的序列类似于保守的beta-TrCP结合基序。但是，尚没有阐明S123磷酸化（EEGFGSSpSPVK）在β-TrCP结合中的作用。在本研究中，我们显示CDK对S123（pS123）的磷酸化通过三种独立的机制促进了Wee1A与β-TrCP的结合。 pS123不仅直接与β-TrCP的WD40重复结构域中的碱性残基相互作用，而且还通过两个独立的蛋白激酶Plk1和CK2（以前称为酪蛋白激酶2）引发了磷酸化作用，从而在Wee1A上产生了两个磷酸腺嘌呤。在Plk1的情况下，S123磷酸化在Wee1A上创建了一个polo box域结合基序（SpSP），以加速Plk1对S53的磷酸化。 CK2可以磷酸化S121，但前提是先将S123磷酸化，从而生成第二个β-TrCP结合位点（EEGFGpS121）。使用特定的CK2抑制剂，我们表明Wee1A的磷酸化依赖性降解对于适当的有丝分裂发作很重要。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号