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首页> 外文学位 >The ever expanding role of Hsp90-Cdc37 chaperone complex in cell signaling networks.
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The ever expanding role of Hsp90-Cdc37 chaperone complex in cell signaling networks.

机译：Hsp90-Cdc37分子伴侣复合物在细胞信号网络中的作用不断扩大。

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摘要

Hsp90 is a well conserved chaperone which plays a role in a wide range of cellular processes including gene regulation, telomere maintenance, protein trafficking, cell signaling, and protein synthesis. Hsp90 functions with other co-chaperones including Cdc37, which interacts specifically with kinases to regulate stability and activity of various kinases. Hsp90 also serves as a scaffold protein to facilitate signaling pathways. Here, we have isolated Hsp90 and Cdc37 from cardiac p38alpha MAPK complex, and we showed p38alpha directly interacts with Cdc37 to form a complex with Hsp90. Interestingly, pharmacological inhibition of Hsp90 led to a robust increase in autophosphorylation of p38alpha both in vivo and in vitro. Furthermore, we found that Cdc37 is both necessary and sufficient to regulate the basal activity of p38 through autophosphorylation. To determine whether the regulation of autophosphorylation by Hsp90-Cdc37 complex is unique to p38alpha MAPK, IRE1alpha, an ER resident protein which can also autophosphorylate, was also investigated. We identified IRE1alpha not only interacts with Hsp90-Cdc37 complex, but it is also activated in response to Hsp90 inhibition or Cdc37 knockdown. This IRE1alpha activation was reversed by kinase-dead mutant of IRE1alpha (IRE1alphaKD), suggesting that Hsp90-Cdc37 complex also regulates IRE1alpha activity through autophosphorylation. Thus, we have demonstrated here a novel role of Hsp90-Cdc37 complex as a negative regulator of autophosphorylation. To examine the relevance of p38 activity at a physiological level, its role in cardiac contractility was also investigated. The result indicated p38 activation results in decreased contractility mediated by depression in maximal tension and maximal ATPase activity associated with phosphorylation of alpha-Tm. Since Hsp90 is associated with many other proteins including receptors, signaling proteins, and cytoskeleton, it is speculated that Hsp90 may function as a hub in different signaling networks to sustain cellular homeostasis.
机译：Hsp90是一个保存完好的分子伴侣，在多种细胞过程中起作用，包括基因调控，端粒维持，蛋白质运输，细胞信号传导和蛋白质合成。 Hsp90与其他辅助伴侣一起起作用，包括Cdc37，后者与激酶特异性相互作用，以调节各种激酶的稳定性和活性。 Hsp90还用作支架蛋白以促进信号传导途径。在这里，我们从心脏p38alpha MAPK复合物中分离了Hsp90和Cdc37，并且我们显示p38alpha与Cdc37直接相互作用，与Hsp90形成复合物。有趣的是，在体内和体外，对Hsp90的药理抑制作用导致p38α自身磷酸化的强烈增加。此外，我们发现Cdc37既必要又足以通过自身磷酸化调节p38的基础活性。为了确定Hsp90-Cdc37复合物对自身磷酸化的调控是否是p38alpha MAPK所独有的，还研究了IRE1alpha，它也是一种能够自磷酸化的ER驻留蛋白。我们发现IRE1alpha不仅与Hsp90-Cdc37复合物相互作用，而且还响应Hsp90抑制或Cdc37敲低而被激活。 IRE1alpha的激酶死亡突变体（IRE1alphaKD）逆转了IRE1alpha的激活，表明Hsp90-Cdc37复合物还通过自身磷酸化调节IRE1alpha的活性。因此，我们在这里证明了Hsp90-Cdc37复合物作为自磷酸化的负调节剂的新作用。为了在生理水平上检查p38活性的相关性，还研究了其在心脏收缩中的作用。结果表明，p38激活导致最大张力降低和与α-Tm磷酸化相关的最大ATPase活性介导的收缩力降低。由于Hsp90与许多其他蛋白质（包括受体，信号蛋白和细胞骨架）相关，因此推测Hsp90可能在不同信号网络中充当枢纽，以维持细胞稳态。

著录项

  • 作者

    Ota, Asuka.;

  • 作者单位

    University of California, Los Angeles.;

  • 授予单位 University of California, Los Angeles.;
  • 学科 Biology Molecular.;Biology Physiology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 122 p.
  • 总页数 122
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:19

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