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首页> 外文学位 >Regulation of MAPK/JNK signaling pathway and TGF-beta signaling pathway by Axin.
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Regulation of MAPK/JNK signaling pathway and TGF-beta signaling pathway by Axin.

机译：Axin对MAPK / JNK信号通路和TGF-β信号通路的调节。

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摘要

Axin was originally identified from the characterization of the Fused locus, the disruption of which leads to duplication of axis and embryonic lethality. Axin is a multidomain protein that interacts with multiple proteins and functions as a negative regulator of Wnt signaling by downregulating the beta-catenin levels. It also plays an important role in a JNK signaling pathway.; Through study functions of Axin C-terminal, we found Axin interacts with three SUMO-1 (small ubiquitin-related modifier) E3 ligases, PIAS1, PIASxbeta, and PIASy. The extreme C-terminal six amino acid residues of Axin are critical for the Axin/E3 interaction. In consistence with the presence of a doublet of the "KVE/D" sumoylation consensus motif at the C-terminal end (KVEKVD), we found that Axin is heavily sumoylated. Deletion of the C-terminal six amino acid drastically reduced sumoylation, indicating that the C-terminal six amino acid stretch is the main sumoylation site for Axin. In addition, Axin lacking last six residues, AxinDeltaC6, failed to activate JNK although it was intact in both its interaction with MEKK1 and homodimerization. AxinDeltaC6 still could effectively destabilize beta-catenin and attenuate LEF1 transcriptional activity. Taken together, we demonstrate that sumoylation plays a role for Axin to function in the JNK pathway.; We also identified Arkadia as novel Axin interacting protein. Arkadia is a protein that enhances signaling activity of TGF-beta/Nodal and BMP through interacting with inhibitory Smad, Smad7, and function as an E3 ubiquitin ligase to introduce poly-ubiquitination of Smad7. We showed that both Axin and Arkadia can activate TGF-beta dependent transcription, and the certain effect of Axin is mainly through Arkadia. Moreover, Axin interacts with inhibitory Smad, Smad7. Axin is able to enhance poly-ubiquitination of Smad7, which also requires Arkadia. Our finding suggests Axin may serve as an adaptor, facilitating Arkadia mediated poly-ubiquitination of Smad7.
机译：Axin最初是从融合基因座的特征中鉴定出来的，破坏该基因会导致轴重复和胚胎致死率的重复。 Axin是一种多域蛋白，可与多种蛋白相互作用，并通过下调β-catenin水平充当Wnt信号的负调节剂。它在JNK信号通路中也起重要作用。通过研究Axin C末端的功能，我们发现Axin与三种SUMO-1（小泛素相关修饰物）E3连接酶，PIAS1，PIASxbeta和PIASy相互作用。 Axin的极端C末端六个氨基酸残基对于Axin / E3相互作用至关重要。与在C末端（KVEKVD）上存在“ KVE / D” sumoylation共有基序的对偶一致，我们发现Axin被高度sumoylated了。 C-末端六个氨基酸的缺失极大地减少了磺酰化，表明C-末端六个氨基酸的延伸是Axin的主要sumoylation位点。此外，缺乏AxinDeltaC6的最后六个残基的Axin未能激活JNK，尽管它与MEKK1的相互作用和同二聚化均完整无缺。 AxinDeltaC6仍然可以有效地破坏β-catenin的稳定性并减弱LEF1转录活性。两者合计，我们证明了sumoylation在Axin在JNK途径中发挥作用。我们还确定Arkadia为新型Axin相互作用蛋白。 Arkadia是一种蛋白质，可通过与抑制性Smad，Smad7相互作用来增强TGF-β/ Nodal和BMP的信号传导活性，并起着E3泛素连接酶的作用，从而引入Smad7的多聚泛素化作用。我们表明，Axin和Arkadia都可以激活TGF-beta依赖性转录，并且Axin的某些作用主要是通过Arkadia。此外，Axin与抑制性Smad，Smad7相互作用。 Axin能够增强Smad7的多聚泛素化，这也需要Arkadia。我们的发现表明Axin可以充当衔接子，促进Arkadia介导的Smad7的多聚泛素化。

著录项

  • 作者

    Rui, Hongliang.;

  • 作者单位

    Hong Kong University of Science and Technology (People's Republic of China).;

  • 授予单位 Hong Kong University of Science and Technology (People's Republic of China).;
  • 学科 Biology Molecular.; Biology Cell.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 151 p.
  • 总页数 151
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;
  • 关键词

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