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Regulation of growth factor receptor downregulation by a deubiquitinating enzyme UBPY

去泛素化酶 UBPY 对生长因子受体下调的调节

基本信息

批准号：
17570156
负责人：
KOMADA Masayuki
金额：
$ 2.24万
依托单位：
Tokyo Institute of Technology
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

1.Regulation of the epidermal growth factor (EGF) receptor downregulation by a deubiquitinating enzyme UBPYUbiquitination of ligand-activated EGF receptor serves as a signal that targets the protein for lysosomal trafficking. We found that UBPY deubiquitinates activated EGF receptor on early endosomes and delays its downregulation. These results indicated that by removing the "lysosome-targeting signal" from the receptor and inhibiting its trafficking to lysosomes, UBPY regulates the downregulation of EGF receptor negatively.2.Regulation of the morphology of early endosomes by a deubiquitinating enzyme UBPYInhibition of the UBPY function by expressing a dominant-negative mutant or siRNA resulted in the accumulation of ubiquitinated proteins on early endosomes and the morphological aberration of the organelle. Electromicroscopic study showed that early endosomes are aberrantly aggregated in UBPY-inhibited cells. These results suggested that the regulation of the level of protein ubiquit … More ination on early endosomes by UBPY is essential for maintaining the morphology of the organelle.3.Regulation of the deubiquitinating activity of UBPY by 14-3-3 proteins in the M phaseWe found that UBPY binds 14-3-3 proteins via a consensus 14-3-3-binding motif, RSYS^<680>SP. The binding required the phosphorylation of S^<680>. We also found that the binding of 14-3-3 inhibits the catalytic activity of UBPY. Finally, UBPY is dephosphorylated, dissociated from 14-3-3 proteins, and catalytically activated in the M phase, suggesting that elevated activity of UBPY regulates the functions of early endosomes in the M phase.4.Mechanism of the localization of a deubiquitinating enzyme AMSH to early endosomesWe found that AMSH and its homolog AMSH-like protein (AMSH-LP) bind to the terminal domain of clathrin heavy chain via a novel ~30-amino-acid clathrin-binding motif which is conserved between AMSH and AMSH-LP. Deletion of the clathrin-binding motif from these deubiquitinating enzymes, as well as siRNA-mediated knockdown of cellular clathrin, led to their mislocalization to the cytoplasm. These results suggested that AMSH and AMSH-LP are anchored to early endosomes through the interaction with the clathrin coat on the endosomal membrane. Less

1.通过去泛素化酶UBPY调节表皮生长因子（EGF）受体下调配体激活的EGF受体的泛素化作为靶向蛋白质进行溶酶体运输的信号。我们发现UBPY去泛素化早期内体上激活的EGF受体并延迟其下调。这些结果表明，通过从受体中去除“溶酶体靶向信号”并抑制其向溶酶体的运输，UBPY负性调节EGF受体的下调。2.去泛素化酶UBPY对早期内体形态的调节通过表达一个显性的-阴性突变体或siRNA导致泛素化蛋白在早期内体上的积累和细胞器的形态畸变。电镜观察显示，UBPY抑制细胞早期内体异常聚集。这些结果表明，蛋白质泛素化水平的调节 ...更多信息 14-3-3蛋白在M期对UBPY去泛素化活性的调节我们发现UBPY通过一个共有的14 - 3-3-结合基序（Rb-SP）与14 -3-3蛋白结合，<680>这种结合需要S^的磷酸化<680>。我们还发现14-3-3的结合抑制了UBPY的催化活性。最后，UBPY被去磷酸化，与14-3-3蛋白质解离，并在M期被催化活化，4.去泛素化酶AMSH定位于早期内体的机制我们发现AMSH及其同源物AMSH-like protein（AMSH-LP）通过一种新的~（18）-结合方式与网格蛋白重链的末端结构域结合。AMSH和AMSH-LP之间保守的30个氨基酸网格蛋白结合基序。从这些去泛素化酶中删除网格蛋白结合基序，以及siRNA介导的细胞网格蛋白敲除，导致它们错误定位于细胞质。这些结果表明AMSH和AMSH-LP通过与内体膜上的网格蛋白涂层相互作用锚定到早期内体。少

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of endosomal membrane traffic by deubiquitinating enzymes.

通过去泛素化酶调节内体膜运输。

DOI：
发表时间：
2006
期刊：
Cell Technology 25
影响因子：
0
作者：
Komada;M.;Mizuno;E.
通讯作者：
E.

エンドソームにおけるメンブレントラフィックの脱ユビキチン化酵素による調節

通过去泛素化酶调节内涵体中的膜运输

DOI：
发表时间：
2006
期刊：
細胞工学 25(11)
影响因子：
0
作者：
駒田雅之;水野英美
通讯作者：
水野英美

bIV-spectrin forms a diffusion barrier against L1CAM at the axon initial segment.

bIV-血影蛋白在轴突起始段形成针对 L1CAM 的扩散屏障。

DOI：
发表时间：
2007
期刊：
Mol Cell Neurosci 34
影响因子：
0
作者：
Nishimura K;Akiyama H;Komada M;Kamiguchi H
通讯作者：
Kamiguchi H

The Ca^<2+>-binding protein ALG-2 is recruited to ER exit sites by Sec31A and stabilizes the localization of Sec31A

Ca^2结合蛋白ALG-2被Sec31A募集至ER出口位点并稳定Sec31A的定位

DOI：
发表时间：
2006
期刊：
Mol. Biol. Cell 17
影响因子：
0
作者：
Moriyama-Kita M;et al.;佐藤博;E. Shirako;A. Kondo;E. Mizuno;M.Nakamura;E.Mizuno;M.Maemura;A.Yamasaki
通讯作者：
A.Yamasaki

Specific role of the truncated bIV-spectrin S6 in sodium channel clustering at axon initial segments and nodes of Ranvier

截短的bIV-血影蛋白S6在朗飞轴突初始段和节点钠通道聚集中的具体作用