Regulation of the ubiquitin-ligase itch

泛素连接酶痒的调节

• 批准号: 288238-2006
• 负责人: Angers, Annie
• 金额: $ 2.42万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2008
• 资助国家: 加拿大
• 起止时间: 2008-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=395745
• 关键词: Regulation; ubiquitin; ligase; itch

Our research interests are focused on endocytic mechanisms, and on protein trafficking along the endocytic pathways. We are particularly interested by a protein named Itch, an enzyme capable of attaching ubiquitin to other proteins. This process called ubiquitination can have many consequences, but in endocytosis it is generally used to tag the proteins to be internalized, or to mediate additional protein-protein interactions when it targets endocytic proteins themselves. We have found that Itch is localized inside cells to the trans-Golgi network and endosomes. This distribution could allow Itch to interact with proteins coming from the plasma membrane after endocytosis, and to potentially modify them. To address this hypothesis, we examine the epidermal growth factor receptor (EGFR), a well studied plasma membrane protein that is readily endocytosed following activation. By modifying Itch expression level, or using Itch mutants designed in our laboratory, we are examining the importance of Itch mediated activity in endosomal protein traffic regulation. Beyond the fundamental importance of this work toward a global understanding of cellular function, our work could reveal new target mechanisms to control tyrosine kinase receptors like EGFR, whose activity is often abnormal in tumorigenic cells.

我们的研究兴趣集中在内吞机制，以及沿内吞途径的蛋白质运输。我们对一种名为Itch的蛋白质特别感兴趣，这种酶能够将泛素附着在其他蛋白质上。这个被称为泛素化的过程可能有许多后果，但在内吞作用中，它通常用于标记要内化的蛋白质，或者当它靶向内吞蛋白本身时介导额外的蛋白质-蛋白质相互作用。我们已经发现瘙痒是定位于细胞内的反式高尔基网络和核内体。这种分布可能允许Itch在内吞作用后与来自质膜的蛋白质相互作用，并可能修饰它们。为了解决这一假设，我们研究了表皮生长因子受体（EGFR），这是一种被充分研究的质膜蛋白，在激活后很容易被内吞。通过修改瘙痒表达水平，或使用我们实验室设计的瘙痒突变体，我们正在研究瘙痒介导的活性在内体蛋白交通调节中的重要性。除了这项工作对全面了解细胞功能的重要意义之外，我们的工作还可以揭示控制酪氨酸激酶受体（如EGFR）的新靶标机制，EGFR的活性在致瘤细胞中经常异常。