Regulation of the ubiquitin-ligase itch

我们的研究兴趣集中在内吞机制和蛋白质沿内吞途径的运输上。我们特别感兴趣的是一种名为Itch的蛋白质，它是一种能够将泛素附着到其他蛋白质上的酶。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，它通常被用来标记要内化的蛋白质，或者当它针对内吞蛋白本身时，介导额外的蛋白质-蛋白质相互作用。我们发现，Itch定位于细胞内的跨高尔基体网络和内小体。这种分布可以使Itch在内吞作用后与来自质膜的蛋白质相互作用，并有可能对它们进行修饰。为了解决这一假设，我们研究了表皮生长因子受体(EGFR)，这是一种经过充分研究的质膜蛋白，在激活后很容易被内吞。通过改变Itch的表达水平，或使用我们实验室设计的Ich突变体，我们正在研究Itch介导的活性在内体蛋白运输调节中的重要性。除了这项工作对全球了解细胞功能的基本重要性之外，我们的工作还可能揭示控制酪氨酸激酶受体(如EGFR)的新靶向机制，EGFR在致瘤细胞中的活性通常是异常的。

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.