Molecular Regulation of Exocytosis

项目摘要 胞吐作用是通过运输、对接和融合来自反式高尔基体的分泌小泡来实现的 网络和内容体连接到质膜上。因为胞吐作用是中心参与的，而且密切相关 在从荷尔蒙释放到胚胎发育的广泛生理过程中，它受到控制 对了解调节胞吐作用的分子机制很重要。我们的研究重点是 胞吐作用途径中的两个独立但相连的“模块”，即Rab GTP酶和胞囊 这两种基因从酵母到人类在进化上都是保守的。在这项提案中，我们将 首先研究控制Rabin8活性的分子机制，即鸟嘌呤 针对Rab8的核苷酸交换因子，这是哺乳动物细胞胞吐作用的主要调节因子。我们 将研究磷脂酰肌醇和上游Rab蛋白Rab11在激活中的作用 拉宾8号。此外，我们还将通过以下方式研究Rabin8蛋白的磷酸化和活性调节 细胞外信号调节蛋白1/2(ERK1/2)在反应性表皮生长因子中的表达 发信号。最后，我们将确定外囊在SNARE介导的膜融合中的作用。我们 采取多学科结合的方法，结合生物化学，生物物理学，酵母遗传学和 显微成像以解决该领域的关键问题。这些研究不仅将帮助我们 在分子水平上阐明胞吐作用的调节机制，也有助于我们的 了解糖尿病和多囊肾病(PKD)等多种疾病。

Project Summary Exocytosis is mediated by transport, docking and fusion of secretory vesicles from trans-Golgi network and endosomes to the plasma membrane. As exocytosis is centrally involved, and tightly controlled, in a wide range of physiological processes from hormone release to embryogenesis, it is important to understand the molecular mechanisms that regulate exocytosis. Our research focuses on two separate but connected "modules" in the exocytosis pathway, the Rab GTPases and the exocyst complex, both of which are evolutionarily conserved from yeast to humans. In this proposal, we will first investigate the molecular mechanisms that control the activation of Rabin8, which is the guanine nucleotide exchange factor (GEF) for Rab8, a major regulator of exocytosis in mammalian cells. We will examine the role of phosphatidylinositides and an upstream Rab protein, Rab11, in the activation of Rabin8. In addition, we will examine the phosphorylation and regulation of Rabin8 GEF activity by Extracellular signal-regulated kinases 1/2 (ERK1/2) in response epidermal growth factor (EGF) signaling. Finally, we will determine the role of the exocyst in SNARE-mediated membrane fusion. We take a multi-disciplinary approach combining biochemistry, biophysics, yeast genetics and microscopic imaging to address key questions in the field. These studies will not only help us elucidate the regulatory mechanisms of exocytosis at the molecular level, but also contribute to our understanding of a number of diseases such as diabetes and polycystic kidney diseases (PKD).