Molecular Regulation of Exocytosis

描述（由申请方提供）：胞吐作用由分泌囊泡从高尔基体网络和内体向质膜的转运、对接和融合介导。 由于胞吐作用在从激素释放到胚胎发生的广泛生理过程中是中心参与的，并且受到严格控制，因此了解调节胞吐作用的分子机制是重要的。我们的研究集中在胞吐途径中两个独立但相连的“模块”，Rab GTP酶和胞吐复合物，这两个模块从酵母到人类都是进化保守的。 在这个提议中，我们将首先研究控制Rabin 8激活的分子机制，Rabin 8是Rab 8的鸟嘌呤核苷酸交换因子（GEF），Rab 8是哺乳动物细胞胞吐的主要调节因子。我们将研究磷脂酰肌醇和上游Rab蛋白Rab 11在Rabin 8激活中的作用。此外，我们还将研究细胞外信号调节激酶1/2（ERK 1/2）在表皮生长因子（EGF）信号转导中对Rabin 8 GEF活性的磷酸化和调节。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。 这些研究不仅有助于从分子水平阐明胞吐的调控机制，而且有助于我们对糖尿病、多囊肾等疾病的认识。

DESCRIPTION (provided by applicant): 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 wil 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 regulatry 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).