Exosome Trafficking and Tumor Cell Invasion

项目概要： 外泌体是一种分泌的细胞外囊泡，含有蛋白质等生物活性分子 和microRNA。外泌体最近引起了相当大的兴趣，因为它们涉及 在许多病理生理过程中，如神经变性、病毒繁殖和肿瘤 入侵尽管在医学领域有很大的兴趣，但基本的细胞生物学理解 外泌体的数量是非常缺乏的。外来体是在限制性的 内体的膜向管腔内陷以形成多泡体（MVB）。 负责转运的内体分选复合物（ESCRT）介导了 外泌体然而，外泌体如何被递送到质膜以用于它们的 释放仍然难以捉摸。外囊是由Sec 3，Sec 5， Sec 6、Sec 8、Sec 10、Sec 15、Exo 70和Exo 84。外囊被认为介导了 蛋白质和脂质从细胞内区室运输到质膜。我们 初步数据显示，外囊直接与ESCRT相互作用，并抑制ESCRT的表达。 细胞中的外囊阻止外泌体分泌。在这个建议中，我们将首先研究分子 外泌体的生物发生和释放是由不同的细胞因子协调的。 外囊复合体的成员。其次，我们将研究外泌体的分泌是如何 在肿瘤细胞侵袭过程中调节;致癌Akt促进肿瘤细胞侵袭的分子途径 将描述通过Rab GT3活化的外泌体分泌。我们的研究将 有助于理解外来体的基础生物学，并阐明 肿瘤细胞侵袭的机制。

PROJECT SUMMARY: Exosomes are secreted extracellular vesicles that contain bioactive molecules such as proteins and microRNAs. The exosomes have recently drawn considerable interest as they are implicated in many pathophysiological processes such as neurodegeneration, viral propagation, and tumor invasion. Despite the great interests in the medical fields, the basic cell biological understanding of the exosomes is disproportionally lacking. The exosomes are generated when the limiting membranes of endosomes invaginate toward the lumen to form multivesicular bodies (MVBs). The Endosomal Sorting Complex Responsible for Transport (ESCRT) mediates the biogenesis of the exosomes. However, how the exosomes are delivered to the plasma membrane for their release remains elusive. The exocyst is an octameric protein complex consisting of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70, and Exo84. The exocyst is thought to mediate the trafficking of protein and lipid cargos from intracellular compartments to the plasma membrane. Our preliminary data revealed that the exocyst directly interacts with the ESCRT and inhibition of the exocyst in cells block exosome secretion. In this proposal, we will first study the molecular mechanisms by which the biogenesis and release of exosomes is coordinated by different members of the exocyst complex. Second, we will investigate how the secretion of exosomes is regulated during tumor cell invasion; a molecular pathway by which oncogenic Akt promotes exosome secretion through the activation of Rab GTPase will be delineated. Our study will contribute to the understanding of the basic biology of exosomes, and shed light to the mechanisms of tumor cell invasion.