Exosome Trafficking and Tumor Cell Invasion

项目总结： 胞外体是分泌在细胞外的囊泡，含有蛋白质等生物活性分子。 和microRNAs。外切体最近引起了相当大的兴趣，因为它们被牵连在一起 在许多病理生理过程中，如神经变性、病毒传播和肿瘤 入侵。尽管医学领域有很大的兴趣，但对细胞生物学的基本理解 不成比例地缺乏外切体。外体的产生是在限制 内体的膜向管腔内陷，形成多囊泡体。 负责运输的内体分选复合体(ESCRT)介导的生物发生 外显体。然而，外切体是如何被运送到质膜上的 释放仍然难以捉摸。外囊是由Sec3、Sec5、Sec3和Sec5组成的八聚体蛋白质复合体。 第6、第8、第10、第15、第70和第84节。排泄物被认为参与了人口贩运。 蛋白质和脂肪货物从细胞内隔间到质膜。我们的 初步数据显示，外囊直接与ESCRT相互作用，并抑制 细胞内的外囊阻碍外切体的分泌。在这个提案中，我们将首先研究分子 外切体的生物发生和释放通过不同的方式协调的机制 外囊复合体的成员。第二，我们将研究外切体的分泌是如何 肿瘤细胞侵袭过程中的调控；致癌Akt促进的分子途径 将描述通过激活Rab GTP酶而产生的外切体分泌。我们的研究将 有助于理解外切体的基本生物学，并为 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.