The Role of the Exocyst in Cell Migration

描述(由申请人提供)：细胞迁移对于从趋化和伤口愈合到神经元发育和胚胎发育等广泛的生理过程都是重要的。细胞迁移需要肌动蛋白网络的动态组装和膜的重塑。在细胞迁移过程中，肌动蛋白动力学和膜活性如何协调是该领域的一个基本问题。胞囊是一种由Sec3、Sec5、Sec6、Sec8、Sec10、Sec15、Exo70和Exo84组成的多蛋白复合体，介导胞吐和极化细胞表面扩张。近年来，胞外囊泡在细胞迁移过程中扮演着重要角色。胞外成分Exo70直接与Arp2/3复合体相互作用，并在动力学上刺激Arp2/3复合体进行肌动蛋白聚合和分支。此外，Exo70还诱导细胞膜弯曲以产生表面突起。因此，Exo70将肌动蛋白动力学与突起形成和细胞迁移的膜重塑结合在一起。在这里，我们建议研究Exo70促进膜曲率诱导和Arp2/3复合体介导的肌动蛋白重塑的分子机制。此外，我们将研究胞外包囊复合体、Arp2/3复合体和EHD家族在从分选内小体产生分泌小泡的过程中的协调作用，该内体介导整合素循环到迁移的前沿。我们采取了结合生物化学、生物物理学、显微成像和分子动力学模拟的多学科方法来解决该领域中正在出现的重要问题。这些研究将有助于我们阐明细胞迁移的分子机制，并有助于我们理解一些疾病，如神经系统疾病和癌症。

DESCRIPTION (provided by applicant): Cell migration is important for a wide range of physiological processes from chemotaxis and wound healing, to neuron development and embryogenesis. Cell migration requires the dynamic assembly of the actin network and remodeling of the membrane. How actin dynamics and membrane activities are coordinated during cell migration is a fundamental question in the field. The exocyst, a multiprotein complex consisting of Sec3, Sec5, Sec6, Sec8, Sec10, Sec15, Exo70 and Exo84, mediates exocytosis and polarized cell surface expansion. Recently, the exocyst emerges as an important player in cell migration. The exocyst component Exo70 directly interacts with, and kinetically stimulates, the Arp2/3 complex for actin polymerization and branching. In addition, Exo70 induces membrane curvature to generate surface protrusions. Exo70 therefore couples actin dynamics with membrane remodeling for protrusion formation and cell migration. Here we propose to examine the molecular mechanisms by which Exo70 promotes membrane curvature induction and the Arp2/3 complex-mediated actin remodeling. Furthermore, we will investigate the coordinated actions of the exocyst complex, the Arp2/3 complex, and the EHD family of "pinchases" in the generation of secretory vesicles from the sorting endosome that mediates integrins recycling to the leading edge for migration. We take a multi-disciplinary approach combining biochemistry, biophysics, microscopic imaging, and molecular dynamics simulation to address important emerging questions in the field. These studies will help us to elucidate the molecular mechanisms of cell migration, and contribute t our understanding of a number of diseases such neurological disorders and cancer.