The role of the exocyst in cell migration

描述（由申请人提供）：细胞通过产生突起开始迁移，这需要分支肌动蛋白网络的动态组装和质膜的重塑。细胞迁移过程中肌动蛋白动力学和膜活动如何协调是该领域的一个基本问题。外泌囊是一种多蛋白复合物，介导胞吐作用和极化细胞表面扩张，最近已被证明在细胞迁移中发挥重要作用。我们最近发现，外囊组分Exo 70直接与Arp 2/3复合物相互作用，Arp 2/3复合物是使肌动蛋白成核的核心机制，用于在质膜的前缘下方产生分支肌动蛋白网络。表皮生长因子（EGF）刺激外泌囊与Arp 2/3的相互作用，这种相互作用对于有效的膜突出和定向迁移是重要的。我们推测外囊通过与Arp 2/3复合物相互作用和物理重塑质膜在调节肌动蛋白动力学中起双重作用。在这里，我们建议研究Exo 70和Arp 2/3之间的分子相互作用，并检查Exo 70对Arp 2/3介导的肌动蛋白聚合和分支的影响。此外，我们将研究Cdc 42/Rac下游效应激酶Pak 1在调节外囊和Arp 2/3之间的相互作用中的作用，以响应EGF刺激。最后，我们将研究外囊在质膜物理重塑中的作用。研究细胞迁移及其调控的分子基础对于我们理解包括胚胎发生和趋化性在内的许多生理过程具有重要意义，并可能揭示诸如神经系统疾病和肿瘤转移等疾病的病因。 公共卫生相关性：定向细胞迁移是许多生理过程如趋化性、胚胎发生和神经元发育的基础。研究细胞迁移的分子基础将有助于我们理解这些生理过程，并阐明神经系统疾病和癌症等疾病的病因。

DESCRIPTION (provided by applicant): Cells start migration by generating protrusions, which require the dynamic assembly of a branched actin network and remodeling of the plasma membrane. How actin dynamics and membrane activities are coordinated during cell migration is a fundamental question in the field. The exocyst is a multiprotein complex that mediates exocytosis and polarized cell surface expansion and has recently been shown to play an important role in cell migration. We have recently found that the exocyst component Exo70 directly interacts with the Arp2/3 complex, the core machinery that nucleates actin for the generation of the branched actin network underneath the leading edges of the plasma membrane. The exocyst-Arp2/3 interaction is stimulated by epidermal growth factor (EGF), and this interaction is important for effective membrane protrusion and directional migration. We hypothesize that the exocyst plays a dual role in regulating actin dynamics through interacting with the Arp2/3 complex and physically remodeling the plasma membrane. Here we propose to investigate the molecular interactions between Exo70 and Arp2/3, and examine the effect of Exo70 on Arp2/3-mediated actin polymerization and branching. In addition, we will investigate the role of the Cdc42/Rac downstream effector kinase, Pak1, in regulating the interaction between the exocyst and Arp2/3 in response to EGF stimulation. Finally, we will examine the effect of the exocyst in the physical remodeling of the plasma membrane. Studying the molecular basis of cell migration and its regulation is important for our understanding of many physiological processes including embryogenesis and chemotaxis, and may shed light on the etiology of diseases such a neurological disorders and tumor metastasis. PUBLIC HEALTH RELEVANCE: Directional cell migration is fundamental to many physiological processes such as chemotaxis, embryogenesis, and neuronal development. Studying the molecular basis of cell migration will help us understand these physiological processes and shed light on the etiologies of diseases such as neurological disorders and cancer.