Role of vimentin in mammalian cell motility

摘要 细胞迁移对许多基本过程至关重要，包括胚胎发育，伤口修复， 和癌症转移。这个过程的中心是由三个聚合物组成的细胞骨架 网络：F-肌动蛋白，微管和中间丝（IF）。波形蛋白是一种IF蛋白， 细胞的机械弹性，并调节细胞骨架之间的串扰，但它在细胞如何 通过组织中的小孔进行挤压的方法知之甚少。我们已经证明，波形蛋白的丢失增强了 细胞运动通过三维3D微流体通道，并保护细胞核免受损伤， 迁移波形蛋白被认为在细胞表面基质粘附力的传递中起着独特的作用 但新的证据表明，波形蛋白也可能在持续的细胞核表面发挥更积极的作用。 细胞运动通过其与肌动蛋白应力纤维形成和微管定位的相互作用。但是，具体 波形蛋白使3D迁移通过致密组织的机制仍不清楚。这个项目 解决了首要问题：波形蛋白如何影响细胞骨架功能，粘附与 细胞外基质和细胞间相互作用来协调3D细胞迁移？为了解决这个 我们将继续推进三个子项目。首先，我们将确定波形蛋白在细胞骨架中的作用- 介导的3D细胞运动。其次，我们将确定波形蛋白在整合素表达和粘着斑中的作用。 第三，我们将确定波形蛋白介导集体细胞迁移的机制 通过细胞外基质网络。这些研究将在2D和3D设置中进行，以定义 细胞环境的变化如何影响细胞骨架聚合物的关键决定因素 能动性我们期望这些项目将确定波形蛋白在细胞迁移中的新功能作用， 对于理解健康组织的维持和疾病的进展有重要的意义。 细胞通过组织的迁移。

ABSTRACT Cell migration is essential to many fundamental processes, including embryonic development, wound repair, and cancer metastasis. Central to this process is the cellular cytoskeleton comprised of three polymeric networks: F-actin, microtubules, and intermediate filaments (IFs). Vimentin is an IF protein that is essential to the mechanical resilience of cells and regulates cross-talk amongst the cytoskeleton, but its role in how cells squeeze through small pores in tissues is poorly understood. We have shown that loss of vimentin enhances cell motility through three-dimensional 3D micro-fluidic channels and protects the nucleus from damage during migration. Vimentin is thought to play a distinct role in the transfer of forces from cell surface matrix adhesions to the nuclear surface, but new evidence suggests that vimentin may also play a more active role in persistent cell motility via its interactions with actin stress fiber formation and microtubule positioning. Still, the specific mechanisms by which vimentin enables 3D migration through dense tissue remains unclear. This project addresses the overarching question: how does vimentin influence cytoskeletal functions, adhesions with the extracellular matrix, and cell-cell interactions to coordinate 3D cell migration? To address this question, we will pursue three sub-projects. First, we will determine the effects of vimentin in cytoskeletal- mediated 3D cell motility. Second, we will identify vimentin’s role in integrin expression and focal adhesion activation, and third, we will identify the mechanisms by which vimentin mediates collective cell migration through extracellular matrix networks. These studies will be conducted in both 2D and 3D settings to define how changes in the cellular environment impact the critical determinants of cytoskeletal polymers in cell motility. We expected that these projects will determine new functional roles of vimentin in cell migration, which has important implications for understanding healthy tissue maintenance and diseases that progress by the migration of cells through tissues.