Administrative Equipment Supplement for GM135160

项目总结 细胞形状变化是后生动物细胞的一个基本特征，这是发育的关键， 生理学和病理学。神经网络的形成和可塑性是细胞形状的关键例子 在发育和生理过程中发生变化，而细胞形状和运动在癌症中出现错误，如 黑色素瘤。细胞骨架的主动控制被认为是细胞形状变化的关键， 然而，质膜的同步重塑可能不那么被人们所了解。虽然很多人 细胞骨架和膜重塑成分已知，它们的生化和结构 特征，我们缺乏系统地了解这些不同的系统是如何被监管的 并协调以协调细胞形状的变化。也许细胞中最重要的问题是 形态发生学是理解细胞如何感知环境中的暗示，并将这种细胞外信号 通过协调的细胞骨架动力学和质膜重塑将信息转化为形状变化。 小分子GTP酶和蛋白激酶在调节细胞骨架动力学和膜方面的功能已被深入研究。 改建。我的实验室工作确定了E3泛素连接酶在调节细胞形状中的新角色 变化。我们鉴定了两种E3泛素连接酶，TRIM9和TRIM67，它们调节细胞骨架和胞外 蛋白质和细胞形状变化对网状蛋白的响应。网织蛋白是一种细胞外形态因子，它能促进 神经形态发生和癌症的进展，如黑色素瘤。因此，TRIM9和TRIM67 为实验室提供了一个很好的切入点来研究细胞骨架和膜重塑是如何 在Netrin过程中的协调触发了形态发生和运动。TRIM9和TRIM67具有相似的序列， 然而，我们的研究确定了这些相关蛋白质的不同功能 以及与其缺失相关的拮抗表型。该程序的主要目标是测试 TRIM9和TRIM67在Netrin依赖过程中协调细胞骨架动力学和胞吐作用的假说 神经元和迁移黑色素瘤细胞的形态发生。我们的工作将提供基本的机制 对发育和发育过程中细胞骨架和膜运输的调节的理解 转移。

PROJECT SUMMARY Cellular shape change is a fundamental characteristic of metazoan cells that is key to development, physiology, and pathology. The formation and plasticity of neural networks are key examples of cell shape change during development and physiology, whereas cell shape and motility goes awry in cancers such as melanoma. The active control of the cytoskeleton is acknowledged as critical to cellular shape change, whereas the concurrent remodeling of the plasma membrane is perhaps less well appreciated. Although many cytoskeletal and membrane remodeling components are known and their biochemical and structural characteristics described, we lack a systematic understanding of how these disparate systems are regulated and coordinated to orchestrate cellular shape change. Perhaps the most important problem in cell morphogenesis is understanding how cells perceive cues in their environment and convert this extracellular information into shape changes through coordinated cytoskeletal dynamics and plasma membrane remodeling. Functions of small GTPases and kinases are well studied in regulating cytoskeletal dynamics and membrane remodeling. Work from my lab identified an emerging role for E3 ubiquitin ligases in regulated cellular shape change. We identified two E3 ubiquitin ligases, TRIM9 and TRIM67, which regulate cytoskeletal and exocytic proteins and cellular shape changes in response to netrin. Netrin is an extracellular morphogen that promotes neuronal morphogenesis and the progression of cancers, such as melanoma. TRIM9 and TRIM67 thus provided an excellent entry point for the lab to investigate how cytoskeletal and membrane remodeling are coordinated during netrin triggered morphogenesis and motility. TRIM9 and TRIM67 share similar sequences, localization, and interaction partners, however our studies identified distinct functions of these related proteins and antagonistic phenotypes associated with their deletion. The overarching goal of this program is to test the hypothesis that TRIM9 and TRIM67 coordinate cytoskeletal dynamics and exocytosis during netrin-dependent morphogenesis in neurons and migrating melanoma cells. Our work will provide fundamental mechanistic understanding of the regulation of the cytoskeleton and membrane trafficking during development and metastasis.