Vinculin and associated signalling networks in the regulation of cell motility

纽蛋白和相关信号网络在细胞运动调节中的作用

• 批准号: BB/G004552/1
• 负责人: Christoph Ballestrem
• 金额: $ 51.36万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG004552%2F1
• 关键词: Vinculin; associated; signalling; networks; regulation

The process whereby cells in the body move from place to place is called cell migration. Cell migration is fundamental for the development of organisms, wound healing, and the immune respose in the body. All these physiological processes are regulated by the interaction of the cell with its environment. The major group of molecules controlling these interactions are cell surface proteins called integrins. Integrins span the cell membrane and are able to attach with their extracellular part to proteins located in the outside surrounding of the cell (extracellular matrix). With their intracellular part, integrins associate with proteins that link them to the cells' highly flexible and dynamic skeleton (actin cytoskeleton). The interaction of integrins with the cytoskeleton is indirect. One of the key molecules, which control the link between integrins and the actin cytoskeleton, is named 'vinculin'. Mice lacking this protein die early during development, and cells deficient in vinculin are highly metastatic. Vinculin is able to interact with 11 other proteins, which have the potential to exert important signals regulating the cell communication with its environment. My aim is to understand how vinculin coordinates the numerous signals and thus modulates the communications between the cell and its outside surroundings. We will explore the function of vinculin by visualizing and monitoring its dynamic behaviour and interactions with other proteins in live cells using advanced imaging techniques. We will genetically modify vinculin and its ability to interact with its potential binding partners and thus test how vinculin controls a network of signals that is important for coordinated cell migration. For coordinated cell movements, the cell needs to exert pulling forces on the extracellular environment. Our recent discoveries suggest that vinculin interactions with the contractile skeleton in the cell are essential for the transmission of forces to the integrins that bind with its extracellular part to the extracellular matrix. Using highly developed nanotechnological devices, we will determine how vinculin signals contribute to such force transmission from the interior to the outside of the cell. Using devices that will mimic forces in the cells outer environment (such as pressure, stretching and shear forces in the body), we will be able to test how vinculin transfers signals from the outside of the cell to the inside cytoskeleton. The outcome of this study will provide us with important information for the better understanding of how cell motility is regulated in health and disease.

体内细胞从一个地方移动到另一个地方的过程称为细胞迁移。细胞迁移是生物体发育、伤口愈合和体内免疫反应的基础。所有这些生理过程都受到细胞与环境的相互作用的调节。控制这些相互作用的主要分子群是称为整合素的细胞表面蛋白。整合素跨越细胞膜，能够与其胞外部分附着到位于细胞外环境(细胞外基质)的蛋白质上。整合素在细胞内与蛋白质结合，这些蛋白质将整合素与细胞高度灵活和动态的骨架(肌动蛋白细胞骨架)联系起来。整合素与细胞骨架的相互作用是间接的。控制整合素和肌动蛋白细胞骨架之间联系的关键分子之一被称为纽蛋白。缺乏这种蛋白的小鼠在发育过程中会过早死亡，而缺乏纽蛋白的细胞是高度转移的。纽蛋白能够与其他11种蛋白质相互作用，这些蛋白质有可能施加重要信号，调节细胞与环境的交流。我的目的是了解纽蛋白如何协调众多信号，从而调节细胞与其外部环境之间的通信。我们将使用先进的成像技术，通过可视化和监测其动态行为以及与活细胞中其他蛋白质的相互作用来探索纽蛋白的功能。我们将对纽蛋白及其与潜在结合伙伴相互作用的能力进行基因修饰，从而测试纽蛋白如何控制对协调细胞迁移至关重要的信号网络。为了协调细胞运动，细胞需要对细胞外环境施加拉力。我们最近的发现表明，纽蛋白与细胞内收缩骨架的相互作用对于将力传递到整合素是必不可少的，整合素与细胞外部分结合到细胞外基质中。利用高度发达的纳米技术设备，我们将确定纽蛋白信号如何促进这种力从细胞内部传递到细胞外部。使用模拟细胞外部环境中的力(如身体内的压力、伸展和剪切力)的设备，我们将能够测试纽蛋白如何将信号从细胞外部传递到细胞内部的细胞骨架。这项研究的结果将为我们更好地理解细胞运动在健康和疾病中是如何调节的提供重要的信息。

项目成果

Focal adhesions are sites of integrin extension.

• DOI: 10.1083/jcb.200907174
• 发表时间: 2010-03-22
• 期刊: The Journal of cell biology
• 作者: Askari JA;Tynan CJ;Webb SE;Martin-Fernandez ML;Ballestrem C;Humphries MJ
• 通讯作者: Humphries MJ

The kinetics of force-induced cell reorganization depend on microtubules and actin.

• DOI: 10.1002/cm.20439
• 发表时间: 2010-04
• 期刊: CYTOSKELETON
• 影响因子: 2.9
• 作者: Goldyn, Alexandra M.;Kaiser, Peter;Spatz, Joachim P.;Ballestrem, Christoph;Kemkemer, Ralf
• 通讯作者: Kemkemer, Ralf

Syndecan-4 phosphorylation is a control point for integrin recycling.

• DOI: 10.1016/j.devcel.2013.01.027
• 发表时间: 2013-03-11
• 期刊: DEVELOPMENTAL CELL
• 影响因子: 11.8
• 作者: Morgan, Mark R.;Hamidi, Hellyeh;Bass, Mark D.;Warwood, Stacey;Ballestrem, Christoph;Humphries, Martin J.
• 通讯作者: Humphries, Martin J.

Vinculin regulates the recruitment and release of core focal adhesion proteins in a force-dependent manner.

• DOI: 10.1016/j.cub.2013.01.009
• 发表时间: 2013-02-18
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Carisey, Alex;Tsang, Ricky;Greiner, Alexandra M.;Nijenhuis, Nadja;Heath, Nikki;Nazgiewicz, Alicja;Kemkemer, Ralf;Derby, Brian;Spatz, Joachim;Ballestrem, Christoph
• 通讯作者: Ballestrem, Christoph

RIAM and vinculin binding to talin are mutually exclusive and regulate adhesion assembly and turnover.

• DOI: 10.1074/jbc.m112.438119
• 发表时间: 2013-03-22
• 期刊: The Journal of biological chemistry
• 作者: Goult BT;Zacharchenko T;Bate N;Tsang R;Hey F;Gingras AR;Elliott PR;Roberts GCK;Ballestrem C;Critchley DR;Barsukov IL
• 通讯作者: Barsukov IL