Vinculin: a key to deciphering mechanotransduction

纽蛋白：破译机械转导的关键

• 批准号: BB/L006669/1
• 负责人: Nicholas Brown
• 金额: $ 78.8万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL006669%2F1
• 关键词: Vinculin; key; deciphering; mechanotransduction

Cells have a sense of touch, and this research proposal aims to discover the underlying molecular machinery that allows cells to respond to mechanical forces. For example, as muscles enlarge and are able to contract with greater force, it is critical that the attachments of the ends of the muscles to the tendon/tendon matrix also become strengthened. We know that this is achieved by a mechanosensitive attachment machinery, but we dont yet know how this machinery works. We therefore have focused our research on a protein, vinculin, that we think will provide the "Rosetta Stone" of mechanotransduction, by providing a key that will reveal the underlying mechanisms. This is because vinculin has the exceptional property of becoming concentrated at different sites within the cell, when these sites are being pulled on by contractile forces. These sites includes the places where cells attach to other cells or to the scaffolding that surrounds cells, the extracellular matrix. The recruitment of vinculin to these sites of adhesion when they are under force helps to strengthen them, but it is not known how vinculin does that. Vinculin exists in an "off" state, where it is tightly curled up, and an uncurled "on" state where it can bind to other proteins. Having too much vinculin in the on state in fact causes more problems to the cell than if vinculin is removed from the cell, but again we dont yet understand why this is the case. Our goal is therefore to discover:1) how vinculin is recruited in response to force.2) how vinculin functions, and what other proteins may be providing a similar function, such that the removal of vinculin can be tolerated surprisingly well.3) how having too much "on" vinculin causes problems to the organism.Our discoveries will impact on human health in multiple ways. Some human diseases result from the weakening of cell adhesion, which could be improved by developing methods to mimic the force signal, thus strengthening adhesion. Similarly, movement of cancer cells, or metastasis, renders cancers much more difficult to treat, and strengthening adhesion will restrain cell movement. Furthermore, understanding the molecular details of mechanotransduction may lead to the design of new nanomachines that can respond to force with local drug delivery. While our goal is to understand how mechanotransduction works in humans, we can answer these questions most effectively by using the experimental advantages of the model organism Drosophila melanogaster, the fruit fly. The proteins involved with vinculin function are also found in Drosophila, and we can use the sophisticated molecular genetics of Drosophila, combined with state of the art microscopy to use vinculin to discover how cells sense and respond to mechanical force.

细胞具有触觉，这项研究提案旨在发现允许细胞对机械力做出反应的潜在分子机制。例如，随着肌肉扩大并能够以更大的力收缩，肌肉末端与肌腱/肌腱基质的附着也得到加强至关重要。我们知道这是通过机械敏感的附着机制实现的，但我们还不知道这种机制是如何工作的。因此，我们将研究重点放在一种蛋白质上，即黏着斑蛋白，我们认为它将通过提供揭示潜在机制的关键来提供机械转导的“罗塞塔石碑”。这是因为黏着斑蛋白具有特殊的性质，当这些部位被收缩力拉动时，黏着斑蛋白会集中在细胞内的不同部位。这些部位包括细胞附着于其他细胞或细胞周围的支架（细胞外基质）的地方。粘着斑蛋白在这些粘连部位受到外力时的募集有助于加强它们，但尚不清楚粘着斑蛋白是如何做到这一点的。白藜芦醇存在于一个“关闭”状态，在那里它是紧密卷曲，和一个未卷曲的“打开”状态，它可以结合到其他蛋白质。事实上，有太多的黏着斑蛋白处于开启状态会给细胞带来更多的问题，而不是从细胞中去除黏着斑蛋白，但我们仍然不明白为什么会这样。因此，我们的目标是发现：1）粘着斑蛋白如何响应外力而被募集。2）粘着斑蛋白如何发挥功能，以及其他哪些蛋白质可能提供类似的功能，使得粘着斑蛋白的去除可以令人惊讶地耐受良好。3）粘着斑蛋白过多“打开”如何对生物体造成问题。我们的发现将在多个方面影响人类健康。一些人类疾病是由于细胞粘附力减弱而引起的，这可以通过开发模拟力信号的方法来改善，从而加强粘附力。类似地，癌细胞的移动或转移使癌症更难以治疗，并且增强粘附将抑制细胞移动。此外，了解机械转导的分子细节可能会导致新的纳米机器的设计，可以响应局部药物输送的力。虽然我们的目标是了解机械转导如何在人类中工作，但我们可以通过使用模式生物果蝇（果蝇）的实验优势来最有效地回答这些问题。与黏着斑蛋白功能相关的蛋白质也在果蝇中发现，我们可以利用果蝇复杂的分子遗传学，结合最先进的显微镜技术，利用黏着斑蛋白来发现细胞如何感知和响应机械力。

项目成果

Novel functions for integrin-associated proteins revealed by analysis of myofibril attachment in Drosophila.

• DOI: 10.7554/elife.35783
• 发表时间: 2018-07-20
• 期刊: eLife
• 影响因子: 7.7
• 作者: Green HJ;Griffiths AG;Ylänne J;Brown NH
• 通讯作者: Brown NH

The mechanical response of talin.

• DOI: 10.1038/ncomms11966
• 发表时间: 2016-07-07
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Yao M;Goult BT;Klapholz B;Hu X;Toseland CP;Guo Y;Cong P;Sheetz MP;Yan J
• 通讯作者: Yan J

Alternative mechanisms for talin to mediate integrin function.

• DOI: 10.1016/j.cub.2015.01.043
• 发表时间: 2015-03-30
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Klapholz, Benjamin;Herbert, Samantha L.;Wellmann, Jutta;Johnson, Robert;Parsons, Maddy;Brown, Nicholas H.
• 通讯作者: Brown, Nicholas H.

$\textit{Drosophila}$ vinculin is more harmful when hyperactive than absent, and can circumvent integrin to form adhesion complexes

$ extit{果蝇}$ 纽蛋白在过度活跃时比缺乏时更有害，并且可以绕过整合素形成粘附复合物

• DOI: 10.17863/cam.6786
• 发表时间: 2016
• 作者: Maartens A

Drosophila vinculin is more harmful when hyperactive than absent, and can circumvent integrin to form adhesion complexes.

• DOI: 10.1242/jcs.189878
• 发表时间: 2016-12-01
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Maartens AP;Wellmann J;Wictome E;Klapholz B;Green H;Brown NH
• 通讯作者: Brown NH