Orchestration of adhesion signalling networks by the tensins and their impact in cell motility and matrix remodelling.

张力蛋白对粘附信号网络的协调及其对细胞运动和基质重塑的影响。

• 批准号: BB/V016326/1
• 负责人: Christoph Ballestrem
• 金额: $ 58.69万
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV016326%2F1
• 关键词: Orchestration; adhesion; signalling; networks; tensins

Tissues in our body consist of a meshwork of fibrillar material and living cells. The cells continuously sense and produce this fibrillar material, the so-called extracellular matrix (ECM), which surrounds the cells and to which they can attach to. Cell-ECM communication is particularly important during regeneration processes that require specific cellular responses to changing ECM environments. Cellular responses include changes in motile behaviour (e.g. closing of wounds) and also active reorganisation of their ECM when forming new functional tissue. Many studies have focused on how cells detect (sense) environmental signals, but we are still far from understanding how these are translated into signals that promote specific cellular responses.The extracellular environment of cells alters enormously particularly during ageing, injury and certain diseases. For example, the mechanical properties of the ECM influences tumour progression, and stiffening of ECM causes fibrosis (excess of matrix production), which in turn can lead to malfunctioning of the affected tissues. Intriguingly, cells produce and simultaneously respond to these environmental changes. Understanding this process is critically important if we want to get a step closer to treating the roots of diseases and promote regeneration. Cells sense their environment by grabbing and pulling the neighbouring extracellular fibrillar material using surface proteins called integrins. These integrins not only bind to the environment of the cells but also connect to a skeleton inside the cells (cytoskeleton). This link is not direct but is regulated by components that couple the two. We published a number of manuscripts showing that two of these coupling proteins, called talin and vinculin, are central to sensing environmental changes. They are particularly important for measuring the stiffness of their surroundings and they control cell migration. In this proposal we present important pilot data demonstrating that members of the tensin protein family, which are critical for ECM reorganisation, interact with a variety of adhesion regulatory proteins including talin and vinculin. How these interactions are mediated, and how different tensin family members are linked to the wider network of proteins that couple integrins to the cytoskeleton, is unclear. Additionally, how these different interactions influence cell behaviour and matrix remodelling is unknown. We will address this problem using long-standing expertise in the fields of integrin mediated cell-matrix interactions in combination with the powerful novel methods established in the Ballestrem laboratory. The proposed research aims are: (i) to identify key interaction partners of tensin; (ii) to determine how interactions between tensin and its binding partners are regulated and how they contribute to tensin recruitment to cell-matrix adhesion sites; (iii) to investigate how tensins, together with their interaction partners, contribute ECM remodelling and cell motility. To reach our goals, we will an interdisciplinary approach of cutting edge microscopy, biochemisty and molecular biology techniques with the aim to gain a better understanding of mechanisms that are fundamental for the generation of functional tissues. Ultimately, the knowledge gained may lead to the development of new way to prevent diseases (e.g. cancer, fibrosis) and promote regeneration (wound healing).

我们体内的组织由纤维材料和活细胞组成的网状结构组成。细胞不断地感知并产生这种纤维状物质，即所谓的细胞外基质（ECM），它包围着细胞并且细胞可以附着在其上。细胞-ECM 通讯在再生过程中尤其重要，再生过程需要特定的细胞对不断变化的 ECM 环境做出反应。细胞反应包括运动行为的变化（例如伤口闭合）以及在形成新的功能组织时其 ECM 的主动重组。许多研究都集中在细胞如何检测（感知）环境信号，但我们还远未了解这些信号如何转化为促进特定细胞反应的信号。细胞的细胞外环境发生巨大变化，特别是在衰老、损伤和某些疾病期间。例如，ECM 的机械特性会影响肿瘤的进展，而 ECM 的硬化会导致纤维化（基质产生过多），进而导致受影响组织的功能障碍。有趣的是，细胞产生并同时响应这些环境变化。如果我们想进一步治疗疾病的根源并促进再生，那么了解这一过程至关重要。细胞通过使用称为整合素的表面蛋白抓住并拉动邻近的细胞外纤维材料来感知环境。这些整合素不仅与细胞的环境结合，还与细胞内的骨架（细胞骨架）连接。该链接不是直接的，而是由将两者耦合的组件调节的。我们发表的许多手稿表明，其中两种耦合蛋白（称为talin和vinculin）对于感知环境变化至关重要。它们对于测量周围环境的硬度特别重要，并且控制细胞迁移。在本提案中，我们提供了重要的试点数据，证明对 ECM 重组至关重要的张力蛋白家族成员与多种粘附调节蛋白（包括踝蛋白和纽蛋白）相互作用。这些相互作用是如何介导的，以及不同的张力蛋白家族成员如何与将整合素偶联到细胞骨架的更广泛的蛋白质网络联系起来，目前尚不清楚。此外，这些不同的相互作用如何影响细胞行为和基质重塑尚不清楚。我们将利用整合素介导的细胞-基质相互作用领域的长期专业知识，结合 Ballestrem 实验室建立的强大的新方法来解决这个问题。 拟议的研究目标是：（i）确定张力蛋白的关键相互作用伙伴； (ii) 确定如何调节张力蛋白与其结合配偶体之间的相互作用以及它们如何促进张力蛋白招募到细胞基质粘附位点； (iii) 研究张力蛋白及其相互作用伙伴如何促进 ECM 重塑和细胞运动。为了实现我们的目标，我们将采用尖端显微镜、生物化学和分子生物学技术的跨学科方法，旨在更好地了解功能组织生成的基础机制。最终，所获得的知识可能会导致开发预防疾病（例如癌症、纤维化）和促进再生（伤口愈合）的新方法。

项目成果

The structural basis of the Talin-KANK1 interaction that coordinates the actin and microtubule cytoskeletons at focal adhesions

Talin-KANK1 相互作用的结构基础，协调粘着斑处的肌动蛋白和微管细胞骨架

• DOI: http://dx.10.1101/2023.02.23.529676
• 发表时间: 2023
• 作者: Li X

The structural basis of the talin-KANK1 interaction that coordinates the actin and microtubule cytoskeletons at focal adhesions.

talin-KANK1 相互作用的结构基础，协调粘着斑处的肌动蛋白和微管细胞骨架。

• DOI: http://dx.10.1098/rsob.230058
• 发表时间: 2023
• 期刊: Open biology
• 影响因子: 5.8
• 作者: Li X

Tensin3 interaction with talin drives the formation of fibronectin-associated fibrillar adhesions.

Tensin3 与踝蛋白的相互作用驱动纤连蛋白相关纤维粘连的形成。

• DOI: http://dx.10.1083/jcb.202107022
• 发表时间: 2022
• 期刊: The Journal of cell biology
• 作者: Atherton P

The ßI domain promotes active ß1 integrin clustering into mature adhesion sites.

αI 结构域促进活性 α1 整合素聚集到成熟的粘附位点。

• DOI: http://dx.10.26508/lsa.202201388
• 发表时间: 2023
• 期刊: Life science alliance
• 影响因子: 4.4
• 作者: Mana G