How tensins transform focal adhesions into fibrillar adhesions and phase separate to form new adhesion signalling hubs.

我们体内的组织是由细胞和周围的纤维物质，即细胞外基质（ECM）组成的。细胞附着、感知和重组ECM，这种能力在生物体的发育、疾病和再生过程中尤为重要，这些过程都需要对不断变化的ECM环境做出特定的细胞反应。细胞反应包括其移动能力的变化（例如伤口闭合），细胞生长的变化，以及合成新的或重塑旧的ECM环境。许多研究都集中在细胞如何感知外基质上，但我们仍然远远不能理解这些信息是如何转化为促进特定细胞反应的信号的。如果我们想进一步治疗疾病的根源，促进再生和恢复，了解这个过程是至关重要的。细胞通过使用一种叫做整合素的蛋白质来抓取和拉动邻近的细胞外纤维物质，从而感知它们的ECM环境，这种蛋白质从内到外延伸到细胞表面。整合素既与外部的ECM结合，也与细胞内的蛋白质结合。这些蛋白质将整合素偶联到肌动蛋白细胞骨架上，肌动蛋白细胞骨架是细胞内纤维的收缩网络，在重组后会引起拉力和细胞运动。我们之前的研究结果表明，将整合素与肌动蛋白结合的两种蛋白质，即talin和vinculin，是感知环境变化的核心。最近，我们已经证明talin与其他蛋白质，张力蛋白的结合对ECM重组至关重要。我们现在有进一步的数据表明，细胞中特定区域张力蛋白浓度的逐渐增加可以导致它们形成小液滴或冷凝物。我们假设这些紧张素凝聚物也可以吸引其他在细胞粘附和细胞迁移调节中起关键作用的蛋白质。要验证这一假设，需要详细了解蛋白质如何相互结合，以及这些蛋白质如何影响特定的细胞功能。为了克服我们在理解上的这一差距，我们建议两个在细胞粘附调节领域拥有丰富专业知识但应用非常不同研究方法的实验室共同努力。Barsukov实验室确定了蛋白质结构的细节，这对于理解蛋白质如何相互结合至关重要。结构细节有助于设计蛋白质的微小变化（突变），目的是通过实验阻断特定蛋白质的相互作用。ballestream实验室在细胞生物学和显微镜方面开发了强大的方法来监测细胞中的蛋白质相互作用，并研究这些相互作用在面对不断变化的ECM环境时决定细胞行为的作用。两个团队已经成功地合作，并揭示了控制细胞基质传感和ECM组织的基本机制。拟议的研究旨在了解(i)张力蛋白如何与talin相互作用，以及这种相互作用在富集参与ECM重组的细胞-基质粘附位点的张力蛋白中起什么作用；（ii）张力蛋白如何凝聚成能吸引其他蛋白质的液滴，形成调节细胞粘附和迁移的分子储存库；（iii）如何调节紧张素与整合素的结合，以及这如何影响整合素与ECM的结合强度。最终，获得的知识将为开发预防疾病（如癌症、纤维化）和促进再生（伤口愈合）的新方法开辟一条途径。

Tissues in our body are made up of cells and surrounding fibrillar material, the extracellular matrix or ECM. The cells attach to, sense and reorganise the ECM, an ability which is particularly important during the development of organisms, in diseases and in regeneration processes, which all require specific cellular responses to changing ECM environments. Cellular responses include changes in their ability to move (e.g. closing of wounds), changes in cell growth, and also in synthesising new or reshaping their old ECM environment. Many studies have focused on how cells sense the ECM, but we are still far from understanding how this information is translated into signals that promote specific cellular responses. Understanding this process is critically important if we want to get a step closer to treating the roots of diseases and promoting regeneration and recovery. Cells sense their ECM environment by grabbing and pulling the neighbouring extracellular fibrillar material using proteins called integrins, which extend across the cell surface from inside to outside. Integrins both bind to the ECM externally and to proteins inside the cells. These proteins couple integrins to the actin cytoskeleton, a contractile network of intracellular fibres, which upon reorganisation induces pulling forces and cell movement. Our previous results show that two proteins that couple integrins to actin, called talin and vinculin, are central to sensing environmental changes. Recently we have shown that the association of talin with other proteins, tensins, is critical for ECM reorganisation. We now have further data showing that a gradual increase in the concentration of tensins in specific areas in cells can lead them to form little droplets or condensates. We hypothesise that these tensin condensates can also attract other proteins that have a critical role in the regulation of cell adhesion and cell migration. Testing this hypothesis requires detailed information on how proteins bind to each other and how these impact on specific cellular functions. To overcome this gap in our understanding, we propose a joint effort of two laboratories that have vast expertise in the field of cell adhesion regulation but apply very different research methods. The Barsukov laboratory determines details of a protein structure, which is critical for the understanding how proteins bind to each other. Structural details help to design small changes (mutations) in proteins with the aim of experimentally blocking specific proteins interactions. The Ballestrem laboratory has developed powerful methods in cell biology and microscopy that monitor protein interactions in cells and investigate what role these interactions play in determining cell behaviour in the face of changing ECM environments. Both teams have already worked successfully together and revealed essential mechanisms that control cell-matrix sensing and ECM organisation.The proposed research aims to understand (i) how tensins interact with talin and what role this interaction has in enriching tensins in cell-matrix adhesion sites that are involved in ECM reorganisation; (ii) how tensins condense to droplets that can attract other proteins to form molecular reservoirs that regulate cell adhesion and migration; (iii) how tensin binding to integrins is regulated and how this affects the binding strength of integrins to the ECM. Ultimately, the knowledge gained will open a pathway to the development of new ways to prevent diseases (e.g. cancer, fibrosis) and promote regeneration (wound healing).