Zhang Hongyuan, Yang Micah, Kim Seong Ho, Li Isaac T S
Department of Chemistry, The University of British Columbia, Kelowna, BC, Canada.
QRB Discov. 2025 Jan 16;6:e9. doi: 10.1017/qrd.2024.28. eCollection 2025.
Integrins are critical transmembrane receptors that connect the extracellular matrix (ECM) to the intracellular cytoskeleton, playing a central role in mechanotransduction - the process by which cells convert mechanical stimuli into biochemical signals. The dynamic assembly and disassembly of integrin-mediated adhesions enable cells to adapt continuously to changing mechanical cues, regulating essential processes such as adhesion, migration, and proliferation. In this review, we explore the molecular clutch model as a framework for understanding the dynamics of integrin - ECM interactions, emphasizing the critical importance of force loading rate. We discuss how force loading rate bridges internal actomyosin-generated forces and ECM mechanical properties like stiffness and ligand density, determining whether sufficient force is transmitted to mechanosensitive proteins such as talin. This force transmission leads to talin unfolding and activation of downstream signalling pathways, ultimately influencing cellular responses. We also examine recent advances in single-molecule DNA tension sensors that have enabled direct measurements of integrin loading rates, refining the range to approximately 0.5-4 pN/s. These findings deepen our understanding of force-mediated mechanotransduction and underscore the need for improved sensor designs to overcome current limitations.
整合素是关键的跨膜受体，它将细胞外基质（ECM）与细胞内细胞骨架相连，在机械转导过程中发挥核心作用，机械转导是细胞将机械刺激转化为生化信号的过程。整合素介导的黏附的动态组装和解聚使细胞能够持续适应不断变化的机械信号，调节诸如黏附、迁移和增殖等重要过程。在这篇综述中，我们探讨分子离合器模型，将其作为理解整合素-ECM相互作用动力学的框架，强调力加载速率的至关重要性。我们讨论力加载速率如何在肌动蛋白-肌球蛋白产生的内力与ECM的机械特性（如硬度和配体密度）之间架起桥梁，决定是否有足够的力传递给诸如踝蛋白等机械敏感蛋白。这种力的传递导致踝蛋白展开并激活下游信号通路，最终影响细胞反应。我们还研究了单分子DNA张力传感器的最新进展，这些进展能够直接测量整合素的加载速率，将范围精确到约0.5-4皮牛/秒。这些发现加深了我们对力介导的机械转导的理解，并强调需要改进传感器设计以克服当前的局限性。
