Venkatesh Bhavya, Golla Kalyan, Hong Felix, Haage Amanda, Kim Hugh, Tanentzapf Guy
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.
Platelets. 2025 Dec;36(1):2555197. doi: 10.1080/09537104.2025.2555197. Epub 2025 Sep 8.
The integrin family of extracellular matrix (ECM) adhesion receptors plays a central role in platelet function, including adhesion and aggregation. In resting platelets, integrins exist in a low-affinity state for their ligands, and are activated upon ligand binding to the extracellular domain or binding of cytoplasmic proteins such as talin to the intracellular β-tail. Talin function is regulated through autoinhibition, which reduces its integrin-activating function. A point mutation that blocks talin autoinhibition, Tln1, therefore increases integrin activation and disrupts cell migration in fibroblasts. Here, we show that talin autoinhibition also plays an important role during hemostasis. Tln1 mutant mice display defective hemostasis when examined using a tail bleeding assay. Furthermore, platelets isolated from Tln1 mice exhibit disrupted aggregation and delayed clot retraction, indicating a defect in integrin signaling. However, integrin activation was not increased in platelets with defective talin autoinhibition, suggesting a different role for talin in platelets, distinct from inside-out integrin signaling. Taken together, our data shows that talin autoinhibition is an important regulatory mechanism in platelets during hemostasis.
细胞外基质（ECM）黏附受体的整合素家族在血小板功能中起着核心作用，包括黏附和聚集。在静息血小板中，整合素对其配体处于低亲和力状态，并在配体与细胞外结构域结合或细胞内蛋白（如踝蛋白）与细胞内β尾结合时被激活。踝蛋白的功能通过自身抑制来调节，这会降低其整合素激活功能。因此，一个阻断踝蛋白自身抑制的点突变Tln1会增加整合素的激活，并破坏成纤维细胞中的细胞迁移。在这里，我们表明踝蛋白自身抑制在止血过程中也起着重要作用。使用尾部出血试验检测时，Tln1突变小鼠表现出止血缺陷。此外，从Tln1小鼠分离的血小板显示出聚集破坏和凝块回缩延迟，表明整合素信号传导存在缺陷。然而，在踝蛋白自身抑制缺陷的血小板中，整合素激活并未增加，这表明踝蛋白在血小板中的作用与从内向外的整合素信号传导不同。综上所述，我们的数据表明，踝蛋白自身抑制是止血过程中血小板的一种重要调节机制。
