全球生产总值
整合素
血小板
菲拉明
化学
FLNA公司
胶原受体
血小板活化
血小板膜糖蛋白
血栓
整合素,β6
血小板糖蛋白GPIIb-iia复合物
细胞生物学
分子生物学
受体
细胞骨架
内科学
生物化学
医学
生物
细胞
作者
Ratnashree Biswas,Emily K. Boyd,Nathan Eaton,Agata Steenackers,Marie L. Schulte,Friedrich Reusswig,Hongyin Yu,Caleb Drew,Walter H.A. Kahr,Qizhen Shi,Markus Plomann,Karin M. Hoffmeister,Hervé Falet
标识
DOI:10.1016/j.jtha.2023.08.026
摘要
Abstract
Background
Upon vessel injury, platelets adhere to exposed matrix constituents via specific membrane receptors, including the von Willebrand factor receptor glycoprotein (GP)Ib-IX-V complex and integrins β1 and β3. In platelets, the Fes/CIP4-homology Bin-Amphiphysin-Rvs protein PACSIN2 associates with the cytoskeletal and scaffolding protein filamin A (FlnA), linking GPIbα and integrins to the cytoskeleton. Objectives
Here we investigated the role of PACSIN2 in platelet function. Methods
Platelet parameters were evaluated in mice lacking PACSIN2 and platelet integrin β1. Results
Pacsin2–/– mice displayed mild thrombocytopenia, prolonged bleeding time, and delayed thrombus formation in a ferric chloride-mediated carotid artery injury model, which was normalized by injection of control platelets. Pacsin2–/– platelets formed unstable thrombi that embolized abruptly in a laser-induced cremaster muscle injury model. Pacsin2–/– platelets had hyperactive integrin β1, as evidenced by increased spreading onto surfaces coated with the collagen receptor α2β1-specific peptide GFOGER and increased binding of the antibody 9EG7 directed against active integrin β1. By contrast, Pacsin2–/– platelets had normal integrin αIIbβ3 function and expressed P-selectin normally following stimulation through the collagen receptor GPVI or with thrombin. Deletion of platelet integrin β1 in Pacsin2–/– mice normalized platelet count, hemostasis, and thrombus formation. A PACSIN2 peptide mimicking the FlnA-binding site mediated the pull-down of a FlnA rod 2 construct by integrin β7, a model for integrin β-subunits. Conclusions
Pacsin2–/– mice displayed severe thrombus formation defects due to hyperactive platelet integrin β1. The data suggest that PACSIN2 binding to FlnA negatively regulates platelet integrin β1 hemostatic function.
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