TY - JOUR AU - Yangfan Zhou, AU - Mengjiao Hu, AU - Xiaoyan Chen, AU - Shuai Wang, AU - Jingke Li, AU - Lina Sa, AU - Li Li, AU - Jiaqi Huang, AU - Hongqiang Cheng, AU - Hu Hu, PY - 2020/11/01 Y2 - 2024/03/28 TI - Migfilin supports hemostasis and thrombosis through regulating platelet αIIbβ3 outside-in signaling. JF - Haematologica JA - haematol VL - 105 IS - 11 SE - Articles DO - 10.3324/haematol.2019.232488 UR - https://haematologica.org/article/view/9589 SP - 2608-2618 AB - Elucidating the regulation mechanism of integrin αIIbβ3 is key to understand platelet biology and thrombotic diseases. Previous in vitro studies have implicated a role of migfilin in the support of platelet αIIbβ3 activation, however, contribution of migfilin to thrombosis and hemostasis in vivo and a detailed mechanism of migfilin in platelets are not known. In this study, with migfilin deletion (migfilin-/-) mice, we report that migfilin is a pivotal positive regulator of hemostasis and thrombosis. Migfilin-/- mice showed a nearly doubled tail-bleeding time and a prolonged occlusion time in Fecl3-induced mesenteric arteriolar thrombosis. Migfilin deficiency impedes platelet thrombi formation on collagen surface and impairs platelet aggregation and dense-granule secretion. Supported by characteristic functional readings and phosphorylation status of distinctive signaling molecules in the bidirectional signaling processes of αIIbβ3, the functional defects of migfilin-/- platelets appear to be mechanistically associated with a compromised outside-in signaling, rather than inside-out signaling. A synthesized cell-permeable migfilin peptide harboring filamin A binding sequence rescued the defective function and phosphorylation of signaling molecules of migfilin-/- platelets. Finally, migfilin does not influence the binding of filamin A and β3 subunit of αIIbβ3 in resting platelets, but hampers the re-association of filamin A and β3 during the conduct of outside-in signaling, suggesting that migfilin functions through regulating the interaction dynamics of αIIbβ3 and filamin A in platelets. Our study enhances the current understanding of platelet integrin αIIbβ3-mediated outside-in signaling and proves that migfilin is an important regulator for platelet activation, hemostasis and thrombosis. ER -