Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan, 333, Taiwan, Republic of China.
Molecular Medicine Research Center, Chang Gung University, Taoyuan, 333, Taiwan, Republic of China.
Nat Commun. 2024 Nov 13;15(1):9816. doi: 10.1038/s41467-024-54093-5.
Understanding platelet protein functions facilitates better assessment of platelet disorders. Megakaryocyte lineage-restricted human Disabled-2 knock-in (hDAB2-KI) mice are generated to delineate the functions of hDab2, a regulator of platelet function, in the control of bleeding associated with thrombocytopenia. Here we show that hDab2-KI mice with thrombocytopenia display decreased bleeding time when compared to the control mice. hDab2 augments thromboxane A (TxA) mimetic U46619- but not other agonists-stimulated granule secretion, integrin activation, and aggregation at a lower platelet concentration in vitro. Binding of hDab2 to phosphatidic acid (PA) facilitates formation of the PA-hDab2-AKT complex leading to an increase in U46619-stimulated AKT-Ser473 phosphorylation and the first wave of ADP/ATP release. Consistent with these findings, hDab2 expression in platelets from patients with immune thrombocytopenic purpura is positively correlated with U46619-stimulated ATP release, which in turn inversely correlated with their bleeding tendency. hDab2 appears crucial in regulating bleeding severity associated with thrombocytopenia by a functional interplay with ADP/ATP release underlying TxA signaling.
了解血小板蛋白的功能有助于更好地评估血小板疾病。为了阐明血小板功能调节剂 hDab2 在控制与血小板减少症相关的出血中的作用，生成了巨核细胞谱系特异性人类Disabled-2 敲入（hDAB2-KI）小鼠。与对照小鼠相比，血小板减少症的 hDAB2-KI 小鼠表现出出血时间缩短。hDab2 在体外增强血栓烷 A（TxA）模拟物 U46619 刺激的颗粒分泌、整合素激活和聚集，但不增强其他激动剂刺激的作用，且需要较低的血小板浓度。hDab2 与磷酸脂酰肌醇（PA）结合有助于形成 PA-hDab2-AKT 复合物，从而增加 U46619 刺激的 AKT-Ser473 磷酸化和第一波 ADP/ATP 释放。与这些发现一致的是，免疫性血小板减少性紫癜患者血小板中的 hDab2 表达与 U46619 刺激的 ATP 释放呈正相关，而与他们的出血倾向呈负相关。hDab2 通过与 TxA 信号相关的 ADP/ATP 释放的功能相互作用，在调节与血小板减少症相关的出血严重程度方面似乎至关重要。
