Human Disabled-2 regulates thromboxane A2 signaling for efficient hemostasis in thrombocytopenia

Hui-Ju Tsai, Ya-Fang Chang, Ya-Ju Hsieh, Jiaan- Der Wang, Chih-Ching Wu, Meng-Ying Ho, Ju-Chien Cheng, Ding-Ping Chen, Hsiang-Rui Liao and Ching-Ping Tseng ()
Additional contact information
Hui-Ju Tsai: Chang Gung University
Ya-Fang Chang: Chang Gung University
Ya-Ju Hsieh: Chang Gung University
Jiaan- Der Wang: Taichung Veterans General Hospital
Chih-Ching Wu: Chang Gung University
Meng-Ying Ho: Chang Gung University
Ju-Chien Cheng: China Medical University
Ding-Ping Chen: Chang Gung University
Hsiang-Rui Liao: Chang Gung University
Ching-Ping Tseng: Chang Gung University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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 A2 (TxA2) 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 TxA2 signaling.

Date: 2024
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DOI: 10.1038/s41467-024-54093-5

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