Human Disabled-2 Regulates Thromboxane A Signaling for Efficient Hemostasis in Thrombocytopenia

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Nov 13

PMID 39537612

Authors

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

Ching-Ping Tseng

Affiliations

Soon will be listed here.

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 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.

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