Human Disabled-2 regulates thromboxane A2 signaling for efficient hemostasis in thrombocytopenia
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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54093-5 |
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| _version_ | 1846165116454699008 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hui-Ju Tsai |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-599012b1089142f7844c7068ea35d2f2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-599012b1089142f7844c7068ea35d2f22024-11-17T12:35:44ZengNature PortfolioNature Communications2041-17232024-11-0115111810.1038/s41467-024-54093-5Human Disabled-2 regulates thromboxane A2 signaling for efficient hemostasis in thrombocytopeniaHui-Ju Tsai0Ya-Fang Chang1Ya-Ju Hsieh2Jiaan-Der Wang3Chih-Ching Wu4Meng-Ying Ho5Ju-Chien Cheng6Ding-Ping Chen7Hsiang-Rui Liao8Ching-Ping Tseng9Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung UniversityDepartment of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung UniversityMolecular Medicine Research Center, Chang Gung UniversityChildren’s Medical Center, Taichung Veterans General HospitalDepartment of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung UniversityDepartment of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung UniversityDepartment of Medical Laboratory Science and Biotechnology, China Medical UniversityDepartment of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung UniversityGraduate Institute of Biomedical Sciences, College of Medicine, Chang Gung UniversityDepartment of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung UniversityAbstract 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.https://doi.org/10.1038/s41467-024-54093-5 |
| spellingShingle | 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 Human Disabled-2 regulates thromboxane A2 signaling for efficient hemostasis in thrombocytopenia Nature Communications |
| title | Human Disabled-2 regulates thromboxane A2 signaling for efficient hemostasis in thrombocytopenia |
| title_full | Human Disabled-2 regulates thromboxane A2 signaling for efficient hemostasis in thrombocytopenia |
| title_fullStr | Human Disabled-2 regulates thromboxane A2 signaling for efficient hemostasis in thrombocytopenia |
| title_full_unstemmed | Human Disabled-2 regulates thromboxane A2 signaling for efficient hemostasis in thrombocytopenia |
| title_short | Human Disabled-2 regulates thromboxane A2 signaling for efficient hemostasis in thrombocytopenia |
| title_sort | human disabled 2 regulates thromboxane a2 signaling for efficient hemostasis in thrombocytopenia |
| url | https://doi.org/10.1038/s41467-024-54093-5 |
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