IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-54093-5.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    National Chung Hsing University)

  • Chih-Ching Wu

    (Chang Gung University
    Chang Gung University
    Chang Gung Memorial Hospital
    Chang Gung University)

  • Meng-Ying Ho

    (Chang Gung University)

  • Ju-Chien Cheng

    (China Medical University)

  • Ding-Ping Chen

    (Chang Gung University
    Chang Gung Memorial Hospital)

  • Hsiang-Rui Liao

    (Chang Gung University
    Chang Gung University
    Chang Gung Memorial Hospital)

  • Ching-Ping Tseng

    (Chang Gung University
    Chang Gung University
    Chang Gung Memorial Hospital)

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.

Suggested Citation

  • 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, 2024. "Human Disabled-2 regulates thromboxane A2 signaling for efficient hemostasis in thrombocytopenia," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54093-5
    DOI: 10.1038/s41467-024-54093-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-54093-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-54093-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Andreas Naschberger & Rozbeh Baradaran & Bernhard Rupp & Marta Carroni, 2021. "The structure of neurofibromin isoform 2 reveals different functional states," Nature, Nature, vol. 599(7884), pages 315-319, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.

      More about this item

      Statistics

      Access and download statistics

      Corrections

      All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54093-5. See general information about how to correct material in RePEc.

      If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

      If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

      If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

      For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

      Please note that corrections may take a couple of weeks to filter through the various RePEc services.

      IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.