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    The proline-rich tyrosine kinase Pyk2 regulates platelet integrin aIIbß3 outside-in signaling

    Access Status
    Open access via publisher
    Authors
    Cipolla, L.
    Consonni, A.
    Guidetti, G.
    Canobbio, I.
    Okigaki, M.
    Falasca, Marco
    Ciraolo, E.
    Hirsch, E.
    Balduini, C.
    Torti, M.
    Date
    2013
    Type
    Journal Article
    
    Metadata
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    Citation
    Cipolla, L. and Consonni, A. and Guidetti, G. and Canobbio, I. and Okigaki, M. and Falasca, M. and Ciraolo, E. et al. 2013. The proline-rich tyrosine kinase Pyk2 regulates platelet integrin aIIbß3 outside-in signaling. Journal of Thrombosis and Haemostasis. 11 (2): pp. 345-356.
    Source Title
    Journal of Thrombosis and Haemostasis
    DOI
    10.1111/jth.12099
    ISSN
    1538-7933
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/17871
    Collection
    • Curtin Research Publications
    Abstract

    Background: The proline-rich tyrosine kinase Pyk2 is a focal adhesion kinase expressed in blood platelets, and is activated downstream of G-protein coupled receptors as well as integrin a2ß1. Objective: In this study we have investigated the involvement of Pyk2 in integrin aIIbß3 outside-in signaling in human and murine platelets. Methods: We analyzed the stimulation of intracellular signaling pathways in platelets from Pyk2 knockout mice adherent to immobilized fibrinogen. Results: Pyk2 was rapidly phosphorylated and activated in human and murine platelets adherent to fibrinogen through integrin aIIbß3. Activation of Pyk2 was Src-dependent, but did not require phospholipase C?2 activity. Platelets from Pyk2 knockout mice showed a defective ability to adhere and spread on fibrinogen, in association with a dramatic reduction of phosphatidylinositol 3-kinase (PI3K) activation and Akt phosphorylation. Pharmacological and genetic analysis demonstrated that integrin aIIbß3 engagement selectively stimulated the ß-isoform of PI3K (PI3Kß), and that, as for Pyk2, PI3Kß activation required Src family kinases activity, but not phospholipase C?2. In fibrinogen-adherent platelets, both Pyk2 and PI3Kß were necessary for stimulation of the small GTPase Rap1b, a regulator of cell adhesion and spreading. Integrin aIIbß3 engagement triggered the association of the PI3Kß regulatory subunit p85 with the adaptor protein c-Cbl, which was mediated by the p85 SH3 domain, and was independent of c-Cbl tyrosine phosphorylation. However, p85-associated c-Cbl was tyrosine phosphorylated by activated Pyk2 in fibrinogen adherent platelets. Conclusions: These results identify a novel pathway of integrin aIIbß3 outside-in signaling and recognize the tyrosine kinase Pyk2 as a major regulator of platelet adhesion and spreading on fibrinogen. © 2012 International Society on Thrombosis and Haemostasis.

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