Molecular priming of Lyn by GPVI enables an immune receptor to adopt a hemostatic role

Alec A Schmaier, Zhiying Zou, Arunas Kazlauskas, Lori Emert-Sedlak, Karen P Fong, Keith B Neeves, Sean F Maloney, Scott L Diamond, Satya P Kunapuli, Jerry Ware, Lawrence F Brass, Thomas E Smithgall, Kalle Saksela, Mark L Kahn

    Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu


    The immune receptor signaling pathway is used by nonimmune cells, but the molecular adaptations that underlie its functional diversification are not known. Circulating platelets use the immune receptor homologue glycoprotein VI (GPVI) to respond to collagen exposed at sites of vessel injury. In contrast to immune cell responses, platelet activation must take place within seconds to successfully form thrombi in flowing blood. Here, we show that the GPVI receptor utilizes a unique intracellular proline-rich domain (PRD) to accelerate platelet activation, a requirement for efficient platelet adhesion to collagen under flow. The GPVI PRD specifically binds the Src-family kinase Lyn and directly activates it, presumably through SH3 displacement. In resting platelets, Lyn is constitutively bound to GPVI in an activated state and platelets lacking Lyn exhibit defective collagen adhesion like that of platelets with GPVI receptors lacking the PRD. These findings define a molecular priming mechanism that enables an immune-type receptor to adopt a hemostatic function. These studies also demonstrate that active kinases can constitutively associate with immune-type receptors without initiating signal transduction before receptor ligation, consistent with a recent molecular model of immune receptor signaling in which receptor ligation is required to bring active kinases to their receptor substrates.
    LehtiProceedings of the National Academy of Sciences of the United States of America
    Sivumäärä1 006
    DOI - pysyväislinkit
    TilaJulkaistu - 2009
    OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

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