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The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function

Author

Listed:
  • Jessica K. Mountford

    (Australian Centre for Blood Diseases, Monash University)

  • Claire Petitjean

    (Australian Centre for Blood Diseases, Monash University)

  • Harun W. Kusuma Putra

    (Australian Centre for Blood Diseases, Monash University)

  • Jonathan A. McCafferty

    (Australian Centre for Blood Diseases, Monash University)

  • Natasha M. Setiabakti

    (Australian Centre for Blood Diseases, Monash University)

  • Hannah Lee

    (Australian Centre for Blood Diseases, Monash University)

  • Lotte L. Tønnesen

    (Australian Centre for Blood Diseases, Monash University)

  • James D. McFadyen

    (Australian Centre for Blood Diseases, Monash University)

  • Simone M. Schoenwaelder

    (Australian Centre for Blood Diseases, Monash University
    The Heart Research Institute and Charles Perkins Centre, The University of Sydney)

  • Anita Eckly

    (Unité mixte de recherche S949 Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Etablissement Français du Sang-Alsace 67000)

  • Christian Gachet

    (Unité mixte de recherche S949 Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Etablissement Français du Sang-Alsace 67000)

  • Sarah Ellis

    (Peter MacCallum Cancer Centre and The University of Melbourne)

  • Anne K. Voss

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Ross A. Dickins

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Justin R. Hamilton

    (Australian Centre for Blood Diseases, Monash University)

  • Shaun P. Jackson

    (Australian Centre for Blood Diseases, Monash University
    The Heart Research Institute and Charles Perkins Centre, The University of Sydney
    The Scripps Research Institute)

Abstract

PI3KC2α is a broadly expressed lipid kinase with critical functions during embryonic development but poorly defined roles in adult physiology. Here we utilize multiple mouse genetic models to uncover a role for PI3KC2α in regulating the internal membrane reserve structure of megakaryocytes (demarcation membrane system) and platelets (open canalicular system) that results in dysregulated platelet adhesion under haemodynamic shear stress. Structural alterations in the platelet internal membrane lead to enhanced membrane tether formation that is associated with accelerated, yet highly unstable, thrombus formation in vitro and in vivo. Notably, agonist-induced 3-phosphorylated phosphoinositide production and cellular activation are normal in PI3KC2α-deficient platelets. These findings demonstrate an important role for PI3KC2α in regulating shear-dependent platelet adhesion via regulation of membrane structure, rather than acute signalling. These studies provide a link between the open canalicular system and platelet adhesive function that has relevance to the primary haemostatic and prothrombotic function of platelets.

Suggested Citation

  • Jessica K. Mountford & Claire Petitjean & Harun W. Kusuma Putra & Jonathan A. McCafferty & Natasha M. Setiabakti & Hannah Lee & Lotte L. Tønnesen & James D. McFadyen & Simone M. Schoenwaelder & Anita , 2015. "The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function," Nature Communications, Nature, vol. 6(1), pages 1-14, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7535
    DOI: 10.1038/ncomms7535
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