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

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 Eckly, Christian Gachet, Sarah Ellis, Anne K. Voss, Ross A. Dickins, Justin R. Hamilton () and Shaun P. Jackson ()
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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
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
Ross A. Dickins: Walter and Eliza Hall Institute of Medical Research
Justin R. Hamilton: Australian Centre for Blood Diseases, Monash University
Shaun P. Jackson: Australian Centre for Blood Diseases, Monash University

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7535

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