The class II PI 3-kinase, PI3KC2 alpha, 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 Tonnesen, James D McFadyen, Simone M Schoenwaelder, Anita Eckly, Christian Gachet, Sarah Ellis, Anne K Voss, Ross A Dickins, Justin R Hamilton, Shaun P Jackson
NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2015
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 p..View full abstract
Awarded by National Health & Medical Research Council of Australia (NHMRC)
We thank the Australian Phenomics Network Transgenic RNAi Service for assisting with the production of shPI3KC2 alpha mice; the staff of AMREP Animal Services for animal husbandry and support; Robyn Slattery for advice regarding ES cell culture and preparation; Stephen Cody from Monash Micro Imaging for microscopy support; Benjamin Kile for comments on the manuscript; and Paul Watson for valuable contributions during the course of this study. This work was supported by a grant from the National Health & Medical Research Council of Australia (NHMRC) to J.R.H. and S.P.J. (1010848). J.R.H. was supported by a Career Development Fellowship from the National Heart Foundation of Australia and a Future Fellowship from the Australian Research Council; S.P.J. by an Australia Fellowship from the NHMRC; A.K.V. by Senior Research Fellowship and project grants from the NHMRC as well as operational infrastructure grants from the Australian Federal Government (IRISS) and the Victorian State Government (OIS); R.A.D. by a Fellowship from the Charles and Sylvia Viertel Charitable Foundation.