The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function.
Fiche publication
Date publication
mars 2015
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GACHET Christian
Tous les auteurs :
Mountford JK, Petitjean C, Putra HW, McCafferty JA, Setiabakti NM, Lee H, Tønnesen LL, McFadyen JD, Schoenwaelder SM, Eckly A, Gachet C, Ellis S, Voss AK, Dickins RA, Hamilton JR, Jackson SP
Lien Pubmed
Résumé
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.
Mots clés
Alleles, Animals, Blood Platelets, metabolism, Bone Marrow Transplantation, Cell Adhesion, Crosses, Genetic, Gene Expression Regulation, Genotype, Hemostasis, Humans, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Mutation, Perfusion, Phosphatidylinositol 3-Kinases, metabolism, Phosphorylation, Platelet Adhesiveness, Platelet Aggregation, Shear Strength, Signal Transduction, Stress, Mechanical, Thrombosis, genetics
Référence
Nat Commun. 2015 Mar 17;6:6535