title: The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function.
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.
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Mountford
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Petitjean
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Harun W Kusuma
authors.initials: HW
authors.lastname: Putra
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCafferty
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Setiabakti
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Hannah
authors.initials: H
authors.lastname: Lee
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Lotte L
authors.initials: LL
authors.lastname: Tønnesen
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: McFadyen
authors.affiliation: 1] Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia [2] The Heart Research Institute and Charles Perkins Centre, The University of Sydney, Newtown 2050, Australia.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Schoenwaelder
authors.affiliation: Unité mixte de recherche S949 Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Etablissement Français du Sang-Alsace 67000, Strasbourg, France.
authors.forename: Anita
authors.initials: A
authors.lastname: Eckly
authors.affiliation: Unité mixte de recherche S949 Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Etablissement Français du Sang-Alsace 67000, Strasbourg, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.affiliation: Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ellis
authors.affiliation: 1] Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Voss
authors.affiliation: 1] Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia [2] Department of Medical Biology, University of Melbourne, Melbourne, Victoria 3052, Australia.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Dickins
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Hamilton
authors.affiliation: 1] Australian Centre for Blood Diseases, Monash University, Level 6, 89 Commercial Road, Melbourne, Victoria 3004, Australia [2] The Heart Research Institute and Charles Perkins Centre, The University of Sydney, Newtown 2050, Australia [3] Department of Molecular and Experimental Medicine, The Scripps Research Institute, San Diego, CA 92037, USA.
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D000483:Alleles; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D003433:Crosses, Genetic; D005786:Gene Expression Regulation; D005838:Genotype; D006487:Hemostasis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D010477:Perfusion; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D033081:Shear Strength; D015398:Signal Transduction; D013314:Stress, Mechanical; D013927:Thrombosis / Q000235:genetics / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C546621:PIK3C2A protein, human; C546635:Pik3c2a protein, mouse