The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function
Blood Platelets
0301 basic medicine
Hemostasis
Genotype
Platelet Aggregation
Mice, Inbred C57BL
Perfusion
Mice
Phosphatidylinositol 3-Kinases
03 medical and health sciences
Platelet Adhesiveness
Gene Expression Regulation
Microscopy, Electron, Transmission
Mutation
Cell Adhesion
Animals
Humans
Phosphorylation
Shear Strength
Alleles
Crosses, Genetic
Bone Marrow Transplantation
DOI:
10.1038/ncomms7535
Publication Date:
2015-03-17T10:58:30Z
AUTHORS (16)
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.
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