title: Essential role of class II PI3K-C2α in platelet membrane morphology.
abstract: The physiologic roles of the class II phosphoinositide 3-kinases (PI3Ks) and their contributions to phosphatidylinositol 3-monophosphate (PI3P) and PI(3,4)P2 production remain elusive. Here we report that mice heterozygous for a constitutively kinase-dead PI3K-C2α display aberrant platelet morphology with an elevated number of barbell-shaped proplatelets, a recently discovered intermediate stage in the final process of platelet production. Platelets with heterozygous PI3K-C2α inactivation have critical defects in α-granules and membrane structure that are associated with modifications in megakaryocytes. These platelets are more rigid and unable to form filopodia after stimulation. Heterozygous PI3K-C2α inactivation in platelets led to a significant reduction in the basal pool of PI3P and a mislocalization of several membrane skeleton proteins known to control the interactions between the plasma membrane and cytoskeleton. These alterations had repercussions on the performance of platelet responses with delay in the time of arterial occlusion in an in vivo model of thrombosis and defect in thrombus formation in an ex vivo blood flow system. These data uncover a key role for PI3K-C2α activity in the generation of a basal housekeeping PI3P pool and in the control of membrane remodeling, critical for megakaryocytopoiesis and normal platelet production and function.
authors.affiliation: Inserm, U1048-Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France;
authors.forename: Colin
authors.initials: C
authors.lastname: Valet
authors.affiliation: Inserm, U1048-Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France;
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Chicanne
authors.affiliation: CNRS, ITAV-USR3505, Toulouse, France; Université de Toulouse, ITAV-USR3505, Toulouse, France.
authors.forename: Childerick
authors.initials: C
authors.lastname: Severac
authors.affiliation: UCL Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom;
authors.forename: Claire
authors.initials: C
authors.lastname: Chaussade
authors.affiliation: UCL Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom;
authors.forename: Maria A
authors.initials: MA
authors.lastname: Whitehead
authors.affiliation: Inserm, U1048-Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France;
authors.forename: Cendrine
authors.initials: C
authors.lastname: Cabou
authors.affiliation: Inserm, U1048-Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France;
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Gratacap
authors.affiliation: Inserm, U1048-Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France;
authors.forename: Frederique
authors.initials: F
authors.lastname: Gaits-Iacovoni
authors.affiliation: UCL Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom;
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.affiliation: Inserm, U1048-Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France; Centre Hospitalier Universitaire de Toulouse, Laboratoire d'Hématologie, Toulouse, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
authors.affiliation: Inserm, U1048-Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France;
authors.forename: Sonia
authors.initials: S
authors.lastname: Severin
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D055879:Gene Knock-In Techniques; D006579:Heterozygote; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D034061:Thrombopoiesis
chemical_list: D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; D019869:Phosphatidylinositol 3-Kinases; C546635:Pik3c2a protein, mouse