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Blood. 2015 Aug 27;126(9):1128-37. doi: 10.1182/blood-2015-03-636670. Epub 2015 Jun 24.

Essential role of class II PI3K-C2α in platelet membrane morphology.

Author information

1
Inserm, U1048-Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France;
2
CNRS, ITAV-USR3505, Toulouse, France; Université de Toulouse, ITAV-USR3505, Toulouse, France.
3
UCL Cancer Institute, Paul O'Gorman Building, University College London, London, United Kingdom;
4
Inserm, U1048-Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France; Centre Hospitalier Universitaire de Toulouse, Laboratoire d'Hématologie, Toulouse, France.

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.

PMID:
26109204
DOI:
10.1182/blood-2015-03-636670
[Indexed for MEDLINE]

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