title: Combined deficiency of PI3KC2α and PI3KC2β reveals a nonredundant role for PI3KC2α in regulating mouse platelet structure and thrombus stability.
abstract: The physiological functions and cellular signaling of Class II phosphoinositide 3-kinases (PI3Ks) remain largely unknown. Platelets express two Class II PI3Ks: PI3KC2α and PI3KC2β. PI3KC2α deficiency was recently reported to cause disruption of the internal membrane reserve structure of platelets (open canalicular system, OCS) that results in dysregulated platelet adhesion and impaired arterial thrombosis in vivo. Notably, these effects on platelets occurred despite normal agonist-induced 3-phosphorylated phosphoinositide (3-PPI) production and cellular activation in PI3KC2α-deficient platelets. However, the potential compensatory actions of PI3KC2β in platelets have not yet been investigated. Here, we report the first mice deficient in both PI3KC2α and PI3KC2β (no Class II PI3Ks in platelets) and reveal a nonredundant role for PI3KC2α in mouse platelet structure and function. Specifically, we show that the disrupted OCS and impaired thrombus stability observed in PI3KC2α-deficient platelets does not occur in PI3KC2β-deficient platelets and is not exaggerated in platelets taken from mice deficient in both enzymes. Furthermore, detailed examination of 3-PPI production in platelets from this series of mice revealed no changes in either unactivated or activated platelets, including those with a complete lack of Class II PI3Ks. These findings indicate a nonredundant role for PI3KC2α in regulating platelet structure and function, and suggest that Class II PI3Ks do not significantly contribute to the acute agonist-induced production of 3-PPIs in these cells.
authors.affiliation: a Australian Centre for Blood Diseases , Monash University , Melbourne , VIC , Australia.
authors.forename: Claire
authors.initials: C
authors.lastname: Petitjean
authors.affiliation: a Australian Centre for Blood Diseases , Monash University , Melbourne , VIC , Australia.
authors.forename: Natasha M
authors.initials: NM
authors.lastname: Setiabakti
authors.affiliation: a Australian Centre for Blood Diseases , Monash University , Melbourne , VIC , Australia.|c School of Animal Biology , The University of Western Australia , Perth , Australia.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Mountford
authors.affiliation: a Australian Centre for Blood Diseases , Monash University , Melbourne , VIC , Australia.
authors.forename: Jane F
authors.initials: JF
authors.lastname: Arthur
authors.affiliation: b Sir Peter MacCallum Department of Oncology , Peter MacCallum Cancer Centre & The University of Melbourne , Melbourne , Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ellis
authors.affiliation: a Australian Centre for Blood Diseases , Monash University , Melbourne , VIC , Australia.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000648:ultrastructure; D058541:Class II Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D010973:Platelet Adhesiveness; D010976:Platelet Count; D010979:Platelet Function Tests; D013927:Thrombosis / Q000097:blood* / Q000235:genetics*
chemical_list: D058541:Class II Phosphatidylinositol 3-Kinases; D058546:Class III Phosphatidylinositol 3-Kinases
keywords: PI3KC2α; PI3KC2β; Phosphoinositide 3-kinases; platelets