Phosphatidylinositol 3 monophosphate metabolizing enzymes in blood platelet production and in thrombosis

Blood platelets, produced by the fragmentation of megakaryocytes, play a key role in hemostasis and thrombosis. Being implicated in atherothrombosis and other thromboembolic disorders, they represent a major therapeutic target for antithrombotic drug development. Several recent studies have highlighted an important role for the lipid phosphatidylinositol 3 monophosphate (PtdIns3P) in megakaryocytes and platelets. PtdIns3P, present in small amounts in mammalian cells, is involved in the control of endocytic trafficking and autophagy. Its metabolism is finely regulated by specific kinases and phosphatases. Class II (α, β and γ) and III (Vps34) phosphoinositide-3-kinases (PI3Ks), INPP4 and Fig4 are involved in the production of PtdIns3P whereas PIKFyve, myotubularins (MTMs) and type II PIPK metabolize PtdIns3P. By regulating the turnover of different pools of PtdIns3P, class II (PI3KC2α) and class III (Vps34) PI3Ks have been recently involved in the regulation of platelet production and functions. These pools of PtdIns3P appear to modulate membrane organization and intracellular trafficking. Moreover, PIKFyve and INPP4 have been recently implicated in arterial thrombosis. In this review, we will discuss the role of PtdIns3P metabolizing enzymes in platelet production and function. Potential new anti-thrombotic therapeutic perspectives based on inhibitors targeting specifically PtdIns3P metabolizing enzymes will also be commented.