Phosphatidylinositol 3-monophosphate: A novel actor in thrombopoiesis and thrombosis

Abstract

Phosphoinositides are lipid second messengers regulating in time and place the formation of protein complexes involved in the control of intracellular signaling, vesicular trafficking, and cytoskeleton/membrane dynamics. One of these lipids, phosphatidylinositol 3 monophosphate (PtdIns3P), is present in small amounts in mammalian cells and is involved in the control of endocytic/endosomal trafficking and in autophagy. Its metabolism is finely regulated by specific kinases and phosphatases including class II phosphoinositide 3-kinases (PI3KC2s) and the class III PI3K, Vps34. Recently, PtdIns3P has emerged as an important regulator of megakaryocyte/platelet structure and functions. Here, we summarize the current knowledge in the role of different pools of PtdIns3P regulated by class II and III PI3Ks in platelet production and thrombosis. Potential new antithrombotic therapeutic perspectives based on the use of inhibitors targeting specifically PtdIns3P-metabolizing enzymes will also be discussed. Finally, we provide report of new research in this area presented at the International Society of Thrombosis and Haemostasis 2019 Annual Congress.

Keywords: megakaryocytes; phosphatidylinositol 3 monophosphate; phosphoinositide 3‐kinases; platelets; thrombosis.

Figure 1

Illustration of PtdIns3P structure (A) and metabolism (B). FIG4: Phosphatidylinositol 3,5‐bisphosphate 5‐phosphatase; INPP4: Inositol polyphosphate 4‐phosphatase type I; MTM: myotubularin; MTMR: myotubularin‐related phosphoinositide phosphatase; PI3K: phosphoinositide 3‐kinase; PIKfyve: phosphatidylinositol 3 monophosphate 5‐kinase; PIP4K: phosphatidylinositol 3 monophosphate 4‐kinase

Figure 2

The class II PI3K PI3KC2α and its housekeeping pool of phosphatidylinositol 3 monophosphate (PtdIns3P) in megakaryocyte and platelet membrane morphology and thrombosis. Class II PI3K PI3KC2α, by regulating a basal pool of PI3P and organizing the spectrin‐rich membrane skeleton, is important for maintaining normal platelet membrane morphology/remodeling that is important for platelet thrombotic capacities under shear stress conditions

Figure 3

The class III PI3K Vps34 regulates specific pools of phosphatidylinositol 3 monophosphate (PtdIns3P) that have different implications in platelet production and activation. The class III PI3K Vps34, by regulating a specific pool of PtdIns3P that controls endocytic/endosomal trafficking, granule biogenesis, and directional migration in megakaryocytes, maintains normal platelet production (platelet granule content and circulating platelet count and size). In platelets, Vps34 regulates a stimulation‐dependent pool of PtdIns3P involved in the control of arterial thrombus growth under shear stress by regulating platelet secretion, NADPH oxidase–dependent reactive oxygen species generation and mammalian target of rapamycin signaling