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.

Identifying lipid traces of atherogenic mechanisms in human carotid plaque

“…We identify an increased abundance of PI in regions with intraplaque hemorrhage and subsequent thrombus formation, which can be identified in histology by their fibrin content. PI compounds, specifically PI 4,5-biphosphate and PI 3-monophosphate, activate several key proteins involved in the blood coagulation pathway, such as platelet phospholipase C [67][68][69]. Previous research has found TAGs surrounding neovessels within plaque [14], potentially related to intra-plaque hemorrhage and the subsequent fibrin formation.…”

The bone marrow niche from the inside out: how megakaryocytes are shaped by and shape hematopoiesis

“…Recently, phosphatidylinositol 3-monophosphate, produced by Vps34 (phosphatidylinositol 3-kinase), has emerged as an important regulator of MK/platelet structure and function 79 ; inhibiting Vps34 at early stages of MK development leads to aberrant demarcation membrane system development. 80 Another important lipid, platelet activation factor (PAF), is present in the BM and regulates the function of HSPCs.…”

Megakaryocyte Cytoskeletal Proteins in Platelet Biogenesis and Diseases

“…39 Megakaryocyte cytoskeleton/membrane dynamics are also regulated by phosphatidylinositol 3 monophosphate (PtdIns3P), and its implication in platelet generation/function has been recently reviewed. 40 Several actin-binding proteins are emerging as critical regulators of megakaryocyte function, 41 and most of them are involved in the complex generation of the DMS (►Fig. 1A).…”

“…39 Megakaryocyte cytoskeleton/membrane dynamics are also regulated by phosphatidylinositol 3 monophosphate (PtdIns3P), and its implication in platelet generation/function has been recently reviewed. 40…”