Regulation of platelet plug formation by phosphoinositide metabolism

Abstract

Phosphatidylinositol and its phosphorylated derivatives, phosphoinositides, are minor constituents of phospholipids at the cellular membrane level. Nevertheless, phosphatidylinositol and phosphoinositides represent essential components of intracellular signaling that regulate diverse cellular processes, including platelet plug formation. Accumulating evidence indicates that the metabolism of phosphoinositides is temporally and spatially modulated by the opposing effects of specific phosphoinositide-metabolizing enzymes, including lipid kinases, lipid phosphatases, and phospholipases. Each of these enzymes generates a selective phosphoinositide or second messenger within precise cellular compartments. Intriguingly, phosphoinositide-metabolizing enzymes exist in different isoforms, which all produce the same phosphoinositide products. Recent studies using isoform-specific mouse models and chemical inhibitors have elucidated that the different isoforms of phosphoinositide-metabolizing enzymes have nonredundant functions and provide an additional layer of complexity to the temporo-spatial organization of intracellular signaling events. In this review, we will discuss recent advances in our understanding of phosphoinositide organization during platelet activation. (Blood. 2013;122(8):1358-1365 Introduction Platelet plug formation is essential during hemostasis, but when perturbed, it can lead to pathological bleeding or thrombosis. Thus, this is a tightly controlled process requiring activation of platelets under carefully modulated intracellular signaling transduction.2,3 When there is a vascular injury, platelets tether to collagen or to von Willebrand factor and initiate an intracellular signaling cascade that leads to firm and stable adhesion to the subendothelium. 4 This is followed by integrin activation on the platelet surface and, subsequently, aggregation between platelets. 3Further stabilization of the platelet plug and prevention of platelet disaggregation requires additional amplification of the platelet signaling pathways. Over the past few decades, accumulating evidence indicates that phosphorylated forms of phosphatidylinositol (PtdIns) are crucial components in this complex network of platelet signaling. Phosphoinositide metabolism and signalingMore than 50 years ago, PtdIns was initially observed to be modified by transient phosphorylation of its inositol head group, which generated various phosphorylated forms of PtdIns, currently known as phosphoinositides. 5,6 Since that seminal observation, numerous studies have demonstrated that PtdIns and phosphoinositides are essential mediators of the signal transduction events that are involved in the regulation of diverse cellular processes, which include membrane trafficking, cytoskeletal dynamics, membrane transports, and nuclear events in many different cells.7 A total of 7 phosphoinositides have been identified that derive from PtdIns following the reversible phosphorylation of the hydroxyls situated in the D3, D4, and D5 positions of the inositol head...

Platelet Lipidomics

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“…This process has been shown to require a series of key platelet activation events that are tightly regulated by several phosphoinositides 16 . However, the regulatory role of PtdIns(3,5)P 2 in platelets remains unknown.…”

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“…7 In platelets, PI3Ks play critical signaling roles during the platelet plug formation. 8 For instance, class I PI3K synthesize phosphatidylinositol 3,4,5 trisphosphate, which recruits downstream effector proteins that are essential for the activation of the key platelet adhesion integrin receptor, aIIbb3. In contrast, class II and class III PI3K isoforms are thought to synthesize the phosphoinositides phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 3,4 bisphosphate, which are involved in the regulation of endosomal trafficking and cell migration in other cell types.…”