Abstract
Platelet cytoskeletal reorganisation is a critical component of platelet activation and thrombus formation in haemostasis. The Rho GTPases RhoA, Rac1 and Cdc42 are the primary drivers in the dynamic reorganisation process, leading to the development of filopodia and lamellipodia which dramatically increase platelet surface area upon activation. Rho GTPases cycle between their active (GTP-bound) and inactive (GDP-bound) states through tightly regulated processes, central to which are the guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs catalyse the dissociation of GDP by inducing changes in the nucleotide binding site, facilitating GTP binding and activating Rho GTPases. By contrast, while all GTPases possess intrinsic hydrolysing activity, this reaction is extremely slow. Therefore, GAPs catalyse the hydrolysis of GTP to GDP, reverting Rho GTPases to their inactive state. Our current knowledge of these proteins is constantly being updated but there is considerably less known about the functionality of Rho GTPase specific GAPs and GEFs in platelets. In the present review, we discuss GAP and GEF proteins for Rho GTPases identified in platelets, their regulation, biological function and present a case for their further study in platelets.
Highlights
The molecular events that stimulate platelet adhesion, aggregation and thrombus formation are crucial to platelet function, both in haemostasis and thrombosis
One of the first RhoA-specific GTPase-activating proteins (GAPs) proteins characterised in platelets was p190RhoGAP (ARHGAP35), where its activity was stimulated during platelet activation via Src-family kinases (SFKs) inhibiting RhoA and facilitating platelet spreading [24]
OPHN1−/− murine platelets exhibit abnormal RhoA hyperactivation and significant increases in thrombus formation both ex- and in vivo [27]. These findings suggest aberrant regulation of Rho GTPases significantly impacts the ability of platelets to adhere and undergo classic shape change responses following stimulation of platelet activation [6]
Summary
The molecular events that stimulate platelet adhesion, aggregation and thrombus formation are crucial to platelet function, both in haemostasis and thrombosis. It has been well documented that platelet regulation at a molecular level is a finely balanced system crosstalk between different signalling pathways, resulting in events such as phosphorylation, Ca2+ fluctuation, lipid modification and more [1]. These processes are regulated and coordinated interdependently by small GTPases, allowing for the rapid alterations seen in the platelet cytoskeleton and overall platelet morphology upon activation [2,3,4]. RhoA, Rac and Cdc have been linked with other processes in platelet activation such as platelet granule release [2], clot retraction [7] and integrin activation via crosstalk with another small GTPase, Rap1 [8, 9]
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