Syk Activity Is Dispensable for Platelet GP1b-IX-V Signaling.

Rachit Badolia,Satya Kunapuli,John Kostyak,Carol Dangelmaier

doi:10.3390/ijms18061238

Rachit Badolia, Satya Kunapuli + Show 2 more

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https://doi.org/10.3390/ijms18061238

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Abstract

The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRγ-ITAM (Fc Receptor γ-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. However, there have been conflicting reports regarding the role of Syk in GP1b signaling. In this study, we sought to resolve these conflicting reports and clarify the role of Syk in VWF-induced platelet activation. The inhibition of Syk with the selective Syk inhibitors, OXSI-2 and PRT-060318, did not inhibit VWF-induced platelet adhesion, agglutination, aggregation, or secretion. In contrast, platelets stimulated with the Glycoprotein VI (GPVI) agonist, collagen-related peptide (CRP), failed to cause any aggregation or secretion in presence of the Syk inhibitors. Furthermore, GP1b-induced platelet signaling was unaffected in the presence of Syk inhibitors, but GPVI-induced signaling was abolished under similar conditions. Thus, we conclude that Syk kinase activity does not play any functional role downstream of GP1b-mediated platelet activation.

Highlights

The process of platelet activation is an important component of normal hemostasis [1]
Another study indicated that the Fc receptor γ (FcRγ) chain or FcγRIIa does not play an important role in GP1b signaling, thereby ruling out the role of spleen tyrosine kinase (Syk) in GP1b signaling, as Syk requires phosphorylated Immunoreceptor tyrosine-based activation motif (ITAM) to become activated [19]
Subsequent reports using platelets treated with the Syk inhibitor, piceatannol, reported normal adhesion under shear stress, suggesting that stable platelet adhesion to von Willebrand factor (VWF) is independent of Syk [21]

Summary

Introduction

The process of platelet activation is an important component of normal hemostasis [1]. The interaction between VWF and GP1b-IX-V (GP1b) mediates transient platelet adhesion and initiates a signaling cascade leading to platelet integrin αIIbβ3 activation and consequent stable platelet adhesion, spreading, and aggregation [4,5,6]. It has been reported in multiple studies that Syk is activated downstream of GP1b-VWF interactions [16,17], mostly via GP1b-associated FcRγ-Immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling [18].

Results

Conclusion