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  • Title: Botrocetin/VWF-induced signaling through GPIb-IX-V produces TxA2 in an alphaIIbbeta3- and aggregation-independent manner.
    Author: Liu J, Pestina TI, Berndt MC, Jackson CW, Gartner TK.
    Journal: Blood; 2005 Oct 15; 106(8):2750-6. PubMed ID: 15985541.
    Abstract:
    Binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein (GP) Ib-IX-V complex initiates a signaling cascade that causes alphaIIbbeta3 activation and platelet aggregation. Previous work demonstrated that botrocetin (bt)/VWF-mediated agglutination activates alphaIIbbeta3 and elicits adenosine triphosphate (ATP) secretion in a thromboxane A2 (TxA2)- and Ca2+-dependent manner. This agglutination-elicited TxA2 production occurs in the absence of ATP secretion. However, the signaling components and signaling network or pathway activated by GPIb-mediated agglutination to cause TxA2 production have not been identified. Therefore, the focus of this study was to elucidate at least part of the signal transduction network or pathway activated by GPIb-mediated agglutination to cause TxA2 production. The phosphatidylinositol 3-kinase (PI3K) selective inhibitor wortmannin, and mouse platelets deficient in Lyn, Src, Syk, Src homology 2 (SH2) domain-containing leukocyte protein 76 (SLP-76), phospholipase Cgamma2 (PLCgamma2), linker for activation of T cells (LAT), or Fc receptor gamma-chain (FcRgamma-chain) were used for these studies. LAT and FcRgamma-chain were found not to be required for agglutination-driven TxA2 production or activation of alphaIIbbeta3, but were required for granule secretion and aggregation. The results also clearly demonstrate that bt/VWF-mediated agglutination-induced TxA2 production is dependent on signaling apparently initiated by Lyn, enhanced by Src, and propagated through Syk, SLP-76, PI3K, PLCgamma2, and protein kinase C (PKC).
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