期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 6, 期 8, 页码 1405-1412出版社
WILEY
DOI: 10.1111/j.1538-7836.2008.03021.x
关键词
14-3-3zeta; ApoER2'; Disabled1; glycoprotein Ib alpha; LRP-8; beta(2)-glycoprotein I
Background: Dimerization of beta(2)-glycoprotein I (beta(2)-GPI) by autoantibodies is thought to trigger the clinical manifestations observed in the antiphospholipid syndrome. Arterial thrombosis, a frequently occurring clinical manifestation of the antiphospholipid syndrome, is a process in which platelets play a crucial role. Previous work has shown that binding of dimeric beta(2)-GPI to the platelet receptors apolipoprotein E receptor 2' (ApoER2') and glycoprotein Ib alpha (GPIb alpha) mediates increased platelet activation in an in vitro thrombosis model. Objective: The individual roles of ApoER2' and GPIb alpha in mediating platelet activation by dimeric beta(2)-GPI has hitherto been unclear. In this study, we have determined the roles of either receptor in platelet activation by dimeric beta(2)-GPI. Methods: Platelet activation by dimeric beta(2)-GPI was studied under conditions of flow. Intracellular signaling induced by dimeric beta(2)-GPI was subsequently analyzed by means of sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and western blot analysis. Results: The increase in platelet deposition onto a fibronectin surface under conditions of flow by dimeric beta(2)-GPI was completely abolished by inhibition of the interaction of dimeric beta(2)-GPI with either GPIb alpha or ApoER2'. Upon platelet stimulation with dimeric beta(2)-GPI, GPIb alpha translocated to the cytoskeleton via the scaffold protein 14-3-3 zeta. Concomitantly, ApoER2' dissociated from the adapter protein Disabled1, presumably through phosphorylation of the cytoplasmic tail. Inhibition of one process could not inhibit the other. Conclusion: We show that dimeric beta(2)-GPI signals via two distinct pathways in platelets, both of which are required for platelet activation. Abrogation of either signal results in loss of activation.
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