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Platelet activation by dimeric β 2 ‐glycoprotein I requires signaling via both glycoprotein Ibα and apolipoprotein E receptor 2′
Author(s) -
URBANUS R. T.,
PENNINGS M. T. T.,
DERKSEN R. H. W. M.,
DE GROOT P. G.
Publication year - 2008
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2008.03021.x
Subject(s) - platelet , platelet activation , glycoprotein , platelet membrane glycoprotein , receptor , tyrosine phosphorylation , microbiology and biotechnology , chemistry , signal transducing adaptor protein , biochemistry , biology , immunology
Summary. Background: Dimerization of β 2 ‐glycoprotein I (β 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 β 2 ‐GPI to the platelet receptors apolipoprotein E receptor 2′ (ApoER2′) and glycoprotein Ibα (GPIbα) mediates increased platelet activation in an in vitro thrombosis model. Objective: The individual roles of ApoER2′ and GPIbα in mediating platelet activation by dimeric β 2 ‐GPI has hitherto been unclear. In this study, we have determined the roles of either receptor in platelet activation by dimeric β 2 ‐GPI. Methods: Platelet activation by dimeric β 2 ‐GPI was studied under conditions of flow. Intracellular signaling induced by dimeric β 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 β 2 ‐GPI was completely abolished by inhibition of the interaction of dimeric β 2 ‐GPI with either GPIbα or ApoER2′. Upon platelet stimulation with dimeric β 2 ‐GPI, GPIbα translocated to the cytoskeleton via the scaffold protein 14‐3‐3ζ. 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 β 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.