Protein C supports platelet binding and activation under flow: Role of glycoprotein Ib and apolipoprotein E receptor 2

T. C. White, M. A. Berny, E. I. Tucker, R. T. Urbanus, P. G. De Groot, J. A. Fernández, J. H. Griffin, A. Gruber, O. J.T. Mccarty

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Background: Activated protein C (APC) regulates thrombin generation and inhibits apoptosis. Endothelial protein C receptor (EPCR)-bound protein C is activated by thrombomodulin-bound thrombin. APC inactivates coagulation factors (F)Va/VIIIa and generates cytoprotective signaling downstream of protease-activated receptor-1 (PAR-1). Binding of APC to EPCR both modifies and induces PAR-1 signaling, but it is unknown if protein C interacts with cells in an alternative manner. Aim: To determine whether platelets possess receptors for protein C that can generate intracellular signals. Results: Immobilized protein C or APC supported platelet adhesion, lamellipodia formation and elevation of intracellular Ca2+. Adhesion of platelets to protein C or APC was inhibited by soluble recombinant apolipoprotein E receptor 2′(ApoER2′) and by receptor-associated protein (RAP), an inhibitor of the low-density lipoprotein receptor family. Under shear, surface-bound protein C supported platelet adhesion and aggregation in a glycoprotein (GP)Ibα-dependent manner, and adhesion of platelets to immobilized protein C was abrogated by the addition of soluble forms of ApoER2′ or RAP. APC bound to purified recombinant ApoER2′ or GPIbα. Conclusions: Our data demonstrate that activation of platelets with rapid intracellular signaling caused by binding to immobilized protein C or APC occurs via mechanisms that require ApoER2 and GPIbα and that APC directly binds to purified ectodomains of the receptors ApoER2 and GPIbα. These findings imply that protein C and APC may directly promote cell signaling in other cells by binding to ApoER2 and/or GPIbα.

Original languageEnglish (US)
Pages (from-to)995-1002
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume6
Issue number6
DOIs
StatePublished - Jun 1 2008

Keywords

  • Activated protein C
  • Apolipoprotein E receptor 2
  • Glycoprotein Ib
  • Platelet activation

ASJC Scopus subject areas

  • Hematology

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