The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex.
Protein C activation on the surface of the endothelium is critical to the negative regulation of blood coagulation. We now demonstrate that monoclonal antibodies that block protein C binding to the endothelial cell protein C receptor (EPCR) reduce protein C activation rates by the thrombin-thrombomodulin complex on endothelium, but that antibodies that bind to EPCR without blocking protein C binding have no effect. The kinetic result of blocking the EPCR-protein C interaction is an increased apparent Km for the activation without altering the affinity of thrombin for thrombomodulin. Activation rates of the protein C derivative lacking the gamma-carboxyglutamic acid domain, which is required for binding to EPCR, are not altered by the anti-EPCR antibodies. These data indicate that the protein C activation complex involves protein C, thrombin, thrombomodulin, and EPCR. These observations open new questions about the control of coagulation reactions on vascular endothelium.
Stearns-Kurosawa
D J
DJ
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, USA.
Kurosawa
S
S
Mollica
J S
JS
Ferrell
G L
GL
Esmon
C T
CT
D000911:Antibodies, Monoclonal; D001665:Binding Sites; D001779:Blood Coagulation Factors; D002460:Cell Line; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D011486:Protein C / Q000378:metabolism* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D018180:Thrombomodulin / Q000378:metabolism*; D014162:Transfection
D000911:Antibodies, Monoclonal; D001779:Blood Coagulation Factors; D011486:Protein C; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D018180:Thrombomodulin; C091963:activated protein C receptor; D013917:Thrombin