Directory | Contact | Careers | Intranet | Home

Research Focus

Protective PAR1 Signaling by the Protein C Pathway

The serine proteases thrombin and activated protein C (APC) are major regulators of the blood coagulation system. Thrombin not only initiates fibrin formation and platelet activation but it also activates protein C on the surface of endothelial cells. The generated APC inhibits blood coagulation by downregulating prothrombin activation in a negative feedback loop. Endothelial cell protein C receptor (EPCR) can bind both protein C and APC and activation of EPCR-bound protein C is enhanced. Results from animal models and clinical trials indicate that APC has potent protective effects in systemic inflammation that are independent from its well established anticoagulant function and recombinant APC was recently approved to treat patients with severe sepsis. The molecular basis for APC's anti-inflammatory effects is incompletely understood. We have identified protease activated receptor 1 (PAR1), the prototypical thrombin receptor, and EPCR as part of a novel APC signaling pathway in endothelial cells. The G-protein-coupled PAR1 is activated by proteolytic cleavage of a specific peptide bond in the aminoterminal exodomain, leading to the exposure of a neo-aminoterminus that folds back and activates the receptor. APC binding to EPCR was required for PAR1 activation by APC and PAR1 activation accounted for all effects of APC on gene expression. Ongoing experiments in vitro and in vivo analyze how the same receptor PAR1 can mediate both proinflammatory signaling by thrombin and the important anti-inflammatory effects of APC.

Education

M.D., Medicine, Ludwig Maximilian University of Munich, 1992

Awards & Professional Activities

Member, American Society of Hematology; Junior Faculty Scholar Award in Basic Research 2003-2005, American Society of Hematology; Thrombosis Research Fellowship Award 1999-2001, International Society of Thrombosis and Hemostasis

Selected References

Riewald, M., Kravchenko, V.V., Petrovan, R.J., O'Brien, P.J., Brass, L.F., Ulevitch, R.J., Ruf, W. Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1. Blood 97:3109-3116, 2001.

Riewald, M., Ruf, W. Mechanistic coupling of protease signaling and initiation of coagulation by tissue factor. Proc. Natl. Acad. Sci. U S A. 98:7742-7747, 2001.

Riewald, M., Petrovan, R.J., Donner, A., Mueller, B.M., Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296:1880-1882, 2002.

Ruf, W., Dorfleutner, A., Riewald, M. Specificity of coagulation factor signaling. J. Thromb. Haemost. 1:1495-1503, 2003.