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PNAS 103 (38): 13932-13937

Copyright © 2006 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

Disulfide isomerization switches tissue factor from coagulation to cell signaling

Jasimuddin Ahamed*,{dagger}, Henri H. Versteeg*,{dagger}, Marjolein Kerver*, Vivien M. Chen{ddagger}, Barbara M. Mueller§, Philip J. Hogg{ddagger}, and Wolfram Ruf*,¶

*Department of Immunology, The Scripps Research Institute, SP258, 10550 North Torrey Pines Road, La Jolla, CA 92037; {ddagger}Centre for Vascular Research, University of New South Wales, Sydney 2052, Australia; and §La Jolla Institute for Molecular Medicine, San Diego, CA 92121

Communicated by Earl W. Davie, University of Washington, Seattle, WA, July 27, 2006

Received for publication June 7, 2006.

Abstract: Cell-surface tissue factor (TF) binds the serine protease factor VIIa to activate coagulation or, alternatively, to trigger signaling through the G protein-coupled, protease-activated receptor 2 (PAR2) relevant to inflammation and angiogenesis. Here we demonstrate that TF·VIIa-mediated coagulation and cell signaling involve distinct cellular pools of TF. The surface-accessible, extracellular Cys186–Cys209 disulfide bond of TF is critical for coagulation, and protein disulfide isomerase (PDI) disables coagulation by targeting this disulfide. A TF mutant (TF C209A) with an unpaired Cys186 retains TF·VIIa signaling activity, and it has reduced affinity for VIIa, a characteristic of signaling TF on cells with constitutive TF expression. We further show that PDI suppresses TF coagulant activity in a nitric oxide-dependent pathway, linking the regulation of TF thrombogenicity to oxidative stress in the vasculature. Furthermore, a unique monoclonal antibody recognizes only the noncoagulant, cryptic conformation of TF. This antibody inhibits formation of the TF·PAR2 complex and TF·VIIa signaling, but it does not prevent coagulation activation. These experiments delineate an upstream regulatory mechanism that controls TF function, and they provide initial evidence that TF·VIIa signaling can be specifically inhibited with minimal effects on coagulation.

Key Words: allosteric disulfide • protein disulfide • isomerase • S-nitrosylation • G protein-coupled receptor

{dagger}J.A. and H.H.V. contributed equally to this work.

Author contributions: J.A., H.H.V., P.J.H., and W.R. designed research; J.A., H.H.V., M.K., V.M.C., and B.M.M. performed research; P.J.H. contributed new reagents/analytic tools; B.M.M., P.J.H., and W.R. analyzed data; and J.A., H.H.V., B.M.M., and W.R. wrote the paper.

Conflict of interest statement: No conflicts declared.

To whom correspondence should be addressed. E-mail: ruf{at}scripps.edu

© 2006 by The National Academy of Sciences of the USA

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