© 1998 American Heart Association, Inc.
Brief Reviews |
Sol Sherry Lecture in Thrombosis
How Thrombin `Talks' to Cells Molecular Mechanisms and Roles In Vivo
From the Cardiovascular Research Institute, Departments of Medicine and Cellular and Molecular Pharmacology, University of California at San Francisco.
Correspondence to Shaun R. Coughlin, Cardiovascular Research Institute, Departments of Medicine and Cellular and Molecular Pharmacology, University of California at San Francisco, 505 Parnassus Ave, San Francisco, CA 94143-0130. E-mail shaun—coughlin@quickmail.ucsf.edu
Key Words: thrombin • protease-activated receptors • platelets • embryonic development • knockout
This article is a summary of the Sol Sherry Lecture of the Council on Arteriosclerosis, Thrombosis, and Vascular Biology, which was presented at the 70th Scientific Sessions of the American Heart Association in November 1997. It highlights work from our laboratory addressing the molecular mechanisms by which the coagulation protease thrombin elicits cellular responses, notes some of the novel issues that protease signaling raises, and cites recent work on the role of thrombin signaling in vivo.
Thrombin is a multifunctional serine protease. In adult animals, active thrombin is generated in the context of vascular injury when activation of the coagulation cascade triggers conversion of the circulating zymogen prothrombin to active protease. Thrombin generation may also be important in other contexts, as will be shown below.
Several of thrombin's functions involve cleavage of circulating protein substrates, eg, conversion of fibrinogen to fibrin monomer or activation of protein C. However, thrombin also has important actions on cells. It is the most potent activator of platelets.1 It causes endothelial cells to deliver the leukocyte adhesion molecule P-selectin to their surfaces,2 to secrete von Willebrand factor,2 and to elaborate growth factors and cytokines.3 4 It is also a mitogen for fibroblasts and vascular smooth muscle cells.5 Such cellular actions of thrombin raised several important questions. How does thrombin, a protease, act like a hormone to control cellular behaviors? And what are the roles of thrombin-regulated cellular events in vivo?
Thrombin's actions on platelets are of particular interest.
Arterial thrombosis underlies most cases of unstable angina
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