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(Circulation Research. 2001;88:651.)
© 2001 American Heart Association, Inc.

Editorial

Thrombin, Thrombomodulin, and Extracellular Signal–Regulated Kinases Regulating Cellular Proliferation

Jane E. Freedman

From the Departments of Pharmacology and Medicine, Georgetown University, Washington, DC.

Correspondence to Jane E. Freedman, MD, Georgetown University, Med-Dent NE 403, 3900 Reservoir Rd NW, Washington, DC 20007. E-mail freedmaj@georgetown.edu

Key Words: thrombomodulin • thrombin • mitogen-activated protein kinase

	Introduction

 
Thrombin, a coagulation protease, is primarily known for its regulation of hemostasis and thrombosis. However, this enzyme also plays important roles in wound healing and pathological situations, such as inflammation and tumorigenesis. In addition, stimulation of the thrombin receptor signals many cellular events that are associated with the response to vascular injury, including smooth muscle cell proliferation.¹ Thrombin activates platelets and regulates the actions of other cells by means of G protein–coupled protease-activated receptors (PARs). PAR1 is activated when thrombin binds to and cleaves the amino terminal extension of its receptor to create a new receptor amino terminus that functions as a tethered ligand (Figure).² This new amino terminus then binds intramolecularly to the body of the receptor to effect transmembrane signaling.³ In response to stimulation with thrombin, endothelial cells release prostaglandin I₂ and von Willebrand factor and undergo cellular proliferation.

View larger version (26K): [in this window] [in a new window]   Figure 1. On endothelial cells (ECs), TM acts as a receptor for thrombin (T), preventing its acting on fibrinogen and leading to activation of protein C (PC). Thrombin also regulates cellular actions by activating PAR1.

Thrombomodulin (TM), a membrane-bound glycoprotein expressed on endothelial cells, has a high affinity of binding to thrombin and converts thrombin from a procoagulant to an anticoagulant. TM binds to thrombin and changes the enzyme’s conformation, allowing thrombin to activate protein C (Figure). Plasma-soluble TMs are cleaved products of cellular TM that also have anticoagulant and antifibrinolytic properties, and plasma levels may reflect the level of endothelial TM expression.⁴ Prospective studies show that high plasma . . . [Full Text of this Article]