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

Abstract

T hrombin, 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 I 2 and von Willebrand factor and undergo cellular proliferation.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 TM levels are associated with a low risk of developing coronary heart disease. 4 It has also been shown that overexpression of TM on smooth muscle cells downregulates proliferation, 5 suggesting that TM could regulate endothelial and smooth muscle cell proliferation via PAR1.Cellular proliferation is also regulated by specific mitogenactivated protein kinases (MAPKs) that translocate into nuclei after activation and play critical roles in connecting the signal to gene expression and allowing cell-cycle entry. MAPKs (p42/p44 MAPK, also called extracellular signalregulated kinase [ERK] 1 and ERK2) are key mediators of signal transduction from the cell surface to the nucleus. Activation of p42/p44 MAPK required for transduction of mitogenic signaling is associated with a rapid nuclear translocation of these kinases. 6 Addition of the pharmacological MAPK inhibitor PD 98059 has been shown to block activation of the p42/p44 MAPK pathway, impeding its nuclear accumulation. It is believed that MAPK nuclear translocation requires both activation of the p42/p44 MAPK module and neosynthesis of short-lived proteins thought to be nuclear anchors. 7 MAPK modules, composed of three protein kinases activated by successive phosphorylation, are involved in the signal transduction of a wide range of extracellular agents. MAPK is only active when both tyrosyl and threonyl residues are phosphorylated, suggesting that the enzyme functions in vivo to integrate signals from two distinct transduction pathways. 8 In mammalian cel...

Thrombin receptors in vascular smooth muscle cells – function and regulation by vasodilatory prostaglandins

“…Accordingly, TM-bound thrombin inhibits PAR-1-mediated proliferation of SMC. Potentially independent actions of TM in response to thrombin also contribute to the net antiproliferative effects of this non-PAR thrombin receptor (38). In agreement with this concept, thrombin-induced SMC proliferation in pig carotid artery is inhibited by recombinant TM (39).…”

Novel genes regulated by Sonic Hedgehog in pluripotent mesenchymal cells

“…It is unclear what role this gene might play in embryonic mesodermal cells, however Thbd knockout mice display embryonic lethality before the cardiovascular system develops, suggesting a function for Thbd in development independent of its anticoagulant activities (Healy et al, 1995;Weiler-Guettler et al, 1996). Further studies have proposed mechanisms by which Thbd and Thrombin may be involved in controlling cell proliferation (reviewed by Freedman, 2001), though a link to the Hh pathway has not previously been described.…”

Overview of Platelet Physiology: Its Hemostatic and Nonhemostatic Role in Disease Pathogenesis

“…Moreover, tumor cells also have the ability to aggregate platelets [130], further increasing the chance of inducing metastasis. Activation of platelets and regulation of other cells have been controlled by thrombin by means of G protein-coupled protease-activated receptors (PARs) [131]. Researchers have shown that thrombin signaling also contributes hugely to the progression of tumorigenesis and angiogenesis [132].…”