Abstract
The multifaceted role of mitogen-activated protein kinases (MAPKs) in modulating signal transduction pathways in inflammatory conditions such as infection, cardiovascular disease, and cancer has been well established. Recently, coagulation factors have also emerged as key players in regulating intracellular signaling pathways during inflammation. Among coagulation factors, thrombomodulin, as a high affinity receptor for thrombin on vascular endothelial cells, has been discovered to be a potent anti-inflammatory and anti-tumorigenic signaling molecule. The protective signaling function of thrombomodulin is separate from its well-recognized role in the clotting cascade, which is to function as an anti-coagulant receptor in order to switch the specificity of thrombin from a procoagulant to an anti-coagulant protease. The underlying protective signaling mechanism of thrombomodulin remains largely unknown, though a few published reports link the receptor to the regulation of MAPKs under different (patho)physiological conditions. The goal of this review is to summarize what is known about the regulatory relationship between thrombomodulin and MAPKs.
Highlights
The most studied mitogen-activated protein kinases (MAPKs) are classified into three types; extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and 38 kDa mitogen-activated protein kinase (p38 MAPK) [1]
The last two MAPKs are classified as stress-activated protein kinases (SAPKs), and inhibitors of SAPKs are widely used in inflammatory disorders and cancer to control the excessive SAPKs signaling [6,7]
It has been found that rTMD23 suppresses LPS-induced ERK1/2 activation and inflammatory responses by targeting CD14 in mouse peritoneal macrophages [41], suggesting a crosstalk between TMD2&3 and MAPKs
Summary
Mitogen-activated protein kinases (MAPKs) are protein serine/threonine (Ser/Thr) kinases involved in regulation of various physiological processes including proliferation, differentiation, migration and apoptosis [1]. They coordinate cellular responses to environmental cues (i.e., hormones) by phosphorylating intracellular signaling molecules on distinct Ser/Thr residues, thereby initiating and integrating a number of phosphorylation cascades which are involved in the regulation of different signal transduction pathway genes [2]. P38 and JNK MAPKs are mainly activated during immune cell responses under conditions of oxidative stress and inflammation [3,4,5]. The last two MAPKs are classified as stress-activated protein kinases (SAPKs), and inhibitors of SAPKs are widely used in inflammatory disorders and cancer to control the excessive SAPKs signaling [6,7]
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