人類凝血酶調節素(Thrombomodulin;簡稱TM)是血管內皮細胞表面的一種醣蛋白，分子量約為75kDa，由557個胺基酸所組成。從N端到C端可依序分為五個不同的功能區間(Functional domain): lectin-like domain、epidermal growth factor(EGF)-like domain、serine/threonine-rich domain、transmembrane domain及C端的cytoplasmic domain。TM主要的生物活性是參與抗凝固反應，當TM與凝血酶(thrombin)以1:1等比例結合成複合體，活化protein C，而活化型的protein C會水解血液中的活化型凝固因子五及八，進而抑制凝血酶生成及一連串的凝固反應，達到抗凝效果。凝血酶是一種絲胺酸蛋白酶(serine protease)，主要生理作用是促進血小板活化及血液凝固作用，然而，此蛋白酶也具有刺激發炎反應、腫瘤生成及傷口癒合等重要功能。陸續有文獻指出， TM會調節蛋白酶活化接受器(protease activated receptor; PAR)的MAPK訊息反應，但是作用的機轉尚未明瞭。為了釐清TM在調控凝血酶作用的分子機轉，本實驗室，利用內生性表現蛋白酶活化接受器的細胞株-人類胚胎腎臟細胞(HEK293)，轉殖入TM基因，我們初步發現表現TM的細胞株會延長凝血酶所誘導ERK的活化長達四個小時之久，截去TM 的lectin-like domain或TM cytoplasmic domain都不會影響TM在延長ERK活化的能力。加入凝血酶接受器擷抗物或抗TM抗體，則會抑制TM調節凝血酶誘導p-ERK活化之結果。阻斷PK C路徑可以完全抑制，在凝血酶活化之ERK訊息傳遞路徑上的延長活化能力。綜合以上結果，我們認為凝血酶與TM形成的複合體，會經由活化PKC路徑來延長ERK之活化，而TM的lectin-like domain及cytoplasmic domain並沒有參與傳導此種調節訊號，至於凝血酶-TM形成複合體活化PKC路徑的方式，則有待進一步實驗來釐清。

Thrombomodulin ( TM ), a 75 kDa glycoprotein of 557 amino acid residues, is expressed on endothelial cells of vasculatures. It consists of five distinct domains including N-terminal lectin-like domain, epidermal growth factor (EGF)-like domain, serine / threonine-rich domain, transmembrane domain, and cytoplasmic tail. By forming a 1:1 complex with thrombin, TM alters the procoagulant activity of thrombin and acts as a cofactor in thrombin-catalyzed activation of protein C. Activated protein C can proteolytically inactive coagulation factor Va and VIIIa which in turn shutdown the generation of thrombin. Thrombin, a serine protease, is primarily known for its regulation of hemostasis and thrombosis. However, this enzyme also plays an important role in wound healing and pathological situations, such as inflammation and tumorigenesis. Thrombin can either bind to thrombin receptor or TM, however, the interaction of these factors is not clear.
Previously reports demonstrated that TM retained the effects induced by thrombin-thrombin receptor interaction, however, the mechanism is ambiguous. In the present studies, we found that TM-overexpressed human embryonic kidney cells could prolong the thrombin-induced extracellular signal regulated kinase (ERK) phosphorylation. The sustained ERK phosphorylation was inhibited by adding PAR1 antagonist or anti-TM antibody. Neither the lectin-like domain truncated or the cytoplasmic domain-deleted mutants of TM could alter the modulating activity of TM. Furthermore, blocking the PKC pathway could completely abolish the prolonged pERK in TM-expressed HEK293 cells. Taken together, we concluded that the thrombin-TM complex could modulate the PAR-1 mediated ERK signaling through a PKC-dependent manner, although the detailed mechanism remained to be clarified.

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