Department of Biochemistry and Molecular Biology, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA.
J Biol Chem. 2012 Nov 16;287(47):39291-302. doi: 10.1074/jbc.M112.404061. Epub 2012 Oct 4.
Tissue factor (TF) is a cell-surface glycoprotein responsible for initiating the coagulation cascade. Besides its role in homeostasis, studies have shown the implication of TF in embryonic development, cancer-related events, and inflammation via coagulation-dependent and -independent (signaling) mechanisms. Tissue factor pathway inhibitor (TFPI) plays an important role in regulating TF-initiated blood coagulation. Therefore, transcriptional regulation of TF expression and its physiological inhibitor TFPI would allow us to understand the critical step that controls many different processes. From a gene profiling study aimed at identifying differentially regulated genes between wild-type (WT) and p21-activated kinase 1-null (PAK1-KO) mouse embryonic fibroblasts (MEFs), we found TF and TFPI are differentially expressed in the PAK1-KO MEFs in comparison with wild-type MEFs. Based on these findings, we further investigated in this study the transcriptional regulation of TF and TFPI by PAK1, a serine/threonine kinase. We found that the PAK1·c-Jun complex stimulates the transcription of TF and consequently its procoagulant activity. Moreover, PAK1 negatively regulates the expression of TFPI and additionally contributes to increased TF activity. For the first time, this study implicates PAK1 in coagulation processes, through its dual transcriptional regulation of TF and its inhibitor.
组织因子（TF）是一种细胞表面糖蛋白，负责启动凝血级联反应。除了在体内平衡中的作用外，研究还表明 TF 在胚胎发育、癌症相关事件和炎症中通过凝血依赖和非依赖（信号）机制发挥作用。组织因子途径抑制剂（TFPI）在调节 TF 引发的血液凝固中起着重要作用。因此，TF 表达的转录调控及其生理抑制剂 TFPI 将使我们能够了解控制许多不同过程的关键步骤。从一项旨在鉴定野生型（WT）和 PAK1 缺失型（PAK1-KO）小鼠胚胎成纤维细胞（MEF）之间差异表达基因的基因谱研究中，我们发现与野生型 MEF 相比，PAK1-KO MEF 中 TF 和 TFPI 的表达存在差异。基于这些发现，我们进一步研究了 PAK1（一种丝氨酸/苏氨酸激酶）对 TF 和 TFPI 的转录调控。我们发现 PAK1·c-Jun 复合物刺激 TF 的转录，从而刺激其促凝血活性。此外，PAK1 负调节 TFPI 的表达，并有助于增加 TF 活性。这项研究首次表明，PAK1 通过其对 TF 和 TFPI 的双重转录调控参与凝血过程。
