Tissue factor: mechanisms of decryption.
Tissue factor: mechanisms of decryption.
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DOI：
10.2741/477
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Pendurthi UR
中科院分区：
文献类型：
--
作者：
Rao LV;Kothari H;Pendurthi UR
组织因子（TF）是凝血因子VII/VIIa（FVII/FVIIa）的细胞受体。在细胞表面上形成TF-FVIIa复合物不仅触发凝血级联反应，而且通过蛋白酶活化受体的活化转导细胞信号传导。通常认为，在细胞表面上发现的TF中只有一小部分在凝血中是活性的，而绝大多数在凝血中是隐蔽的（非功能性的）。目前尚不清楚隐藏TF与凝血活性TF的区别，也不清楚隐藏TF转化为凝血活性形式的潜在机制。隐蔽和凝血活性TF形式都可以结合FVIIa。通常认为，隐蔽的TF-FVIIa复合物不能激活因子X，因为蛋白质底物结合位点被掩埋在加密的复合物中，并且暴露底物结合位点的TF-FVIIa复合物的变化导致其解密。暴露于各种化学或病理生理刺激的磷脂酰丝氨酸（PS）已被认为是TF解密的最有效的诱导剂。除了PS之外，TF自缔合和与专门的膜结构域的缔合也可以在TF解密中发挥作用。最近的研究表明，TF的隐蔽形式在膜近端结构域中的Cys 186和Cys 209处含有未配对的半胱氨酸巯基，而TF的凝血活性形式被认为具有氧化的Cys 186-Cys 209二硫键。有人认为，蛋白质二硫键异构酶（PDI）调节TF解密通过其氧化还原酶活性，通过靶向这个二硫键或调节PS平衡质膜。然而，这一假设需要进一步验证，才能成为公认的机制。在这篇文章中，我们严格审查TF加密/解密的文献，特别强调最近发表的数据，并提供我们对这个问题的看法。
Tissue factor (TF) is a cellular receptor for clotting factor VII/VIIa (FVII/FVIIa). Formation of TF-FVIIa complexes on cell surfaces not only triggers the coagulation cascade but also transduces cell signaling via activation of protease-activated receptors. It is generally believed that only a small fraction of the TF found on cell surfaces is active in coagulation whereas the vast majority is cryptic (non-functional) in coagulation. It is unclear how cryptic TF differs from the coagulant active TF or potential mechanisms involved in transformation of cryptic TF to the coagulant active form. Both cryptic and coagulant active TF forms can bind FVIIa. It is generally believed that cryptic TF-FVIIa complexes fail to activate factor X as the protein substrate binding site is buried in the encrypted complex and a change in TF-FVIIa complex that exposes the substrate binding site leads to its decryption. Exposure of phosphatidylserine (PS) in response to various chemical or pathophysiological stimuli has been considered as the most potent inducer of TF decryption. In addition to PS, TF self-association and association with specialized membrane domains may also play a role in TF decryption. Recent studies suggest that cryptic form of TF contains unpaired cysteine thiols at Cys186 and Cys209 in the membrane-proximal domain, whereas the coagulant active form of TF is thought to have an oxidized Cys186-Cys209 disulfide bond. It has been suggested that protein disulfide isomerase (PDI) regulates TF decryption through its oxidoreductase activity by targeting this disulfide bond or regulating the PS equilibrium at the plasma membrane. However, this hypothesis requires further validation to become an accepted mechanism. In this article, we critically review literature on TF encryption/decryption with specific emphasis on recently published data and provide our perspective on this subject.