禽纤溶酶原激活物和基质金属蛋白酶-2的结构和功能揭示了它们在哺乳动物中的对应酶、调控及其在肿瘤侵袭中的作用。

Enzyme & protein Pub Date : 1996-01-01 DOI:10.1159/000468615
D S Alexander, R T Aimes, J P Quigley
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引用次数: 9

摘要

劳斯肉瘤病毒转化的鸡胚成纤维细胞(RSVCEF)是一种具有良好特征的致癌转化、基质降解和肿瘤侵袭的模型系统。由于RSVCEF培养物在基质降解过程中使用丝氨酸蛋白酶和金属蛋白酶级联,因此它们对理解这些参与侵袭细胞行为的分子的性质和调控做出了重大贡献。RSVCEF产生基质金属蛋白酶2 (MMP-2)水平升高,其血凝素结构域与哺乳动物的MMP-2不同。RSVCEF产生的大部分MMP-2以不含timp的形式存在,这增强了其活化、催化活性和底物特异性,从而增强了其基质降解能力。RSVCEFs也表现出高水平的尿激酶型纤溶酶原激活剂(uPA),在完全缺乏纤溶酶原的条件培养基中以活性形式存在。重组表达的禽uPA也处于活性状态,而其活性位点突变体保持其酶原形式,表明鸡uPA的激活机制是自催化的。对鸡和人uPA的结构域和序列进行比较,试图确定可能导致禽uPA酶原不稳定及其自动激活能力的基序。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
What structure and function of avian plasminogen activator and matrix metalloproteinase-2 reveal about their counterpart mammalian enzymes, their regulation and their role in tumor invasion.

Rous sarcoma virus-transformed chick embryo fibroblasts (RSVCEF) constitute a well-characterized model system for oncogenic transformation, matrix degradation, and cancer invasion. As RSVCEF cultures employ both serine protease and metalloprotease cascades in the process of matrix degradation, they have contributed significantly to understanding the nature and regulation of these molecules involved in invasive cell behavior. RSVCEF produce elevated levels of a matrix metalloprotease-2 (MMP-2) whose hemopexin domain differs from mammalian MMP-2. The majority of MMP-2 produced by RSVCEF is present in a TIMP-free form which enhances its activation, catalytic activity and substrate specificity and therefore its matrix-degrading ability. RSVCEFs also exhibit high levels of urokinase-type plasminogen activator (uPA), which is found in active form in their conditioned medium in complete absence of plasminogen. Recombinantly expressed avian uPA is also in active form, while an active-site mutant of the same maintains its zymogen form, indicating the mechanism of activation of chicken uPA is autocatalytic. A domain and sequence comparison between chicken and human uPA attempts to identify motifs potentially responsible for the zymogen instability of avian uPA and its capability to autoactivate.

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