Initiation of plasminogen activation on the surface of monocytes expressing the type II transmembrane serine protease matriptase
Initiation of plasminogen activation on the surface of monocytes expressing the type II transmembrane serine protease matriptase
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DOI：
10.1182/blood-2006-02-001073
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发表时间：
2006-10-15
期刊：
影响因子：
20.3
通讯作者：
Ellis, Vincent
中科院分区：
文献类型：
--
作者：
Kilpatrick, Lynette M.;Harris, Roger L.;Ellis, Vincent
uPA（尿激酶型纤溶酶原激活剂）在与细胞受体uPAR结合时能高效激活纤溶酶原，但只有在产生的纤溶酶激活前uPA的较长滞后期后才能激活。这种蛋白水解系统的活性是如何迅速启动的尚不清楚。我们现在已经发现两种单核细胞系表现出不同的纤溶酶原激活模式。U937细胞而非THIP-1细胞表现出预期的滞后期，提示后者存在本构性启动机制。结果表明，这是由于细胞表面相关蛋白酶对upar结合的前upa的纤溶酶独立激活，并与基质酶的表达有关，基质酶是一种II型跨膜丝氨酸蛋白酶，在THP-1细胞中高度表达，但在U937细胞中检测不到。动力学分析表明基质酶在溶液中是一种相对较差的pro-uPA激活剂，其效率约为纤溶酶(k(cat)/ k - M 1.16 X 10(5) M(-1)s(-1) cf 1.21 X 10(7) M（-1)s(-1)）的100倍。然而，通过siRNA下调THP-1细胞中基质酶的表达降低了细胞相关的pro-uPA的激活以及随后快速启动的纤溶酶原激活76%至93%。基质酶也被发现在外周血单核细胞中表达，因此可能是这些细胞快速启动和调节纤溶酶原激活的特定机制。
uPA (urokinase-type plasminogen activator) activates plasminogen with high efficiency when bound to its cellular receptor uPAR, but only after a prolonged lag phase during which generated plasmin activates pro-uPA. How the activity of this proteolytic system might be rapidly initiated is unknown. We have now found that 2 monocytic cell lines display distinct patterns of plasminogen activation. U937 cells, but not THIP-1 cells, displayed the expected lag phase, suggesting a constitutive initiation mechanism on the latter. This was shown to be due to the plasmin-independent activation of uPAR-bound pro-uPA by a cell surface-associated protease and to correlate with the expression of matriptase, a type II transmembrane serine protease that was highly expressed in THP-1 cells but undetectable in U937 cells. Kinetic analysis demonstrated that matriptase is a relatively poor activator of pro-uPA in solution, approximately 100-fold less efficient than plasmin (k(cat)/K-m 1.16 X 10(5) M(-1)s(-1) cf 1.21 X 10(7) M(-1)s(-1)). However, down-regulation of matriptase expression in THP-1 cells by siRNA reduced the activation of cell-associated pro-uPA and the subsequent rapid initiation of plasminogen activation by 76% to 93%. Matriptase was also found to be expressed by peripheral blood monocytes and may therefore be a specific mechanism for the rapid initiation and regulation of plasminogen activation by these cells.