Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor
Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor
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DOI：
10.1172/jci119669
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发表时间：
1997-09-15
影响因子：
15.9
通讯作者：
McCrae, KR
中科院分区：
文献类型：
--
作者：
Colman, RW;Pixley, RA;McCrae, KR
尿激酶受体（uPAR）通过与uPAR结构域1的特异性相互作用结合尿激酶型纤溶酶原激活物（u-PA），通过与uPAR结构域2和3内的一个位点相互作用结合玻璃体连接蛋白。这些相互作用分别促进细胞表面纤溶酶原激活物活性的表达和细胞对玻璃体粘连蛋白的粘附。高分子量激肽原（High molecular weight kininogen， HK）也通过其作为prekallikrein的获得性受体的能力刺激细胞表面纤溶酶原激活物活性的表达，而prekallikrein在被激活后可能直接激活prourokinase。在这里，我们报道了裂解形式的HK （HKa）与人脐静脉内皮细胞（HUVEC）的结合是通过锌依赖与uPAR的相互作用介导的。由于I-125-HKa与HUVEC的结合受到玻璃体连接蛋白、抗uPAR结构域2和3抗体和可溶性重组uPAR （suPAR）的抑制，这些反应通过uPAR结构域2和3内的一个位点发生，但不受抗体7E3的抑制，抗体7E3识别内皮细胞玻璃体连接蛋白受体(整合素α (v) β(3))的β链，或纤维蛋白原，另一个α (v) β(3)配体。我们还证明了suPAR和HKa之间锌依赖复合物的形成。HKa与内皮细胞uPAR的相互作用可能是其促进钾化钾素依赖性细胞表面纤溶酶生成的能力的基础，也部分解释了其抗粘附特性。
The urokinase receptor (uPAR) binds urokinase-type plasminogen activator (u-PA) through specific interactions with uPAR domain I, and vitronectin through interactions with a site within uPAR domains 2 and 3. These interactions promote the expression of cell surface plasminogen activator activity and cellular adhesion to vitronectin, respectively. High molecular weight kininogen (HK) also stimulates the expression of cell surface plasminogen activator activity through its ability to serve as an acquired receptor for prekallikrein, which, after its activation, may directly activate prourokinase. Here, we report that binding of the cleaved form of HK (HKa) to human umbilical vein endothelial cells (HUVEC) is mediated through zinc-dependent interactions with uPAR. These occur through a site within uPAR domains 2 and 3, since the binding of I-125-HKa to HUVEC is inhibited by vitronectin, anti-uPAR domain 2 and 3 antibodies and soluble, recombinant uPAR (suPAR), but not by antibody 7E3, which recognizes the beta chain of the endothelial cell vitronectin receptor (integrin alpha(v) beta(3)), or fibrinogen, another alpha(v) beta(3) ligand. We also demonstrate the formation of a zinc-dependent complex between suPAR and HKa. Interactions of HKa with endothelial cell uPAR may underlie its ability to promote kallikrein-dependent cell surface plasmin generation, and also explain, in part, its antiadhesive properties.