Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin
Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin
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DOI：
10.1172/jci119521
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发表时间：
1997-07-01
影响因子：
15.9
通讯作者：
Chapman, HA
中科院分区：
文献类型：
--
作者：
Waltz, DA;Natkin, LR;Chapman, HA
尿激酶受体（uPAR）通过与玻连蛋白的结合位点协调纤溶酶介导的细胞表面蛋白水解并促进细胞粘附。由于玻连蛋白也与纤溶酶原激活物抑制剂1型（派-1）结合，纤溶酶切割玻连蛋白降低派-1结合，我们探讨了纤溶酶和派-1对uPAR和玻连蛋白之间相互作用的影响。派-1阻断细胞与玻连蛋白的结合和粘附超过80%纤溶酶对玻连蛋白的有限切割也消除了细胞结合和粘附并诱导细胞脱离，在玻连蛋白羧基末端附近的纤溶酶切割位点（精氨酸361）周围合成了一系列肽。两个跨越res 364-380的肽阻断uPAR与玻连蛋白的结合（IC 50类似于8-25 μ M），鉴定该区域为uPAR-玻连蛋白相互作用的重要位点。这些数据阐明了uPAR依赖性细胞粘附于玻连蛋白的复杂调控方案：活性尿激酶通过激活纤溶酶或与派-1形成复合物来促进粘附和随后的脱离，过量派-1也可能通过阻断细胞粘附和/或促进脱离而促进迁移，这可能部分解释了派-1表达与肿瘤细胞转移之间的强相关性。
The urokinase receptor (uPAR) coordinates plasmin-mediated cell-surface proteolysis and promotes cellular adhesion via a binding site for vitronectin on uPAR, Because vitronectin also binds plasminogen activator inhibitor type 1 (PAI-1), and plasmin cleavage of vitronectin reduces PAI-1 binding, we explored the effects of plasmin and PAI-1 on the interaction between uPAR and vitronectin. PAI-1 blocked cellular binding of and adhesion to vitronectin by over 80% (IC50 similar to 5 nM), promoted detachment of uPAR-bearing cells from vitronectin, and increased cellular migration on vitronectin, Limited cleavage of vitronectin by plasmin also abolished cellular binding and adhesion and induced cellular detachment, A series of peptides surrounding a plasmin cleavage site (arginine 361) near the carboxy-terminal end of vitronectin were synthesized. Two peptides spanning res 364-380 blocked binding of uPAR to vitronectin (IC50 similar to 8-25 mu M) identifying this region as an important site of uPAR-vitronectin interaction, These data illuminate a complex regulatory scheme for uPAR-dependent cellular adhesion to vitronectin: Active urokinase promotes adhesion and also subsequent detachment through activation of plasmin or complex formation with PAI-1, Excess PAI-1 may also promote migration by blocking cellular adhesion and/or promoting detachment, possibly accounting in part for the strong correlation between PAI-1 expression and tumor cell metastasis.