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The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin.

机译:丝氨酸蛋白酶抑制剂PAI-1通过阻断整联蛋白αVβ3与玻连蛋白的结合来抑制细胞迁移。

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During wound healing, migrating cells increase expression of both the vitronectin receptor (VNR) integrins and plasminogen activators. Here we report that vitronectin significantly enhances the migration of smooth muscle cells (SMCs), and that the specific VNR alpha V beta 3 is required for cell motility. We also show that the alpha V beta 3 attachment site on vitronectin overlaps with the binding site for plasminogen activator inhibitor (PAI)-1, and that the active conformation of PAI-1 blocks SMC migration. This effect requires high-affinity binding to vitronectin, and is not dependent on the ability of PAI-1 to inhibit plasminogen activators. Formation of a complex between PAI-1 and plasminogen activators results in loss of PAI-1 affinity for vitronectin and restores cell migration. These data demonstrate a direct link between plasminogen activators and integrin-mediated cell migration, and show that PAI-1 can control cell-matrix interactions by regulating the accessibility of specific cell-attachment sites. This indicates that the localization of plasminogen activators at sites of focal contact does not initiate a proteolytic cascade leading to generalized matrix destruction, but instead is required to expose cryptic cell-attachment sites necessary for SMC migration.
机译:在伤口愈合过程中,迁移细胞会增加玻连蛋白受体(VNR)整合素和纤溶酶原激活剂的表达。在这里我们报告玻连蛋白显着增强平滑肌细胞(SMCs)的迁移,并且特定的VNR alpha V beta 3是细胞运动所必需的。我们还显示玻连蛋白上的Alpha V beta 3附着位点与纤溶酶原激活物抑制剂(PAI)-1的结合位点重叠,并且PAI-1的活性构象阻止SMC迁移。该作用需要与玻连蛋白具有高亲和力结合,并且不依赖于PAI-1抑制纤溶酶原激活剂的能力。 PAI-1和纤溶酶原激活物之间形成复合物会导致PAI-1对玻连蛋白的亲和力丧失并恢复细胞迁移。这些数据表明纤溶酶原激活剂和整合素介导的细胞迁移之间存在直接联系,并表明PAI-1可以通过调节特定细胞附着位点的可及性来控制细胞与基质的相互作用。这表明纤溶酶原激活物在焦点接触部位的定位不会引发导致普遍基质破坏的蛋白水解级联反应,而是需要暴露SMC迁移所必需的隐秘细胞附着位点。

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