Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
PLoS One. 2011;6(10):e26355. doi: 10.1371/journal.pone.0026355. Epub 2011 Oct 17.
Cell adhesion and migration depend on engagement of extracellular matrix ligands by integrins. Integrin activation is dynamically regulated by interactions of various cytoplasmic proteins, such as filamin and integrin activators, talin and kindlin, with the cytoplasmic tail of the integrin β subunit. Although filamin has been suggested to be an inhibitor of integrin activation, direct functional evidence for the inhibitory role of filamin is limited. Migfilin, a filamin-binding protein enriched at cell-cell and cell-extracellular matrix contact sites, can displace filamin from β1 and β3 integrins and promote integrin activation. However, its role in activation and functions of different β integrins in human vascular cells is unknown. In this study, using flow cytometry, we demonstrate that filamin inhibits β1 and αIIbβ3 integrin activation, and migfilin can overcome its inhibitory effect. Migfilin protein is widely expressed in different adherent and circulating blood cells and can regulate integrin activation in naturally-occurring vascular cells, endothelial cells and neutrophils. Migfilin can activate β1, β2 and β3 integrins and promote integrin mediated responses while migfilin depletion impairs the spreading and migration of endothelial cells. Thus, filamin can act broadly as an inhibitor and migfilin is a promoter of integrin activation.
细胞黏附和迁移依赖于整合素与细胞外基质配体的结合。整合素的激活受到各种细胞质蛋白相互作用的动态调节，如细丝蛋白和整合素激活剂、血栓蛋白和伴肌动蛋白，与整合素β亚基的细胞质尾部相互作用。尽管细丝蛋白被认为是整合素激活的抑制剂，但细丝蛋白的抑制作用的直接功能证据有限。黏着斑蛋白，一种在细胞-细胞和细胞-细胞外基质接触部位丰富的细丝蛋白结合蛋白，可将细丝蛋白从β1 和β3 整合素上置换，并促进整合素的激活。然而，它在人血管细胞中不同β整合素的激活和功能中的作用尚不清楚。在这项研究中，我们通过流式细胞术证明，细丝蛋白抑制β1 和αIIbβ3 整合素的激活，而黏着斑蛋白可以克服其抑制作用。黏着斑蛋白在不同的贴壁和循环血细胞中广泛表达，并能调节天然存在的血管细胞、内皮细胞和中性粒细胞中的整合素激活。黏着斑蛋白可以激活β1、β2 和β3 整合素，并促进整合素介导的反应，而黏着斑蛋白耗竭则会损害内皮细胞的扩展和迁移。因此，细丝蛋白可以作为广泛的整合素激活抑制剂，而黏着斑蛋白是整合素激活的促进剂。
