Migfilin and filamin as regulators of integrin activation in endothelial cells and neutrophils.
Migfilin and filamin as regulators of integrin activation in endothelial cells and neutrophils.
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DOI：
10.1371/journal.pone.0026355
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Plow EF
中科院分区：
文献类型：
--
作者：
Das M;Ithychanda SS;Qin J;Plow EF
细胞的粘附和迁移依赖于整合素与细胞外基质配体的结合。整合素的激活受多种细胞质蛋白（如丝蛋白和整合素激活因子、talin和kindlin）与整合素β亚基细胞质尾部的相互作用的动态调节。虽然丝蛋白被认为是整合素激活的抑制剂，但丝蛋白抑制作用的直接功能证据有限。Migfilin是一种丝蛋白结合蛋白，富集于细胞-细胞和细胞-细胞外基质接触位点，可以取代β1和β3整合素中的丝蛋白，促进整合素的激活。然而，其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。在本研究中，我们利用流式细胞术证实丝蛋白抑制β1和αIIbβ3整合素的激活，而米格菲林可以克服其抑制作用。Migfilin蛋白广泛表达于不同的贴壁和循环血细胞中，可调节天然血管细胞、内皮细胞和中性粒细胞中整合素的活化。Migfilin可激活β1、β2和β3整合素，促进整合素介导的应答，而Migfilin耗竭会损害内皮细胞的扩散和迁移。因此，丝蛋白可以广泛地作为一种抑制剂，而米格菲林是整合素激活的启动子。
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.