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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Ligand occupancy of the alpha-V-beta3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor.
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Ligand occupancy of the alpha-V-beta3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor.

机译：α-V-β3整联蛋白的配体占据是平滑肌细胞响应胰岛素样生长因子迁移所必需的。

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Smooth muscle cells (SMCs) have been shown to migrate in response to insulin-like growth factor I (IGF-I). However, the mechanism mediating this response has not been determined. The migration rates of porcine and human vascular SMCs were assessed in a monolayer wounding assay. IGF-I and IGF-II induced increases of 141% and 97%, respectively, in the number of cells that migrated in 4 days. The presence of 0.2% fetal bovine serum in the culture medium was necessary for the IGFs to stimulate migration over uncoated plastic surfaces. However, if vitronectin was used as the substratum, IGF-I stimulated migration by 162% even in the absence of serum. To determine the role of integrins in mediating this migration, SMC surface proteins were labeled with 125I and immunoprecipitated with specific anti-integrin antibodies. Integrins containing alpha-V (vitronectin receptor), alpha5 (fibronectin receptor), and alpha3 (collagen/laminin receptor) subunits were the most abundant. IGF-I treatment caused a 73% reduction in alpha5-integrin subunit protein and a 25% increase in alpha-V subunit. More importantly, ligand binding of alpha-V-beta3 was increased by 2.4-fold. We therefore examined whether the function of the alpha-V-beta3 integrin was important for IGF-I-mediated migration. The disintegrin kistrin was shown by affinity crosslinking to specifically bind with high affinity to alpha-V-beta3 and not to alpha5-beta1 or other abundant integrins. The related disintegrin echistatin specifically inhibited 125I-labeled kistrin binding to alpha-V-beta3, while a structurally distinct disintegrin, decorsin, had 1000-fold lower affinity. The addition of increasing concentrations of either kistrin or echistatin inhibited IGF-I-induced migration, whereas decorsin had a minimal effect. The potency of these disintegrins in inhibiting IGF-I-induced migration paralleled their apparent affinity for the alpha-V integrin. Furthermore, an alpha-V-beta3 blocking antibody inhibited SMC migration by 80%. In summary, vitronectin receptor activation is a necessary component of IGF-I-mediated stimulation of smooth muscle migration, and alpha-V-beta3 integrin antagonists appear to be important reagents for modulating this process.
机译：平滑肌细胞（SMC）已显示出对胰岛素样生长因子I（IGF-1）的响应而迁移。但是，尚未确定介导该响应的机制。猪和人血管SMC的迁移率通过单层伤口测定法进行评估。在4天内迁移的细胞数量中，IGF-I和IGF-II分别诱导增加141％和97％。培养基中存在0.2％的胎牛血清对于IGF刺激在未涂覆的塑料表面上的迁移是必需的。但是，如果将玻连蛋白用作基质，即使在没有血清的情况下，IGF-I也会刺激162％的迁移。为了确定整联蛋白在介导这种迁移中的作用，将SMC表面蛋白标记为125I，并用特定的抗整联蛋白抗体进行免疫沉淀。含有α-V（玻连蛋白受体），α5（纤连蛋白受体）和α3（胶原/纤溶酶受体）亚基的整合素含量最高。 IGF-1处理导致alpha5-integrin亚基蛋白减少73％，而alpha-V亚基增加25％。更重要的是，α-V-β3的配体结合增加了2.4倍。因此，我们检查了α-V-β3整联蛋白的功能对于IGF-I介导的迁移是否重要。通过亲和力交联显示了整联蛋白鞭毛蛋白与α-V-β3而不是α5-β1或其他丰富的整联蛋白高亲和力地特异性结合。相关的整联蛋白echistatin特异性抑制125I标记的整联蛋白与α-V-β3的结合，而结构上不同的整联蛋白decorsin的亲和力低1000倍。添加浓度增加的麒麟菜或echistatin抑制IGF-I诱导的迁移，而decorsin作用最小。这些整联蛋白在抑制IGF-I诱导的迁移中的效力与其对α-V整联蛋白的表观亲和力平行。此外，α-V-β3阻断抗体可抑制SMC迁移80％。总之，玻连蛋白受体激活是IGF-I介导的平滑肌迁移刺激的必要组成部分，而α-V-β3整联蛋白拮抗剂似乎是调节该过程的重要试剂。

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