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首页> 外文期刊>Molecular and Cellular Biology >Proteomic Identification of Desmoglein 2 and Activated Leukocyte Cell Adhesion Molecule as Substrates of ADAM17 and ADAM10 by Difference Gel Electrophoresis
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Proteomic Identification of Desmoglein 2 and Activated Leukocyte Cell Adhesion Molecule as Substrates of ADAM17 and ADAM10 by Difference Gel Electrophoresis

机译：差异凝胶电泳通过蛋白质组学鉴定桥粒芯蛋白2和活化的白细胞粘附分子作为ADAM17和ADAM10的底物

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In contrast with the early view of metalloproteases as simple extracellular matrix-degrading entities, recent findings show that they are highly specific modulators of different signaling pathways involved, positively or negatively, in tumor development. Thus, before considering a given metalloprotease a therapeutic target, it seems advisable to characterize its function by identifying its repertoire of substrates. Here, we present a proteomic approach to identify ADAM17 substrates by difference gel electrophoresis. We found that the shedding of the extracellular domain of the transferrin receptor and those of two cell-cell adhesion molecules, activated leukocyte cell adhesion molecule (ALCAM) and desmoglein 2 (Dsg-2), is increased in cells overexpressing ADAM17. Genetic evidence shows that while ADAM17 is responsible for the shedding of ALCAM, both ADAM17 and ADAM10 can act on Dsg-2. Activation of the epidermal growth factor receptor leads to the upregulation of the shedding of Dsg-2 and to the concomitant upregulation of ADAM17, but not ADAM10, supporting the ability of overexpressed ADAM17 to shed Dsg-2. These results unveil a role of ADAM10 and ADAM17 in the shedding of cell-cell adhesion molecules. Since loss of cell adhesion is an early event in tumor development, these results suggest that ADAM17 is a useful target in anticancer therapy.
机译：与金属蛋白酶作为简单的细胞外基质降解实体的早期观点相反，最近的发现表明它们是正或负参与肿瘤发展的不同信号通路的高度特异性调节剂。因此，在考虑给定的金属蛋白酶作为治疗靶标之前，建议通过鉴定其底物组成来表征其功能。在这里，我们提出了一种蛋白质组学方法，通过差异凝胶电泳鉴定ADAM17底物。我们发现，在过度表达ADAM17的细胞中，转铁蛋白受体的胞外域和两个细胞-细胞粘附分子，活化的白细胞粘附分子（ALCAM）和桥粒芯蛋白2（Dsg-2）的脱落增加。遗传证据表明，虽然ADAM17负责ALCAM的脱落，但ADAM17和ADAM10均可作用于Dsg-2。表皮生长因子受体的激活导致Dsg-2脱落的上调并导致ADAM17（而不是ADAM10）随之上调，从而支持了过表达的ADAM17脱落Dsg-2的能力。这些结果揭示了ADAM10和ADAM17在细胞-细胞粘附分子脱落中的作用。由于细胞粘附的丧失是肿瘤发展的早期事件，因此这些结果表明ADAM17是抗癌治疗中的有用靶标。

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