Gln-362 of Angiopoietin-2 Mediates Migration of Tumor and Endothelial Cells through Association with α5β1 Integrin
Gln-362 of Angiopoietin-2 Mediates Migration of Tumor and Endothelial Cells through Association with α5β1 Integrin
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DOI：
10.1074/jbc.m114.572594
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发表时间：
2014-11-07
影响因子：
4.8
通讯作者：
Han, Sangyeul
中科院分区：
文献类型：
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作者：
Lee, Hyo Seon;Oh, Seung Ja;Han, Sangyeul
血管生成素-2(Ang-2)不仅通过与内皮细胞上已知的受体Tie2结合来调控血管生成，而且通过与整合素结合来调控Tie2阴性血管生成内皮细胞的萌发和Tie2阴性非内皮细胞的侵袭。然而，Ang-2/整合素结合的分子机制尚不清楚。在本研究中，我们发现Ang-2的Gln-362残基是与α5β1整合素结合所必需的。一个Q362E Ang-2突变体仍与Tie2结合，不能与α5β1整合素结合，也不能激活粘着斑激酶的整合素下游信号。此外，与野生型Ang-2不同，Q362E Ang-2突变体在介导Tie2阴性胶质瘤或Tie2阳性内皮细胞的侵袭方面存在缺陷。此外，α5β1整合素中α5亚基的尾片结构域对于与Ang-2结合是关键的。综上所述，这些结果为Ang-2调控整合素的机制提供了新的见解，Ang-2以非Tie2依赖的方式促进肿瘤侵袭和内皮细胞迁移。
Angiopoietin-2 (Ang-2) not only regulates angiogenesis by binding to its well known receptor Tie2 on endothelial cells but also controls sprouting of Tie2-negative angiogenic endothelial cells and invasion of Tie2-negative non-endothelial cells by binding to integrins. However, the molecular mechanism of the Ang-2/ integrin association has been unclear. In this study, we found that the Gln-362 residue of Ang-2 was essential for binding to alpha 5 beta 1 integrin. A Q362E Ang-2 mutant, which still bound to Tie2, failed to associate with alpha 5 beta 1 integrin and was unable to activate the integrin downstream signaling of focal adhesion kinase. In addition, unlike wild-type Ang-2, the Q362E Ang-2 mutant was defective in mediating invasion of Tie2-negative glioma or Tie2-positive endothelial cells. Furthermore, the tailpiece domain of the alpha 5 subunit in alpha 5 beta 1 integrin was critical for binding to Ang-2. Taken together, these results provide a novel insight into the mechanism of integrin regulation by Ang-2, which contributes to tumor invasion and endothelial cell migration in a Tie2-independent manner.