Constitutive Association of Tie1 and Tie2 with Endothelial Integrins is Functionally Modulated by Angiopoietin-1 and Fibronectin.
Constitutive Association of Tie1 and Tie2 with Endothelial Integrins is Functionally Modulated by Angiopoietin-1 and Fibronectin.
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DOI：
10.1371/journal.pone.0163732
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Barton WA
中科院分区：
文献类型：
--
作者：
Dalton AC;Shlamkovitch T;Papo N;Barton WA
Tie 2和整合素信号通路之间的功能性串扰对于协调内皮细胞响应细胞外基质的粘附和迁移是必不可少的，但这种现象背后的机制尚不清楚。在这里，我们研究的可能性，受体的串扰是通过未表征的Tie整合素相互作用的内皮细胞表面驱动。使用基于活细胞FRET的邻近测定，我们监测Tie-整联蛋白受体识别，并证明Tie 1和Tie 2都容易通过其各自的胞外域与整联蛋白α 5 β 1和α V β 3缔合。虽然不是必需的，但Tie 2-整联蛋白缔合在细胞外组分和整联蛋白配体纤连蛋白存在下显著增强。用纯化的组分进行的体外结合测定揭示Tie-整联蛋白识别是直接的，并进一步证明Tie 2配体Ang-1的受体结合结构域，而不是Ang-2的受体结合结构域，可以独立地与α 5 β 1或α V β 3缔合。最后，我们揭示了合作Tie/整合素的相互作用选择性刺激ERK/MAPK信号在Ang-1和纤连蛋白的存在下，这表明Tie 2敏感细胞外基质的分子机制。我们提供了一个机制模型，强调受体的定位和协会在调节不同的信号级联反应，反过来，血管生成开关的作用。
Functional cross-talk between Tie2 and Integrin signaling pathways is essential to coordinate endothelial cell adhesion and migration in response to the extracellular matrix, yet the mechanisms behind this phenomenon are unclear. Here, we examine the possibility that receptor cross-talk is driven through uncharacterized Tie-integrin interactions on the endothelial surface. Using a live cell FRET-based proximity assay, we monitor Tie-integrin receptor recognition and demonstrate that both Tie1 and Tie2 readily associate with integrins α5ß1 and αVß3 through their respective ectodomains. Although not required, Tie2-integrin association is significantly enhanced in the presence of the extracellular component and integrin ligand fibronectin. In vitro binding assays with purified components reveal that Tie-integrin recognition is direct, and further demonstrate that the receptor binding domain of the Tie2 ligand Ang-1, but not the receptor binding domain of Ang-2, can independently associate with α5ß1 or αVß3. Finally, we reveal that cooperative Tie/integrin interactions selectively stimulate ERK/MAPK signaling in the presence of both Ang-1 and fibronectin, suggesting a molecular mechanism to sensitize Tie2 to extracellular matrix. We provide a mechanistic model highlighting the role of receptor localization and association in regulating distinct signaling cascades and in turn, the angiogenic switch.
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影响因子：
2.9
作者：
Chen X;Fu W;Tung CE;Ward NL
通讯作者：
Ward NL
影响因子：
4.8
作者：
Dallabrida, Susan M.;Ismail, Nesreen S.;Rupnick, Maria A.
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Rupnick, Maria A.
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Lee, Hyo Seon;Oh, Seung Ja;Han, Sangyeul
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Han, Sangyeul
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BROOKS, PC;CLARK, RAF;CHERESH, DA
通讯作者：
CHERESH, DA
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作者：
Chen, Y;Periasamy, A
通讯作者：
Periasamy, A