Effects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface.
Effects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface.
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DOI：
10.1016/j.cellsig.2009.11.007
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发表时间：
2010-03
影响因子：
4.8
通讯作者：
Brindle NP
中科院分区：
文献类型：
--
作者：
Hansen TM;Singh H;Tahir TA;Brindle NP
血管生成素-1(Ang1)和Ang2是受体酪氨酸激酶Tie2的配体。结构数据表明，这两个配体与Tie2结合的方式类似。然而，在内皮细胞中，Ang1激活Tie2，而Ang2可以作为明显的拮抗剂。此外，每个配体在结合后表现出不同的释放动力学。这些观察表明，在细胞环境中，其他因素影响血管生成素的功能和与受体的结合。以前的工作表明，Tie1抑制Ang1结合和激活Tie2，Tie1是一种与Tie2在细胞内形成络合物的相关受体。在本研究中，我们研究了血管内皮细胞中Ang1和Ang2与Tie2的结合。与Ang1相反，Tie2与Ang2的结合不受Tie1的影响。PMA诱导的Tie1胞外区切割和siRNA抑制Tie1的表达均不影响Ang2结合Tie2的能力。免疫共沉淀和血管生成素结合的Tie2的水平分析表明，Ang2可以结合Tie2：Tie1复合体中的Tie2，而Ang1优先结合非络合的Tie2。刺激Tie1胞外区的切割并不增加Ang2对Tie2的激动剂活性。同样，Ang2的Tie2激动剂活性不受siRNA抑制Tie1表达的影响。与以前的报道一致，失去Tie1胞外结构域增强了Ang1对Tie2的激动剂活性。重要的是，Ang2仍然能够拮抗Tie1胞外结构域丢失时Tie2的Ang1激活。总之，这些数据表明，Ang1和Ang2在细胞表面与Tie2结合的方式不同，这是由Tie1控制的。这种对血管生成素结合的不同调节允许在不影响Ang2激动剂活性的情况下控制Tie2对Ang1的激活反应，并保持Ang2对抗Tie2的增强的Ang1激活的能力，这种激活发生在Tie1胞外结构域丢失时。这提供了一种机制，通过该机制，通过Tie2的信号可以被细胞微环境中的刺激改变。
Angiopoietin-1 (Ang1) and Ang2 are ligands for the receptor tyrosine kinase Tie2. Structural data suggest that the two ligands bind Tie2 similarly. However, in endothelial cells Ang1 activates Tie2 whereas Ang2 can act as an apparent antagonist. In addition, each ligand exhibits distinct kinetics of release following binding. These observations suggest that additional factors influence function and binding of angiopoietins with receptors in the cellular context. Previous work has shown that Ang1 binding and activation of Tie2 are inhibited by Tie1, a related receptor that complexes with Tie2 in cells. In this study we have investigated binding of Ang1 and Ang2 to Tie2 in endothelial cells. In contrast to Ang1, binding of Ang2 to Tie2 was found to be not affected by Tie1. Neither PMA-induced Tie1 ectodomain cleavage nor suppression of Tie1 expression by siRNA affected the ability of Ang2 to bind Tie2. Analysis of the level of Tie1 co-immunoprecipitating with angiopoietin-bound Tie2 demonstrated that Ang2 can bind Tie2 in Tie2:Tie1 complexes whereas Ang1 preferentially binds non-complexed Tie2. Stimulation of Tie1 ectodomain cleavage did not increase the agonist activity of Ang2 for Tie2. Similarly, the Tie2-agonist activity of Ang2 was not affected by siRNA suppression of Tie1 expression. Consistent with previous reports, loss of Tie1 ectodomain enhanced the agonist activity of Ang1 for Tie2. Importantly, Ang2 was still able to antagonize the elevated Ang1-activation of Tie2 that occurs on Tie1 ectodomain loss. Together these data demonstrate that Ang1 and Ang2 bind differently to Tie2 at the cell surface and this is controlled by Tie1. This differential regulation of angiopoietin binding allows control of Tie2 activation response to Ang1 without affecting Ang2 agonist activity and maintains the ability of Ang2 to antagonize even the enhanced Ang1 activation of Tie2 that occurs on loss of Tie1 ectodomain. This provides a mechanism by which signalling through Tie2 can be modified by stimuli in the cellular microenvironment.
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DOI：
10.1038/nsb880
发表时间：
2003-01-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Davis, S;Papadopoulos, N;Yancopoulos, GD
通讯作者：
Yancopoulos, GD
影响因子：
20.3
作者：
Yabkowitz, R;Meyer, S;Ratzkin, B
通讯作者：
Ratzkin, B
影响因子：
56.9
作者：
Maisonpierre, PC;Suri, C;Yancopoulos, GD
通讯作者：
Yancopoulos, GD
DOI：
10.1073/pnas.0611177104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Suchting, Steven;Freitas, Catarina;Eichmann, Anne
通讯作者：
Eichmann, Anne
影响因子：
4.8
作者：
Chen-Konak, L;Guetta-Shubin, Y;Resnick, N
通讯作者：
Resnick, N