Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts
Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts
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DOI：
10.1038/ncb1715
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发表时间：
2008-05-01
影响因子：
21.3
通讯作者：
Alitalo, Kari
中科院分区：
文献类型：
--
作者：
Saharinen, Pipsa;Eklund, Lauri;Alitalo, Kari
受体酪氨酸激酶 Tie2 及其激活配体血管生成素-1 (Ang1) 是血管重塑和血管完整性所必需的，而 Ang2 可能会抵消这些功能。然而，目前尚不清楚 Tie2 如何转换这些不同的信号。在这里，我们证明 Ang1 在移动和融合的内皮细胞中诱导独特的 Tie2 复合物。基质结合的 Ang1 诱导细胞-基质接触中的细胞粘附、运动和 Tie2 激活，这些接触在迁移的内皮细胞中易位到后缘。相反，在接触细胞中，Ang1诱导Tie2易位至细胞-细胞接触，并形成包含血管内皮磷酸酪氨酸磷酸酶的同型Tie2-Tie2反式相关复合物，从而抑制细胞旁通透性。细胞-基质和细胞-细胞接触中的不同信号蛋白优先被 Tie2 激活，其中 Ang2 抑制 Ang1 诱导的 Tie2 激活。这种新型的细胞微环境依赖性受体酪氨酸激酶激活可以解释血管生成素在血管生成和血管稳定中的一些作用。
The receptor tyrosine kinase Tie2, and its activating ligand Angiopoietin-1 (Ang1), are required for vascular remodelling and vessel integrity, whereas Ang2 may counteract these functions. However, it is not known how Tie2 transduces these different signals. Here, we show that Ang1 induces unique Tie2 complexes in mobile and confluent endothelial cells. Matrix-bound Ang1 induced cell adhesion, motility and Tie2 activation in cell-matrix contacts that became translocated to the trailing edge in migrating endothelial cells. In contrast, in contacting cells Ang1 induced Tie2 translocation to cell-cell contacts and the formation of homotypic Tie2-Tie2 trans-associated complexes that included the vascular endothelial phosphotyrosine phosphatase, leading to inhibition of paracellular permeability. Distinct signalling proteins were preferentially activated by Tie2 in the cell-matrix and cell -cell contacts, where Ang2 inhibited Ang1-induced Tie2 activation. This novel type of cellular microenvironment-dependent receptor tyrosine kinase activation may explain some of the effects of angiopoietins in angiogenesis and vessel stabilization.