Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1
Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1
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DOI：
10.1038/ncb1714
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发表时间：
2008-05-01
影响因子：
21.3
通讯作者：
Mochizuki, Naoki
中科院分区：
文献类型：
--
作者：
Fukuhara, Shigetomo;Sako, Keisuke;Mochizuki, Naoki
Tie2属于受体酪氨酸激酶家族，是血管生成素-1(Ang1)的受体。在小鼠中对Ang1或Tie2进行的基因靶向分析表明，Ang1-Tie2信号在发育血管形成中起着关键作用。目前尚不清楚Tie2信号通路如何在血管静止和血管生成中发挥不同的作用。我们在这里证明了Ang1在细胞-细胞接触处桥接Tie2，导致在细胞-细胞接触存在的情况下Tie2的反式结合。与之形成鲜明对比的是，在分离的细胞中，细胞外基质结合的Ang1位于细胞-底物接触处。此外，在细胞-细胞或细胞-底物接触时激活的Tie2分别导致Akt和Erk的优先激活。微阵列分析和实时定量聚合酶链式反应验证清楚地显示了血管内皮细胞在有或没有细胞接触的情况下Ang1刺激时的差异基因表达谱，这意味着下游信号取决于Tie2的空间定位。
Tie2 belongs to the receptor tyrosine kinase family and functions as a receptor for Angiopoietin-1 (Ang1). Gene-targeting analyses of either Ang1 or Tie2 in mice reveal a critical role of Ang1-Tie2 signalling in developmental vascular formation. It remains elusive how the Tie2 signalling pathway plays distinct roles in both vascular quiescence and angiogenesis. We demonstrate here that Ang1 bridges Tie2 at cell-cell contacts, resulting in trans-association of Tie2 in the presence of cell-cell contacts. In clear contrast, in isolated cells, extracellular matrix-bound Ang1 locates Tie2 at cell-substratum contacts. Furthermore, Tie2 activated at cell-cell or cell-substratum contacts leads to preferential activation of Akt and Erk, respectively. Microarray analyses and real-time PCR validation clearly show the differential gene expression profile in vascular endothelial cells upon Ang1 stimulation in the presence or absence of cell-cell contacts, implying downstream signalling is dependent upon the spatial localization of Tie2.