Activation of Rac by cadherin through the c-Src-Rap1-phosphatidylinositol 3-kinase-Vav2 pathway
Activation of Rac by cadherin through the c-Src-Rap1-phosphatidylinositol 3-kinase-Vav2 pathway
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DOI：
10.1038/sj.onc.1209010
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发表时间：
2006-01-01
期刊：
影响因子：
8
通讯作者：
Takai, Y
中科院分区：
文献类型：
--
作者：
Fukuyama, T;Ogita, H;Takai, Y
钙粘蛋白首先在相同细胞的细胞表面上形成同-顺-二聚体，然后以Ca 2+依赖的方式形成同-反-二聚体（反式相互作用），最终导致粘附连接。此外，反式相互作用钙粘蛋白诱导Rac小G蛋白的激活，从而通过肌动蛋白细胞骨架的重组抑制其内吞作用来稳定质膜上的非反式相互作用钙粘蛋白。然而，钙粘蛋白如何诱导Rac的激活尚未完全了解。我们在这里研究的分子机制激活的Rac的反式相互作用钙粘蛋白。成纤维细胞和上皮细胞。反式相互作用的钙粘蛋白诱导激活c-Src局部在钙粘蛋白为基础的细胞-细胞粘附网站。c-Src然后酪氨酸磷酸化Vav 2，一种Rac-GDP/GTP交换因子（GEF），并通过Crk衔接蛋白诱导C3 G，一种Rap 1-GEF的活化，导致Rap 1在基于钙粘蛋白的细胞-细胞粘附位点局部活化。c-Src催化的酪氨酸磷酸化不明显。C-Src诱导的Rap 1的激活是Vav 2激活的必要条件，但单独激活Rap 1并不足够。对非酪氨酸磷酸化的Vav 2的激活有效。Rap 1对Vav 2的这种作用是由磷脂酰肌醇3-激酶介导的。我们在这里描述的信号通路从反式相互作用的钙粘蛋白的激活Rac。
Cadherin first forms homo-cis-dimerson the cell surface of the same cells, followed by formation of homo-trans-dimers(trans interactions) in a Ca2+ dependent manner, eventually causing adherens junctions. In addition, transinteracting cadherin induces activatio n of Rac small G protein, which stabilizes non-trans-interacting cadherin on the plasma membrane by inhibiting its endocytosis through the reorganization of the actin cytoskeleton. However, it has not fully been understood how cadherin induces the activation of Rac. We examined here the molecular mechanism of the activation of Rac by transinteracting cadherin in. fibroblasts and epithelial cells. Trans-interacting cadherin induced activation of c-Src locally at the cadherin-based cell-cell adhesion sites. c-Src then tyrosine- phosphorylated Vav2, one of the Rac-GDP/GTP exchange factors(GEFs), and induced activation of C3G, one of the Rap1-GEFs, through Crk adaptor protein, resulting in the activation of Rap1 locally at the cadherin-based cell-cell adhesion sites. The c-Src-catalysed tyrosine phosphorylation was not suf. cient for the activation of Vav2 and the c-Src-induced activation of Rap1 was additionally necessary for it, although activated Rap1 alone was not suf. cient for the activation of non-tyrosine-phosphorylated Vav2. This effect of Rap1 on Vav2 was mediated by phosphatidylinositol 3- kinase. We describe here the signaling pathway from trans-interacting cadherin to the activation of Rac.