Activation of the protein kinase Akt PKB by the formation of E-cadherin-mediated cell-cell junctions - Evidence for the association of phosphatidylinositol 3-kinase with the E-cadherin adhesion complex
Activation of the protein kinase Akt PKB by the formation of E-cadherin-mediated cell-cell junctions - Evidence for the association of phosphatidylinositol 3-kinase with the E-cadherin adhesion complex
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DOI：
10.1074/jbc.274.27.19347
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发表时间：
1999-07-02
影响因子：
4.8
通讯作者：
Gutkind, JS
中科院分区：
文献类型：
--
作者：
Pece, S;Chiariello, M;Gutkind, JS
E-钙粘蛋白是位于粘附连接水平的表面粘附分子，通过介导细胞与细胞接触部位的钙依赖性同源相互作用，在细胞粘附性中发挥主要作用。最近，E-钙粘蛋白还与许多生物过程有关，包括细胞生长和分化、细胞识别和发育形态发生过程中的分类，以及聚集依赖性细胞存活。由于磷脂酰肌醇 (PI) 3-激酶和 Akt 在响应生长因子和细胞外刺激的生存途径中发挥着关键作用，这些观察结果促使我们探索 E-钙粘蛋白是否可以影响调节 PI 3-激酶/Akt 信号级联活性的细胞内分子。使用 Madin-Darby 犬肾细胞作为模型系统，我们在此表明，E-钙粘蛋白参与同源钙依赖性细胞相互作用，导致 Akt 快速 PI 3 激酶依赖性激活，并随后将 Akt 转位至细胞核。此外，我们证明，响应细胞-细胞接触形成而激活的 PI 3-激酶涉及酪氨酸残基中 PI 3-激酶的磷酸化，以及伴随的 PI 3-激酶向含有 E-钙粘蛋白的蛋白质复合物的募集。这些发现表明，E-钙粘蛋白可以启动由外向内的信号转导途径，调节PI 3-激酶和Akt的活性，从而提供一种新的分子机制，相邻细胞之间的相互作用及其粘附状态可能最终控制上皮细胞的命运。
E-cadherins are surface adhesion molecules localized at the level of adherens junctions, which play a major role in cell adhesiveness by mediating calcium-dependent homophylic interactions at sites of cell-cell contacts. Recently, E-cadherins have been also implicated in a number of biological processes, including cell growth and differentiation, cell recognition, and sorting during developmental morphogenesis, as well as in aggregation-dependent cell survival. As phosphatidylinositol (PI) 3-kinase and Akt play a critical role in survival pathways in response to both growth factors and extracellular stimuli, these observations prompted us to explore whether E-cadherins could affect intracellular molecules regulating the activity of the PI 3-kinase/Akt signaling cascade. Using Madin-Darby canine kidney cells as a model system, we show here that engagement of E-cadherins in homophylic calcium-dependent cell cell interactions results in a rapid PI 3-kinase-dependent activation of Akt and the subsequent translocation of Akt to the nucleus. Moreover, we demonstrate that the activation of PI 3-kinase in response to cell-cell contact formation involves the phosphorylation of PI 3-kinase in tyrosine residues, and the concomitant recruitment of PI 3-kinase to E-cadherin-containing protein complexes. These findings indicate that E-cadherins can initiate outside-in signal transducing pathways that regulate the activity of PI 3-kinase and Akt, thus providing a novel molecular mechanism whereby the interaction among neighboring cells and their adhesion status may ultimately control the fate of epithelial cells.