Distinct tyrosine autophosphorylation sites mediate induction of epithelial mesenchymal like transition by an activated ErbB-2/Neu receptor
Distinct tyrosine autophosphorylation sites mediate induction of epithelial mesenchymal like transition by an activated ErbB-2/Neu receptor
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DOI：
10.1038/sj.onc.1204166
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发表时间：
2001-02-15
期刊：
影响因子：
8
通讯作者：
Park, M
中科院分区：
文献类型：
--
作者：
Khoury, H;Dankort, DL;Park, M
需要严格控制细胞增殖和形态发生以确保正常的组织模式并防止癌症形成。ErbB-2/Neu受体酪氨酸激酶的过表达与人乳腺癌的进展增加相关，但在乳腺外植体培养中，ErbB-2/Neu受体有助于肺泡分化。为了研究ErbB-2/Neu激活失调对上皮形态发生的影响，我们在Madin-Darby犬肾（MDCK）上皮细胞模型中表达了ErbB-2/Neu组成型激活突变体。使用二维培养，我们证明，激活的ErbB-2/Neu诱导细胞-细胞连接的破坏，增加细胞运动性和分散的上皮集落。这与肌动蛋白细胞骨架的重组和胎儿粘连以及涉及E-钙粘蛋白的不溶性细胞-细胞连接复合物的丢失相关。有趣的是，组成性激活的ErbB-2/Neu受体促进MDCK细胞在三维基质中的侵入性形态发生程序。我们发现，两个酪氨酸在羧基末端尾部的ErbB-2/Neu，参与磷酸化的Shc衔接蛋白，每个都足以促进上皮-间充质样过渡和增强细胞运动性的二维培养和细胞侵袭，而不是在基质培养的形态发生反应。这为研究ErbB-2/Neu诱导的上皮细胞扩散和侵袭与形态发生所需的信号传导途径提供了一个模型系统。
Tight control of cell proliferation and morphogenesis is required to ensure normal tissue patterning and prevent cancer formation. Overexpression of the ErbB-2/Neu receptor tyrosine kinase is associated with increased progression in human breast cancer, yet in breast explant cultures, the ErbB-2/Neu receptor contributes to alveolar differentiation. To examine the consequence of deregulated ErbB-2/Neu activation on epithelial morphogenesis, we have expressed a constitutively activated mutant of ErbB-2/Neu in a Madin-Darby canine kidney (MDCK) epithelial cell model. Using two-dimensional cultures we demonstrate that activated ErbB-2/Neu induces breakdown of cell-cell junctions, increased cell motility and dispersal of epithelial colonies. This correlates with reorganization of the actin cytoskeleton and fetal adhesions and loss of insoluble cell-cell junction complexes involving E-cadherin. Interestingly, a constitutively activated ErbB-2/Neu receptor promotes an invasive morphogenic program in MDCK cells in a three-dimensional matrix. We show that two tyrosines in the carboxy-terminal tail of ErbB-2/Neu, involved in the phosphorylation of the Shc adapter protein, are each sufficient to promote epithelial-mesenchymal like transition and enhanced cell motility in two-dimensional culture and cell invasion rather than a morphogenic response in matrix culture. This provides a model system to investigate ErbB-2/Neu induced signaling pathways required for epithelial cell dispersal and invasion versus morphogenesis.