Enhanced activation of epidermal growth factor receptor caused by tumor-derived E-cadherin mutations
Enhanced activation of epidermal growth factor receptor caused by tumor-derived E-cadherin mutations
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DOI：
10.1158/0008-5472.can-07-1588
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发表时间：
2008-02-01
期刊：
影响因子：
11.2
通讯作者：
Luber, Birgit
中科院分区：
文献类型：
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作者：
Bremm, Anja;Walch, Axel;Luber, Birgit
肿瘤抑制因子E-钙粘蛋白的突变和受体酪氨酸激酶表皮生长因子受体（EGFR）的过度表达是弥漫型胃癌最常见的遗传改变。越来越多的证据表明，E-钙粘蛋白和EGFR之间的功能关系，调节这两种蛋白质。我们报告说，体细胞突变的E-钙粘蛋白是与EGFR的激活增加，随后增强招聘的下游作用信号成分生长因子受体结合蛋白2和她，并激活Ras。与野生型E-钙粘蛋白相比，观察到突变型E-钙粘蛋白与EGFR的复合物形成减少-胞外结构域中外显子8的框内缺失导致粘附减少和运动性增加。我们的结论是，减少结合突变E-钙粘蛋白EGFR在一个多组分复合物或减少复合物的稳定性可能会增强EGFR表面的运动性，从而促进FGFR二聚化和激活。此外，减少表面定位由于增强的内化突变E-钙粘蛋白相比，野生型蛋白质进行了观察。表皮生长因子刺激表达突变型E-钙粘蛋白的细胞，EGFR的内化减少，表明E-钙粘蛋白的突变也影响EGFR的内吞作用。此外，我们发现突变型E-钙粘蛋白缺乏外显子8或9的胃癌样本中EGFR的激活增加。总之，我们描述了突变型E-钙粘蛋白激活EGFR作为一种新的机制，在肿瘤细胞中，解释了增强的运动性的肿瘤细胞的存在下，细胞外突变的E-钙粘蛋白。
Mutations of the tumor suppressor E-cadherin and overexpression of the receptor tyrosine kinase epidermal growth factor receptor (EGFR) are among the most frequent genetic alterations associated with diffuse-type gastric carcinoma. Accumulating evidence suggests a functional relationship between E-cadherin and EGFR that regulates both proteins. We report that somatic mutation of E-cadherin is associated with increased activation of EGFR followed by enhanced recruitment of the downstream acting signaling components growth factor receptor binding protein 2 and She, and activation of Ras. Reduced complex formation of mutant E-cadherin - with an in frame deletion of exon 8 in the extracellular domain resulting in reduced adhesion and increased motility - with EGFR was observed compared with wild-type E-cadherin. We conclude that reduced binding of mutant E-cadherin to EGFR in a multicomponent complex or reduced stability of the complex may enhance EGFR surface motility, thereby facilitating FGFR dimerization and activation. Furthermore, reduced surface localization due to enhanced internalization of mutant E-cadherin compared with the wild-type protein was observed. The internalization of EGFR was decreased in response to epidermal growth factor stimulation in cells expressing mutant E-cadherin, suggesting that mutation of E-cadherin also influences the endocytosis of EGFR. Moreover, we show increased activation of EGFR in gastric carcinoma samples with mutant E-cadherin lacking exons 8 or 9. In summary, we describe activation of EGFR by mutant E-cadherin as a novel mechanism in tumor cells that explains the enhanced motility of tumor cells in the presence of an extracellular mutation of E-cadherin.