journal contribution
posted on 2023-03-30, 18:12 authored by Anja Bremm, Axel Walch, Margit Fuchs, Jörg Mages, Justus Duyster, Gisela Keller, Christine Hermannstädter, Karl-Friedrich Becker, Sandra Rauser, Rupert Langer, Claus Hann von Weyhern, Heinz Höfler, Birgit Luber Supplementary Results, Figure 1, Methods and Materials from Enhanced Activation of Epidermal Growth Factor Receptor Caused by Tumor-Derived E-Cadherin Mutations
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ARTICLE ABSTRACT
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 Shc, 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 EGFR 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. [Cancer Res 2008;68(3):707–14]
