Enhanced activation of epidermal growth factor receptor caused by tumor-derived E-cadherin mutations

Cancer Res. 2008 Feb 1;68(3):707-14. doi: 10.1158/0008-5472.CAN-07-1588.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Carcinoma, Ductal / enzymology
  • Carcinoma, Ductal / genetics
  • Carcinoma, Ductal / metabolism
  • Cell Line, Tumor
  • Endocytosis / genetics
  • Enzyme Activation
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism*
  • Exons
  • Gene Deletion*
  • Humans
  • Mice
  • Phosphorylation
  • Signal Transduction
  • Stomach Neoplasms / enzymology
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Transfection
  • ras Proteins / metabolism


  • Cadherins
  • Epidermal Growth Factor
  • ErbB Receptors
  • ras Proteins