This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bremm, A. Articles by Luber, B. Search for Related Content PubMed PubMed Citation Articles by Bremm, A. Articles by Luber, B.

Enhanced Activation of Epidermal Growth Factor Receptor Caused by Tumor-Derived E-Cadherin Mutations

¹ Technische Universität München, Klinikum rechts der Isar, Institut für Allgemeine Pathologie und Pathologische Anatomie; ² Technische Universität München, III. Medizinische Klinik; and ³ Technische Universität München, Klinikum rechts der Isar, Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, München, Germany; and ⁴ GSF-Forschungszentrum für Umwelt und Gesundheit, Institut für Pathologie, Neuherberg, Germany

Requests for reprints: Birgit Luber, Institut für Allgemeine Pathologie und Pathologische Anatomie, Trogerstr. 18, 81675 München, Germany. Phone: 49-89-4140-6100; Fax: 49-89-4140-4915; E-mail: luber{at}lrz.tu-muenchen.de.

Key Words: E-cadherin mutations • cell adhesion • epidermal growth factor receptor • receptor tyrosine kinase • gastric cancer

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]

This article has been cited by other articles:

				J. Deplazes, M. Fuchs, S. Rauser, H. Genth, E. Lengyel, R. Busch, and B. Luber Rac1 and Rho contribute to the migratory and invasive phenotype associated with somatic E-cadherin mutation Hum. Mol. Genet., October 1, 2009; 18(19): 3632 - 3644. [Abstract] [Full Text] [PDF]

				H. Schmidt-Glenewinkel, E. Reinz, R. Eils, and N. R. Brady Systems Biological Analysis of Epidermal Growth Factor Receptor Internalization Dynamics for Altered Receptor Levels J. Biol. Chem., June 19, 2009; 284(25): 17243 - 17252. [Abstract] [Full Text] [PDF]