title: Enhanced activation of epidermal growth factor receptor caused by tumor-derived E-cadherin mutations.
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.
authors.affiliation: Technische Universität München, Klinikum rechts der Isar, Institut für Allgemeine Pathologie und Pathologische Anatomie, München, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Bremm
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.forename: Margit
authors.initials: M
authors.lastname: Fuchs
authors.forename: Jörg
authors.initials: J
authors.lastname: Mages
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.forename: Gisela
authors.initials: G
authors.lastname: Keller
authors.forename: Christine
authors.initials: C
authors.lastname: Hermannstädter
authors.forename: Karl-Friedrich
authors.initials: KF
authors.lastname: Becker
authors.forename: Sandra
authors.initials: S
authors.lastname: Rauser
authors.forename: Rupert
authors.initials: R
authors.lastname: Langer
authors.forename: Claus Hann
authors.initials: CH
authors.lastname: von Weyhern
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.forename: Birgit
authors.initials: B
authors.lastname: Luber
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D044584:Carcinoma, Ductal / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000235:genetics; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005091:Exons; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism
chemical_list: D015820:Cadherins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D018631:ras Proteins