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. [Cancer Res 2008;68(3):707-14]

Systems Biological Analysis of Epidermal Growth Factor Receptor Internalization Dynamics for Altered Receptor Levels

“…Furthermore, various mutations of the EGFR, which potentially affect proper internalization, are associated with different types of cancer (1,14,15).…”

“…Endosomal EGFR can be transited back to the plasma membrane or to the late endosome/lysosome for degradation (2). As the majority of internalized receptors are targeted for lysosomal degradation upon EGF stimulation (13), endocytic entry of active EGFR is a crucial step for signal attenuation, which is also highlighted by the findings that impaired or delayed internalization is highly oncogenic (14,15).…”

SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity

“…Mutual downregulation between E-cadherin and ligandactivated EGFR has been described (Qian et al, 2004). Mutation of E-cadherin in diffuse-type gastric carcinoma associates with increased activation of EGFR (Bremm et al, 2008). In non-small cell lung cancer, E-cadherin has an important function in prognosis and progression and interacts with EGFR.…”

Effects of two monoclonal antibodies, MLS128 against Tn-antigen and 1H7 against insulin-like growth factor-I receptor, on the growth of colon cancer cells

“…In addition, IB experiments were carried out using anti-E-cadherin and CD44 antibodies since E-cadherin and CD44 were reported to have a size close to that of 110 kDa GP, which MLS128 binds to (22,23). Interestingly, LS180 cells did not express E-cadherin whereas two other colon cancer and MCF-7 breast cancer cell lines expressed similar levels of E-cadherin ( Figure 4E).…”