Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of γ-secretase

Tong Li, Hongjin Wen, Cory Brayton, Pritam Das, Lisa A. Smithson, Abdul Fauq, Xing Fan, Barbara J. Crain, Donald L. Price, Todd E. Golde, Charles G. Eberhart, Philip C. Wong

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

γ-Secretase, a unique aspartyl protease, is required for the regulated intramembrane proteolysis of Notch and APP, pathways that are implicated, respectively, in the pathogenesis of cancer and Alzheimer disease. However, the mechanism whereby reduction of γ-secretase causes tumors such as squamous cell carcinoma (SCC) remains poorly understood. Here, we demonstrate that γ-secretase functions in epithelia as a tumor suppressor in an enzyme activity-dependent manner. Notch signaling is down-regulated and epidermal growth factor receptor (EGFR) is activated in SCC caused by genetic reduction of γ-secretase. Moreover, the level of EGFR is inversely correlated with the level of γ-secretase in fibroblasts, suggesting that the up-regulation of EGFR stimulates hyperproliferation in epithelia of mice with genetic reduction of γ-secretase. Supporting this notion is our finding that the proliferative response of fibroblasts lacking γ-secretase activity is more sensitive when challenged by either EGF or an inhibitor of EGFR as compared with wild type cells. Interestingly, the up-regulation of EGFR is independent of Notch signaling, suggesting that the EGFR pathway functions in parallel with Notch in the tumorigenesis of SCC. Collectively, our results establish a novel mechanism linking the EGFR pathway to the tumor suppressor role of γ-secretase and that mice with genetic reduction of γ-secretase represent an excellent rodent model for clarifying pathogenesis of SCC and for testing therapeutic strategy to ameliorate this type of human cancer.

Original languageEnglish (US)
Pages (from-to)32264-32273
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number44
DOIs
StatePublished - Nov 2 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Li, T., Wen, H., Brayton, C., Das, P., Smithson, L. A., Fauq, A., Fan, X., Crain, B. J., Price, D. L., Golde, T. E., Eberhart, C. G., & Wong, P. C. (2007). Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of γ-secretase. Journal of Biological Chemistry, 282(44), 32264-32273. https://doi.org/10.1074/jbc.M703649200