Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells

Christopher Y. Thomas, Michael Chouinard, Michael Cox, Sarah Parsons, Melody Stallings-Mann, Roy Garcia, Richard Jove, Robert Wharen

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Overexpressed epidermal growth receptor factor receptors (EGFRs) are thought to contribute to the malignant phenotype of human glioblastomas (GBMs), but the mechanism is not well understood. We found that SKMG-3 cells, a rare GBM cell line that maintains EGFR gene amplification in vitro, produced high levels of EGFR protein. The cells also expressed the related receptors HER2/neu and HER4, but not HER3. Immunoblots and tryptic phosphopeptide maps showed that the SKMG-3 EGFRs were intact and functional and that a subset of these receptors were spontaneously autophosphorylated. EGF treatment stimulated phosphorylation of the EGFRs as well as the downstream effectors Erk, AKT1, stat3 and c-Cb1. Under minimal growth conditions, the unstimulated SKMG-3 cells contained constitutively phosphorylated Erk and AKT1 but no detectable stat3 DNA-binding complexes. The EGFR kinase inhibitor PD158780 reduced the constitutive phosphorylation of the receptor and Erk but not that of AKT1. In contrast, inhibition of phosphatidylinositol-3-kinase (P13K) blocked the constitutive phosphorylation of Erk and AKT-1 but not the EGFR. We conclude that the SKMG-3 cells represent the subset of GBMs with amplified EGFR genes that overexpress intact receptors. The results also suggest that in some GBMs, signals from overexpressed EGFRs contribute to the constitutive phosphorylation of Erk, but these signals may not required for the constitutive activation of P13K or AKT1.

Original languageEnglish (US)
Pages (from-to)19-27
Number of pages9
JournalInternational Journal of Cancer
Volume104
Issue number1
DOIs
StatePublished - Mar 10 2003

Keywords

  • Mitogen activated protein kinases
  • Receptor protein-tyrosine kinases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Thomas, C. Y., Chouinard, M., Cox, M., Parsons, S., Stallings-Mann, M., Garcia, R., Jove, R., & Wharen, R. (2003). Spontaneous activation and signaling by overexpressed epidermal growth factor receptors in glioblastoma cells. International Journal of Cancer, 104(1), 19-27. https://doi.org/10.1002/ijc.10880