Ras-independent oncogenic transformation by an EGF-receptor mutant

Julie L. Boerner, Michael J. McManus, G. Steven Martin, Nita Jane Maihle

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Mutations in the ligand-binding domain of the epidermal growth factor receptor have been identified in several types of human cancers, including malignant gliomas. These mutations render signaling by this receptor to be constitutively ligand-independent. In fibroblasts transformed with ligand-independent epidermal growth factor receptor mutants, there is a correlation between the formation of a unique phosphotyrosine protein complex and oncogenic transformation. This phosphoprotein complex includes Grb2, Shc, Sos, tyrosine-phosphorylated form of caldesmon, and two, as yet, unidentified proteins. The presence of Grb2, Shc, and Sos in this complex implicates Ras in ligand-independent signaling by these oncogenic epidermal growth factor receptor mutants. We, therefore, have used retroviral co-infections of cultured primary fibroblasts to determine if Ras activation is required for phosphoprotein complex formation, stress fiber loss, or transformation. As predicted, expression of a dominant-negative Ras mutant (N17Ras) completely abrogates ligand-stimulated soft agar colony growth of primary fibroblasts. In contrast, N17Ras expression has no effect on v-ErbB mediated stress fiber disassembly, soft agar colony growth, or phosphoprotein complex assembly. In addition, our data suggest that ligand-dependent Ras activation may be suppressed by oncogenic v-ErbB expression. Together these observations suggest that oncogenic signaling by v-ErbB does not require Ras activation, and implicate an alternative signal transduction pathway in ligand-independent epidermal growth factor receptor oncogenic signaling.

Original languageEnglish (US)
Pages (from-to)935-942
Number of pages8
JournalJournal of Cell Science
Volume113
Issue number6
StatePublished - Apr 12 2000

Keywords

  • Chicken embryo fibroblast
  • Dominant-negative Ras
  • Stress fiber
  • V-ErbB

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Boerner, J. L., McManus, M. J., Martin, G. S., & Maihle, N. J. (2000). Ras-independent oncogenic transformation by an EGF-receptor mutant. Journal of Cell Science, 113(6), 935-942.