A conditional feedback loop regulates Ras activity through EphA2

Madhu Macrae, Richard M. Neve, Pablo Rodriguez-Viciana, Christopher Haqq, Jennifer Yeh, Chira Chen, Joe W. Gray, Frank McCormick

Research output: Contribution to journalArticlepeer-review

109 Scopus citations


The EphA2 receptor tyrosine kinase is frequently overexpressed in many cancers, including 40% of breast cancers. Here, we show that EphA2 is a direct transcriptional target of the Ras-Raf-MAPK pathway and that ligand-stimulated EphA2 attenuates the growth factor-induced activation of Ras. Thus, a negative feedback loop is created that regulates Ras activity. Interestingly, the expression of EphA2 and ephrin-A1 is mutually exclusive in a panel of 28 breast cancer cell lines. We show that the MAPK pathway inhibits ephrin-A1 expression, and the ligand expression inhibits EphA2 levels contributing to the receptor-ligand reciprocal expression pattern in these cell lines. Our results suggest that an escape from the negative effects of this interaction may be important in the development of cancer.

Original languageEnglish (US)
Pages (from-to)111-118
Number of pages8
JournalCancer Cell
Issue number2
StatePublished - Aug 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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