Activation of the EGFR Gene Target EphA2 Inhibits Epidermal Growth Factor-Induced Cancer Cell Motility

Mol Cancer Res. 2007 Mar;5(3):283-93. doi: 10.1158/1541-7786.MCR-06-0321.

Abstract

EphA2 overexpression has been reported in many cancers and is believed to play an important role in tumor metastasis and angiogenesis. We show that the activated epidermal growth factor receptor (EGFR) and the cancer-specific constitutively active EGFR type III deletion mutant (EGFRvIII) induce the expression of EphA2 in mammalian cell lines, including the human cancer cell lines A431 and HN5. The regulation is partially dependent on downstream activation of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase and is a direct effect on the EphA2 promoter. Furthermore, EGFR and EphA2 both localize to the plasma membrane and EphA2 coimmunoprecipitates with activated EGFR and EGFRvIII. Ligand activation of EphA2 and EphA2 knockdown by small interfering RNA inhibit EGF-induced cell motility of EGFR-overexpressing human cancer cells, indicating a functional role of EphA2 in EGFR-expressing cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Membrane / chemistry
  • Cell Movement / drug effects
  • Cell Movement / genetics*
  • Epidermal Growth Factor / antagonists & inhibitors*
  • Epidermal Growth Factor / metabolism
  • ErbB Receptors / agonists
  • ErbB Receptors / analysis
  • ErbB Receptors / metabolism*
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Promoter Regions, Genetic
  • Protein Biosynthesis / genetics
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Small Interfering / pharmacology
  • Receptor, EphA2 / analysis
  • Receptor, EphA2 / genetics*
  • Receptor, EphA2 / metabolism
  • Transcriptional Activation*

Substances

  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • epidermal growth factor receptor VIII
  • Epidermal Growth Factor
  • ErbB Receptors
  • Receptor, EphA2
  • MAP Kinase Kinase Kinases