Expression of the BRK tyrosine kinase in mammary epithelial cells enhances the coupling of EGF signalling to PI 3-kinase and Akt, via erbB3 phosphorylation

Oncogene. 2000 Nov 16;19(48):5471-6. doi: 10.1038/sj.onc.1203931.

Abstract

A high proportion of human breast cancers, in contrast with normal mammary tissue, express the intracellular tyrosine kinase BRK. BRK expression enhances the mitogenic response of mammary epithelial cells to epidermal growth factor, and conferment of a proliferative advantage through this mechanism may account for the frequent elevation of BRK expression in tumours. Here we report that BRK expression in mammary epithelial cells, at pathologically relevant levels, results in an enhanced phosphorylation of the epidermal growth factor receptor-related receptor erbB3 in response to epidermal growth factor. As a consequence, erbB3 recruits increased levels of phosphoinositide 3-kinase, and this is associated with a potentiated activation of Akt. This effect of BRK on the regulation of phosphoinositide 3-kinase and Akt activity may account for BRK's ability to enhance mammary cell mitogenesis, and raises the possibility that breast tumours expressing BRK may acquire a resistance to pro-apoptotic signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast / enzymology*
  • Breast / metabolism
  • Cells, Cultured
  • Epidermal Growth Factor / pharmacology
  • Epidermal Growth Factor / physiology*
  • Epithelial Cells / enzymology
  • Epithelial Cells / metabolism
  • Humans
  • Neoplasm Proteins
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / biosynthesis
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / physiology*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins*
  • Receptor, ErbB-3 / metabolism*
  • Signal Transduction / physiology*
  • Transfection
  • Tyrosine / metabolism

Substances

  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Tyrosine
  • Epidermal Growth Factor
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Receptor, ErbB-3
  • PTK6 protein, human
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt