NDF/heregulin activates MAP kinase and p70/p85 S6 kinase during proliferation or differentiation of mammary epithelial cells

Oncogene. 1995 Jan 5;10(1):167-75.


Neu differentiation factors (NDF) are a novel family of polypeptide factors which activate sub-class I tyrosine kinase receptors. In all mammary epithelial cells analysed in this study, NDF activates the same signalling pathways while it induces different, cell-specific biological effects. In AU565 cells which are growth inhibited, as well as in T47D or HC11 cells which proliferate in response to NDF, the MAP kinase isoforms p44ERK1 and p42ERK2 and the p70/p85 S6 kinase are activated. NDF stimulates tyrosine phosphorylation and the in vitro kinase activity of ErbB-2. When PKC is activated by TPA, NDF is no longer able to activate ErbB-2 in T47D cells, leading to a blockage of cell proliferation. Activation of ErbB-2 by point mutation, or by monoclonal antibodies, also stimulates both the MAPK and the p70/p85 S6 kinase pathways. The same monoclonal antibodies can induce AU565 cell differentiation. In summary, during growth or differentiation of mammary epithelial cells, NDF stimulates several independent signalling pathways which can also be triggered by ErbB-2 stimulation alone. PKC activation blocks the biological effect induced by NDF through negative modulation of ErbB-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / physiology
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Differentiation / physiology
  • Cell Division / physiology
  • Cell Line
  • Enzyme Activation
  • Glycoproteins / physiology*
  • Humans
  • Mammary Glands, Animal / cytology*
  • Mammary Glands, Animal / enzymology*
  • Mice
  • Molecular Sequence Data
  • Neuregulins
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Receptor, ErbB-2 / immunology
  • Receptor, ErbB-2 / metabolism
  • Ribosomal Protein S6 Kinases


  • Antibodies, Monoclonal
  • Glycoproteins
  • Neuregulins
  • Receptor, ErbB-2
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases