Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells

EMBO J. 1996 Mar 15;15(6):1292-300.


The mechanism by which estradiol acts on cell multiplication is still unclear. Under conditions of estradiol-dependent growth, estradiol treatment of human mammary cancer MCF-7 cells triggers rapid and transient activation of the mitogen-activated (MAP) kinases, erk-1 and erk-2, increases the active form of p21ras, tyrosine phosphorylation of Shc and p190 protein and induces association of p190 to p21ras-GAP. Both Shc and p190 are substrates of activated src and once phosphorylated, they interact with other proteins and upregulate p21ras. Estradiol activates the tyrosine kinase/p21ras/MAP-kinase pathway in MCF-7 cells with kinetics which are similar to those of peptide mitogens. It is only after introduction of the human wild-type 67 kDa estradiol receptor cDNA that Cos cells become estradiol-responsive in terms of erk-2 activity. This finding, together with the inhibition by the pure anti-estrogen ICI 182 780 of the stimulatory effect of estradiol on each step of the pathway in MCF-7 cells proves that the classic estradiol receptor is responsible for the transduction pathway activation. Transfection experiments of Cos cells with the estradiol receptor cDNA and in vitro experiments with c-src show that the estradiol receptor activates c-src and this activation requires occupancy of the receptor by hormone. Our experiments suggest that c-src is an initial and integral part of the signaling events mediated by the estradiol receptor.

MeSH terms

  • Breast Neoplasms / metabolism*
  • CSK Tyrosine-Protein Kinase
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Enzyme Activation
  • Estradiol / metabolism*
  • Female
  • Guanine Nucleotide Exchange Factors*
  • Guanosine Triphosphate / metabolism
  • Humans
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Nuclear Proteins / metabolism
  • Phosphoproteins / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Receptors, Estradiol / metabolism*
  • Repressor Proteins
  • Signal Transduction*
  • Tumor Cells, Cultured
  • ras-GRF1
  • src Homology Domains
  • src-Family Kinases


  • ARHGAP35 protein, human
  • Guanine Nucleotide Exchange Factors
  • Nuclear Proteins
  • Phosphoproteins
  • RASGRF1 protein, human
  • Receptors, Estradiol
  • Repressor Proteins
  • ras-GRF1
  • Estradiol
  • Guanosine Triphosphate
  • Protein-Tyrosine Kinases
  • CSK Tyrosine-Protein Kinase
  • Proto-Oncogene Proteins pp60(c-src)
  • src-Family Kinases
  • CSK protein, human
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)