Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase

Science. 1995 Dec 1;270(5241):1491-4. doi: 10.1126/science.270.5241.1491.

Abstract

The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser118 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser118. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • Enzyme Activation
  • Epidermal Growth Factor / pharmacology
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Estrogen Antagonists / pharmacology
  • Humans
  • Mitogen-Activated Protein Kinase Kinases
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation
  • Polyunsaturated Alkamides
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-raf
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Receptors, Estrogen / chemistry
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Serine / metabolism*
  • Somatomedins / pharmacology
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Transcriptional Activation* / drug effects
  • Transfection

Substances

  • Estrogen Antagonists
  • Polyunsaturated Alkamides
  • Proto-Oncogene Proteins
  • Receptors, Estrogen
  • Recombinant Fusion Proteins
  • Somatomedins
  • Tamoxifen
  • afimoxifene
  • Serine
  • Estradiol
  • Epidermal Growth Factor
  • ICI 164384
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)