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pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167.

The estrogen receptor alpha (ER), a member of the steroid receptor superfamily, contains an N-terminal hormone-independent transcriptional activation function (AF-1) and a C-terminal hormone-dependent transcriptional activation function (AF-2). Here, we used in-gel kinase assays to determine that pp90rsk1 activated by either epidermal growth factor (EGF) or phorbol myristate acetate specifically phosphorylates Ser-167 within AF-1. In vitro kinase assays demonstrated that pp90rsk1 phosphorylates the N terminus of the wild-type ER but not of a mutant ER in which Ser-167 was replaced by Ala. In vivo, EGF stimulated phosphorylation of Ser-167 as well as Ser-118. Ectopic expression of active pp90rsk1 increased the level of phosphorylation of Ser-167 compared to that of either a mutant pp90rsk1, which is catalytically inactive in the N-terminal kinase domain, or to that of vector control. The ER formed a stable complex with the mutant pp90rsk1 in vivo. Transfection of the mutant pp90rsk1 depressed ER-dependent transcription of both a wild-type ER and a mutant ER that had a defective AF-2 domain (ER TAF-1). Furthermore, replacing either Ser-118 or Ser-167 with Ala in ER TAF-1 showed similar decreases in transcription levels. A double mutant in which both Ser-118 and Ser-167 were replaced with Ala demonstrated a further decrease in transcription compared to either of the single mutations. Taken together, our results strongly suggest that pp90rsk1 phosphorylates Ser-167 of the human ER in vivo and that Ser-167 aids in regulating the transcriptional activity of AF-1 in the ER.

Pubmed ID: 9528769


  • Joel PB
  • Smith J
  • Sturgill TW
  • Fisher TL
  • Blenis J
  • Lannigan DA


Molecular and cellular biology

Publication Data

April 21, 1998

Associated Grants

  • Agency: NCI NIH HHS, Id: CA-55887

Mesh Terms

  • Animals
  • COS Cells
  • Catalysis
  • Chromosomal Proteins, Non-Histone
  • Cricetinae
  • DNA-Binding Proteins
  • Epidermal Growth Factor
  • Furylfuramide
  • Histone Chaperones
  • Humans
  • Leucine Zippers
  • Phosphorylation
  • Protein Kinases
  • Receptors, Estrogen
  • Receptors, Interferon
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Serine
  • Transcription Factors
  • Transcription, Genetic
  • Tumor Cells, Cultured