Phosphorylation of the c-Fos transrepression domain by mitogen-activated protein kinase and 90-kDa ribosomal S6 kinase

Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10952-6. doi: 10.1073/pnas.90.23.10952.


Phosphorylation of the C terminus of c-Fos has been implicated in serum response element-mediated repression of c-fos transcription after its induction by serum growth factors. The growth-regulated enzymes responsible for this phosphorylation in early G1 phase of the cell cycle and the sites of phosphorylation have not been identified. We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kDa ribosomal S6 kinase (RSK) and mitogen-activated protein kinase (MAP kinase), contribute to the serum-induced phosphorylation of c-Fos. The major phosphopeptides derived from biosynthetically labeled c-Fos correspond to phosphopeptides generated after phosphorylation of c-Fos in vitro with both RSK and MAP kinase. The phosphorylation sites identified for RSK (Ser-362) and MAP kinase (Ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear RSK and MAP kinase in modulating newly synthesized c-Fos phosphorylation and downstream signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Gene Expression Regulation
  • Genes, fos*
  • In Vitro Techniques
  • Mice
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Peptide Mapping
  • Phosphoserine / metabolism
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-fos / metabolism*
  • RNA, Messenger / genetics
  • Rats
  • Recombinant Proteins / metabolism
  • Ribosomal Protein S6 Kinases
  • Sequence Deletion
  • Structure-Activity Relationship


  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Recombinant Proteins
  • Phosphoserine
  • Protein Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases