Molecular interpretation of ERK signal duration by immediate early gene products

Nat Cell Biol. 2002 Aug;4(8):556-64. doi: 10.1038/ncb822.


The duration of intracellular signalling is associated with distinct biological responses, but how cells interpret differences in signal duration are unknown. We show that the immediate early gene product c-Fos functions as a sensor for ERK1 (extracellular-signal-regulated kinase 1) and ERK2 signal duration. When ERK activation is transient, its activity declines before the c-Fos protein accumulates, and under these conditions c-Fos is unstable. However, when ERK signalling is sustained, c-Fos is phosphorylated by still-active ERK and RSK (90K-ribosomal S6 kinase). Carboxy-terminal phosphorylation stabilizes c-Fos and primes additional phosphorylation by exposing a docking site for ERK, termed the FXFP (DEF) domain. Mutating the DEF domain disrupts the c-Fos sensor and c-Fos-mediated signalling. Other immediate early gene products that control cell cycle progression, neuronal differentiation and circadium rhythms also contain putative DEF domains, indicating that multiple sensors exist for sustained ERK signalling. Together, our data identify a general mechanism by which cells can interpret differences in ERK activation kinetics.

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
  • Binding Sites
  • Enzyme Activation
  • Immediate-Early Proteins / chemistry
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Kinetics
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / chemistry
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Models, Biological
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-fos / chemistry
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Ribosomal Protein S6 Kinases / metabolism
  • Signal Transduction


  • Immediate-Early Proteins
  • Proto-Oncogene Proteins c-fos
  • Recombinant Proteins
  • Ribosomal Protein S6 Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases