c-Fos Transcriptional Activity Stimulated by H-Ras-activated Protein Kinase Distinct From JNK and ERK

Nature. 1994 Sep 8;371(6493):171-5. doi: 10.1038/371171a0.

Abstract

Ras proteins exert their mitogenic and oncogenic effects through activation of downstream protein kinases. An important question is how Ras-generated signals reach the nucleus to activate downstream target genes. AP-1, a heterodimeric complex of Jun and Fos proteins, which activates mitogen-inducible genes, is a major nuclear target of Ras. Ras can stimulate AP-1 activity by inducing c-fos transcription, a process which is probably mediated by the ERK1 and -2 mitogen-activated protein (MAP) kinases, which phosphorylate the transcription factor Elk-1/TCF. Besides inducing transcription from fos and jun genes, mitogens and Ras proteins enhance AP-1 activity through phosphorylation of c-Jun. Phosphorylation of the c-Jun activation domain leads to c-jun induction through an autoregulatory loop. Ras- and ultra-violet-responsive protein kinases that phosphorylate c-Jun on serine residues at positions 63 and 73 and stimulate its transcriptional activity have been identified. These proline-directed kinases, termed JNKs, are novel MAP kinases. It is not clear, however, whether c-Jun is the only recipient and JNK the only transducer of the Ras signal to AP-1 proteins. A short sequence surrounding the major JNK phosphorylation site of c-Jun is conserved in c-Fos and is part of its activation domain, suggesting that c-Fos may be similarly regulated. Here we show that Ras does indeed augment the transcriptional activity of c-Fos through phosphorylation at Thr 232, the homologue of Ser 73 of c-Jun. However, this is mediated by a novel Ras- and mitogen-responsive proline-directed protein kinase that is different from JNKs and ERKs. Therefore, at least three types of proline-directed kinases transmit Ras- and mitogen-generated signals to the transcriptional machinery.

Publication types

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

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Epidermal Growth Factor / metabolism
  • Humans
  • Mitogen-Activated Protein Kinase 1
  • Phosphorylation / radiation effects
  • Proline-Directed Protein Kinases
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-fos / genetics*
  • Proto-Oncogene Proteins c-jun / metabolism
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Tetradecanoylphorbol Acetate / pharmacology
  • Threonine / metabolism
  • Transcription Factor Pit-1
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Ultraviolet Rays

Substances

  • DNA-Binding Proteins
  • POU1F1 protein, human
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Recombinant Fusion Proteins
  • Transcription Factor Pit-1
  • Transcription Factors
  • Threonine
  • Epidermal Growth Factor
  • Protein-Tyrosine Kinases
  • Proline-Directed Protein Kinases
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • Tetradecanoylphorbol Acetate