Regulation of c-Fos and Fra-1 by the MEK5-ERK5 pathway

Genes Cells. 2003 Mar;8(3):263-73. doi: 10.1046/j.1365-2443.2003.00631.x.


Background: ERK5 is the newest subfamily member of the mitogen-activated protein kinase (MAPK) family, and is activated by various extracellular signals including growth factors. MEK5 is a specific activator of ERK5. c-Fos and Fra-1, well-known immediate early gene products, are members of the AP-1 family. We previously reported that activation of the MEK5-ERK5 pathway is able to induce expression of c-Fos.

Results: We have found that activation of the MEK5-ERK5 pathway causes the phosphorylation and stabilization of c-Fos and Fra-1. Phosphorylation of c-Fos appears to be mediated by ERK5 and a kinase(s) lying downstream of ERK5, and the MEK5-ERK5 pathway-dependent phosphorylation sites on c-Fos are different from the ERK1/2 pathway-dependent ones. Interestingly, activation of the MEK5-ERK5 pathway, but not that of the ERK1/2 pathway, is found to markedly increase the transactivation activity of c-Fos. Furthermore, our results show that the C-terminal half of ERK5 is necessary for the maximal activation of the transactivation activity of c-Fos and Fra-1.

Conclusion: These results reveal a role of the MEK5-ERK5 pathway in modulating the function of the Fos family proteins which is different from the role of the ERK1/2 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • COS Cells
  • Gene Expression Regulation / physiology*
  • Humans
  • MAP Kinase Kinase 5
  • Mice
  • Mitogen-Activated Protein Kinase 7
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-fos / genetics*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Transcriptional Activation


  • Proto-Oncogene Proteins c-fos
  • fos-related antigen 1
  • Mitogen-Activated Protein Kinase 7
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 5
  • MAP2K5 protein, human
  • Mitogen-Activated Protein Kinase Kinases