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


CONCLUSIONS
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.
Terasawa
Kazuya
K
Department of Biophysics, Graduate School of Science, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Okazaki
Kenji
K
Nishida
Eisuke
E
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D048671:MAP Kinase Kinase 5; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D000099169:Fos-Related Antigen 1
D048671:MAP Kinase Kinase 5; D048054:Mitogen-Activated Protein Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1; C482563:MAP2K5 protein, human