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Genes Cells. 2003 Mar;8(3):263-73.

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

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Department of Biophysics, Graduate School of Science, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.



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.


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.


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.

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