Extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase family, plays an important role in growth factor signaling to the nucleus. However, molecular mechanism Show more
Extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase family, plays an important role in growth factor signaling to the nucleus. However, molecular mechanisms regulating subcellular localization of ERK5 have remained unclear. Here, we show that nucleocytoplasmic shuttling of ERK5 is regulated by a bipartite nuclear localization signal-dependent nuclear import mechanism and a CRM1-dependent nuclear export mechanism. Our results show that the N-terminal half of ERK5 binds to the C-terminal half and that this binding is necessary for nuclear export of ERK5. They further show that the activating phosphorylation of ERK5 by MEK5 results in the dissociation of the binding between the N- and C-terminal halves and thus inhibits nuclear export of ERK5, causing its nuclear import. These results reveal the mechanism by which the activating phosphorylation of ERK5 induces its nuclear import and suggest a novel example of a phosphorylation-dependent control mechanism for nucleocytoplasmic shuttling of proteins. Show less
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 E Show more
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. Show less