Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway

Ole-Morten Seternes, Theresa Mikalsen, Bjarne Johansen, Espen Michaelsen, Christopher G. Armstrong, Nick A. Morrice, Benjamin Turgeon, Sylvain Meloche, Ugo Moens, Stephen M. Keyse

    Research output: Contribution to journalArticlepeer-review

    119 Citations (Scopus)


    Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), which is regulated by protein stability. However, its function is unknown and no physiological substrates for ERK3 have yet been identified. Here we demonstrate a specific interaction between ERK3 and MAPK-activated protein kinase-5 (MK5). Binding results in nuclear exclusion of both ERK3 and MK5 and is accompanied by ERK3-dependent phosphorylation and activation of MK5 in vitro and in vivo. Endogenous MK5 activity is significantly reduced by siRNA-mediated knockdown of ERK3 and also in fibroblasts derived from ERK3-/- mice. Furthermore, increased levels of ERK3 protein detected during nerve growth factor-induced differentiation of PC12 cells are accompanied by an increase in MK5 activity. Conversely, MK5 depletion causes a dramatic reduction in endogenous ERK3 levels. Our data identify the first physiological protein substrate for ERK3 and suggest a functional link between these kinases in which MK5 is a downstream target of ERK3, while MK5 acts as a chaperone for ERK3. Our findings provide valuable tools to further dissect the regulation and biological roles of both ERK3 and MK5.
    Original languageEnglish
    Pages (from-to)4780-4791
    Number of pages12
    JournalThe EMBO Journal
    Issue number24
    Publication statusPublished - Dec 2004


    • Signal transduction
    • Differentiation
    • Extracellular signal-regulated kinase 3 (ERK3)
    • ERK3
    • MAPK-activated protein kinase-5 (MK5)
    • MK5
    • Phosphorylation
    • Signalling


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