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 journalArticle

    97 Citations (Scopus)

    Abstract

    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
    Volume23
    Issue number24
    DOIs
    Publication statusPublished - Dec 2004

    Fingerprint

    Mitogen-Activated Protein Kinase 6
    Signal transduction
    Mitogen-Activated Protein Kinase Kinases
    Signal Transduction
    Chemical activation
    Mitogen-Activated Protein Kinases
    MAP-kinase-activated kinase 5
    Phosphorylation
    Proteins
    Protein Stability
    PC12 Cells
    Nerve Growth Factor
    Substrates

    Keywords

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

    Cite this

    Seternes, O-M., Mikalsen, T., Johansen, B., Michaelsen, E., Armstrong, C. G., Morrice, N. A., ... Keyse, S. M. (2004). Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. The EMBO Journal, 23(24), 4780-4791. https://doi.org/10.1038/sj.emboj.7600489
    Seternes, Ole-Morten ; Mikalsen, Theresa ; Johansen, Bjarne ; Michaelsen, Espen ; Armstrong, Christopher G. ; Morrice, Nick A. ; Turgeon, Benjamin ; Meloche, Sylvain ; Moens, Ugo ; Keyse, Stephen M. / Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. In: The EMBO Journal. 2004 ; Vol. 23, No. 24. pp. 4780-4791.
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    abstract = "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.",
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    Seternes, O-M, Mikalsen, T, Johansen, B, Michaelsen, E, Armstrong, CG, Morrice, NA, Turgeon, B, Meloche, S, Moens, U & Keyse, SM 2004, 'Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway', The EMBO Journal, vol. 23, no. 24, pp. 4780-4791. https://doi.org/10.1038/sj.emboj.7600489

    Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. / Seternes, Ole-Morten; Mikalsen, Theresa; Johansen, Bjarne; Michaelsen, Espen; Armstrong, Christopher G.; Morrice, Nick A.; Turgeon, Benjamin; Meloche, Sylvain; Moens, Ugo; Keyse, Stephen M.

    In: The EMBO Journal, Vol. 23, No. 24, 12.2004, p. 4780-4791.

    Research output: Contribution to journalArticle

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    T1 - Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway

    AU - Seternes, Ole-Morten

    AU - Mikalsen, Theresa

    AU - Johansen, Bjarne

    AU - Michaelsen, Espen

    AU - Armstrong, Christopher G.

    AU - Morrice, Nick A.

    AU - Turgeon, Benjamin

    AU - Meloche, Sylvain

    AU - Moens, Ugo

    AU - Keyse, Stephen M.

    N1 - dc.publisher: Nature Publishing Group dc.description.sponsorship: NFR (project numbers 151907/150,135823/310 and 16099/V40) DNK Aakres Foundation CIHR (grant MOP-64320) Cancer Research UK

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    N2 - 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.

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    KW - Differentiation

    KW - Extracellular signal-regulated kinase 3 (ERK3)

    KW - ERK3

    KW - MAPK-activated protein kinase-5 (MK5)

    KW - MK5

    KW - Phosphorylation

    KW - Signalling

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    Seternes O-M, Mikalsen T, Johansen B, Michaelsen E, Armstrong CG, Morrice NA et al. Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. The EMBO Journal. 2004 Dec;23(24):4780-4791. https://doi.org/10.1038/sj.emboj.7600489