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  • The EMBO Journal (2004) 23, 4780 - 4791
  • doi:10.1038/sj.emboj.7600489

Published online: 2 December 2004

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

Ole-Morten Seternes1, Theresa Mikalsen2, Bjarne Johansen2, Espen Michaelsen1, Chris G Armstrong3,a, Nick A Morrice3, Benjamin Turgeon4, Sylvain Meloche4, Ugo Moens2 and Stephen M Keyse5

  1. Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway
  2. Department of Biochemistry, Institute of Medical Biology, University of Tromsø, Tromsø, Norway
  3. MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
  4. Department of Molecular Biology, Institut de Recherche en Immunovirologie et Cancerologie, Universite de Montreal, Quebec, Canada
  5. Cancer Research UK, Molecular Pharmacology Unit, Biomedical Research Centre, Level 5, Ninewells Hospital, Dundee, UK

Correspondence to:

Ole-Morten Seternes, Department of Pharmacology, Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway. Tel.: +47 77 64 65 06; Fax: +47 77 64 53 10; E-mail: olems@fagmed.uit.no

Stephen M Keyse, Cancer Research UK, Molecular Pharmacology Unit, Biomedical Research Centre, Level 5, Ninewells Hospital, Dundee DD1 9SY, UK. Tel.: +44 1382 632 622; Fax: +44 1382 669 993; E-mail: stephen.keyse@cancer.org.uk

aPresent address: Invitrogen, 501 Charmany Drive, Madison, WI, USA

Received 9 July 2004; Accepted 28 October 2004

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.

  • Keywords:

    • differentiation,
    • ERK3,
    • MK5,
    • phosphorylation,
    • signalling