Article
- The EMBO Journal (2004) 23, 4780 - 4791
- doi:10.1038/sj.emboj.7600489
Published online: 2 December 2004
Subject Category:
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
- Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway
- Department of Biochemistry, Institute of Medical Biology, University of Tromsø, Tromsø, Norway
- MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
- Department of Molecular Biology, Institut de Recherche en Immunovirologie et Cancerologie, Universite de Montreal, Quebec, Canada
- 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
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.
Keywords:
- differentiation,
- ERK3,
- MK5,
- phosphorylation,
- signalling
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