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J. Biol. Chem., Vol. 281, Issue 46, 35499-35510, November 17, 2006

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Regulation of MAPK-activated Protein Kinase 5 Activity and Subcellular Localization by the Atypical MAPK ERK4/MAPK4^*

Espen Åberg, Maria Perander, Bjarne Johansen, Catherine Julien, Sylvain Meloche¹, Stephen M. Keyse^¶, and Ole-Morten Seternes²

From the Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037 Tromsø, Norway, the Institut de Recherche en Immunovirologie et Cancérologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada, and the ^¶Cancer Research UK Stress Response Laboratory, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom

MAPK-activated protein kinase 5 (MK5) was recently identified as a physiological substrate of the atypical MAPK ERK3. Complex formation between ERK3 and MK5 results in phosphorylation and activation of MK5, concomitant stabilization of ERK3, and the nuclear exclusion of both proteins. However, ablation of ERK3 in HeLa cells using small interfering RNA or in fibroblasts derived from ERK3 null mice reduces the activity of endogenous MK5 by only 50%, suggesting additional mechanisms of MK5 regulation. Here we identify the ERK3-related kinase ERK4 as a bona fide interaction partner of MK5. Binding of ERK4 to MK5 is accompanied by phosphorylation and activation of MK5. Furthermore, complex formation also results in the relocalization of MK5 from nucleus to cytoplasm. However unlike ERK3, ERK4 is a stable protein, and its half-life is not modified by the presence or absence of MK5. Finally, although knock-down of ERK4 protein in HeLa cells reduces endogenous MK5 activity by 50%, a combination of small interfering RNAs targeting both ERK4 and ERK3 causes a further reduction in the MK5 activity by more than 80%. We conclude that MK5 activation is dependent on both ERK3 and ERK4 in these cells and that these atypical MAPKs are both physiological regulators of MK5 activity.

Received for publication, June 29, 2005 , and in revised form, September 7, 2006.

^* This work was supported by the National Programme for Research in Functional Genomics in Norway (FUGE) of the Research Council of Norway and the Norwegian Cancer Society, the Erna and Olav Aakres Foundation, a grant from the Canadian Institutes for Health Research (to S. M.), and Cancer Research UK program support (to S. M. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Canada Research Chair in Cellular Signaling.

² A fellow of the Norwegian Cancer Society. To whom correspondence should be addressed. Tel.: 47-776-46506; Fax: 47-776-45310; E-mail: olems{at}fagmed.uit.no.

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