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Originally published In Press as doi:10.1074/jbc.M009286200 on January 3, 2001

J. Biol. Chem., Vol. 276, Issue 14, 10870-10878, April 6, 2001
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Molecular Cloning of Mouse ERK5/BMK1 Splice Variants and Characterization of ERK5 Functional Domains*

Chen YanDagger §, Honglin Luo§||, Jiing-Dwan Lee**, Jun-ichi AbeDagger , and Bradford C. BerkDagger Dagger Dagger

From the Dagger  Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, the || Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195, and the ** Department of Immunology, Scripps Research Institute, La Jolla, California 92037

The mitogen-activated protein kinases (MAPKs) play important roles in regulation of cell growth and survival. Human MAPK 5 (ERK5) or Big MAP kinase 1 (BMK1) is a recently cloned member of the MAPK family. To identify ERK5-related kinases, we searched the GenBankTM expressed sequence tag (EST) data base for mouse cDNAs with homology to human ERK5. A full-length mouse cDNA that was highly homologous to the human ERK5 was identified. Further analysis of ERK5 polymerase chain reaction products generated from mouse embryo cDNA yielded three mouse ERK5 cDNAs (mERK5a, mERK5b, and mERK5c). Sequence analysis showed that these cDNAs are alternative splice products of the mouse ERK5 gene. Interestingly, expressed mERK5b and mERK5c act as dominant negative inhibitors based on inhibition of mERK5a kinase activity and mERK5a-mediated MEF2C transactivation. However, the physiological significance of mERK5b and mERK5c is not fully understood. Further investigation using these mouse ERK5 splice variants and other constructed mutants identified functional roles of several regions of mERK5, which appear to be important for protein-protein interaction and intracellular localization. Specifically, we found that the long C-terminal tail, which contains a putative nuclear localization signal, is not required for activation and kinase activity but is responsible for the activation of nuclear transcription factor MEF2C due to nuclear targeting. In addition, the N-terminal domain spanning amino acids (aa) 1-77 is important for cytoplasmic targeting; the domain from aa 78 to 139 is required for association with the upstream kinase MEK5; and the domain from aa 140-406 is necessary for oligomerization. Taken together, these observations indicate that ERK5 is regulated by distinct mechanisms determined by its unique structure and presumably the presence of multiple splice variants.

* This work was supported in part by National Institutes of Health Grants HL49192 and HL18645 (to B. C. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Both authors contributed equally to this work.

Recipient of National Institutes of Health Cardiovascular Training Grant T32HL07828.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF126159 (mERK5a), AF126160 (mERK5b), and AF126161 (mERK5c).

Dagger Dagger To whom correspondence should be addressed: Center for Cardiovascular Research, Box 679, 601 Elmwood Ave., University of Rochester School of Medicine and Dentistry, Rochester, NY 14642. Tel.: 716-273-1946; Fax: 716-273-1497; E-mail: bradford_berk@urmc.rochester.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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