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Molecular and Cellular Biology, November 2005, p. 9820-9828, Vol. 25, No. 22
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.22.9820-9828.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

A Novel Mitogen-Activated Protein Kinase Docking Site in the N Terminus of MEK5{alpha} Organizes the Components of the Extracellular Signal-Regulated Kinase 5 Signaling Pathway

Jan Seyfried, Xin Wang, Giorgi Kharebava, and Cathy Tournier*

Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom

Received 24 May 2005/ Returned for modification 30 June 2005/ Accepted 29 August 2005

The alternative splicing of the mek5 gene gives rise to two isoforms. MEK5ß lacks an extended N terminus present in MEK5{alpha}. Comparison of their activities led us to identify a novel mitogen-activated protein kinase (MAPK) docking site in the N terminus of MEK5{alpha} that is distinct from the consensus motif identified in the other MAPK kinases. It consists of a cluster of acidic residues at position 61 and positions 63 to 66. The formation of the MEK5/extracellular signal-regulated kinase 5 (ERK5) complex is critical for MEK5 to activate ERK5, to increase transcription via MEF2, and to enhance cellular survival in response to osmotic stress. Certain mutations in the ERK5 docking site that prevent MEK5/ERK5 interaction also abrogate the ability of MEKK2 to bind and activate MEK5. However, the identification of MEK5{alpha} mutants with selective binding defect demonstrates that the MEK5/ERK5 interaction does not rely on the binding of MEK5{alpha} to MEKK2 via their respective PB1 domains. Altogether these results establish that the N terminus of MEK5{alpha} is critical for the specific organization of the components of the ERK5 signaling pathway.

* Corresponding author. Mailing address: Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom. Phone: 44 161 275 5417. Fax: 44 161 275 5082. E-mail: cathy.tournier{at}manchester.ac.uk.

Molecular and Cellular Biology, November 2005, p. 9820-9828, Vol. 25, No. 22
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.22.9820-9828.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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