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Molecular and Cellular Biology, August 2003, p. 5692-5705, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5692-5705.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The N and C Termini of the Splice Variants of the Human Mitogen-Activated Protein Kinase-Interacting Kinase Mnk2 Determine Activity and Localization

Gert C. Scheper,1 Josep L. Parra,1 Mary Wilson,1 Barbara van Kollenburg,1,{dagger} Alfred C. O. Vertegaal,2 Ze-Guang Han,3 and Christopher G. Proud1*

Division of Molecular Physiology,1 Division of Gene Regulation and Expression, Faculty of Life Sciences, University of Dundee, Dundee, United Kingdom,2 Chinese National Human Genome Center, Shanghai, People's Republic of China3

Received 23 December 2002/ Returned for modification 6 March 2003/ Accepted 7 May 2003

The cap-binding eukaryotic initiation factor eIF4E is phosphorylated by the mitogen-activated protein (MAP) kinase-interacting kinases (Mnk's). Three forms of the Mnk's exist in human cells: Mnk1, Mnk2a, and Mnk2b. These last two are derived from the same gene by alternative splicing and differ only at their C termini. While Mnk2a contains a MAP kinase-binding site in this region, Mnk2b lacks such a sequence and is much less readily activated by MAP kinases in vitro. Expression of Mnk2b in mammalian cells leads to increased phosphorylation of eIF4E, showing that it acts as an eIF4E kinase in vivo. While Mnk2a is cytoplasmic, a substantial amount of Mnk2b is found in the nucleus. Both enzymes contain a stretch of basic residues in their N termini that plays a role in binding to eIF4G and functions as a nuclear localization signal. Binding of eIF4G or nuclear import appears to be regulated by the C terminus of Mnk2a. Furthermore, the MAP kinase-binding site of Mnk2a regulates nuclear entry. Within the nucleus, Mnk2b and certain variants of Mnk2a that are present in the nucleus colocalize with the promyelocytic leukemia protein PML, which also binds to eIF4E.

* Corresponding author. Mailing address: Division of Molecular Physiology, Faculty of Life Sciences, University of Dundee, MSI/WTB Complex, Dow St., Dundee, DD1 5EH, United Kingdom. Phone: 44-1382-344919. Fax: 44-1382-322424. E-mail: c.g.proud{at}dundee.ac.uk.

{dagger} Present address: Department for Clinical Chemistry, Free University Medical Center, Amsterdam, The Netherlands.

Molecular and Cellular Biology, August 2003, p. 5692-5705, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5692-5705.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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