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Mol. Biol. Cell 15 (10): 4457-4466

Copyright © 2004 by The American Society for Cell Biology.

A Novel Mechanism for Mitogen-activated Protein Kinase Localization

Eric Bind, Yelena Kleyner, Dorota Skowronska-Krawczyk, Emily Bien, Brian David Dynlacht, and Irma Sánchez *

Department of Pathology, New York University School of Medicine, New York, NY 10016

Received for publication March 18, 2004. Revision received June 16, 2004. Accepted for publication July 7, 2004.

Monitoring Editor: Benjamin Glick

Abstract: Mitogen-activated protein kinases/extracellular signal regulated kinases (MAPKs/ERKs) are typically thought to be soluble cytoplasmic enzymes that translocate to the nucleus subsequent to their phosphorylation by their activating kinases or mitogen-activated protein/extracellular signal regulated kinase kinase. We report here the first example of nuclear translocation of a MAPK that occurs via temporally regulated exit from a membranous organelle. Confocal microscopy examining the subcellular localization of ERK3 in several cell lines indicated that this enzyme was targeted to the Golgi/endoplasmic reticulum Golgi intermediate compartment. Deletion analysis of green fluorescent protein (GFP)-ERK3 uncovered a nuclear form that was carboxy-terminally truncated and established a Golgi targeting motif at the carboxy terminus. Immunoblot analysis of cells treated with the proteasome inhibitor MG132 further revealed two cleavage products, suggesting that in vivo, carboxy-terminal cleavage of the full-length protein controls its subcellular localization. In support of this hypothesis, we found that deletion of a small region rich in acidic residues within the carboxy terminus eliminated both the cleavage and nuclear translocation of GFP-ERK3. Finally, cell cycle synchronization studies revealed that the subcellular localization of ERK3 is temporally regulated. These data suggest a novel mechanism for the localization of an MAPK family member, ERK3, in which cell cycle-regulated, site-specific proteolysis generates the nuclear form of the protein.


Article published online ahead of print. Mol. Biol. Cell 10.1091/mbc.E04–03–0234. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E04–03–0234.

* Corresponding author. E-mail address: irma.sanchez{at}med.nyu.edu.



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