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J. Biol. Chem., Vol. 282, Issue 39, 28759-28767, September 28, 2007

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Mutations in ERK2 Binding Sites Affect Nuclear Entry^*

Mustafa N. Yazicioglu¹², Daryl L. Goad¹³, Aarati Ranganathan⁴, Angelique W. Whitehurst⁵, Elizabeth J. Goldsmith, and Melanie H. Cobb⁶

From the Departments of Pharmacology and Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9041

The MAPK ERK2 can enter and exit the nucleus by an energy-independent process that is facilitated by direct interactions with nuclear pore proteins. Several studies also suggest that the localization of ERK2 can be influenced by carrier proteins. Using import reconstitution assays, we examined a group of ERK2 mutants defective in known protein interactions to determine structural properties of ERK2 that contribute to its nuclear entry. ERK2 mutants defective in binding to substrates near the active site or to basic/hydrophobic docking (D) motifs were imported normally. Several ERK2 mutants defective in interactions with FXF motifs displayed slowed rates of nuclear import. The import-impaired mutants also showed reduced binding to a recombinant C-terminal fragment of nucleoporin 153 that is rich in FXF motifs. Despite the deficit revealed in some mutants via reconstitution assays, all but one of the ERK2 mutants accumulated in nuclei of stimulated cells in a manner comparable with the wild type protein; the mutant most defective in import remained in the cytoplasm. These results further support the idea that direct interactions with nucleoporins are involved in ERK2 nuclear entry and that multiple events contribute to the ligand-dependent relocalization of these protein kinases.

Received for publication, April 25, 2007 , and in revised form, July 25, 2007.

^* This work was supported in part by National Institutes of Health Grant DK34128 (to M. H. C.) and Grants I1243 (to M. H. C.) and I1128 (to E. J. G.) from the Welch Foundation. 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 In partial fulfillment of the requirements for the Ph.D.

² Present address: The Children's Hospital of Philadelphia, Philadelphia, PA 19104.

³ Supported by NIGMS, National Institutes of Health T32 training grant in cell and molecular biology.

⁴ Present address: Physician's Education Resource, Dallas, TX 75219.

⁵ Present address: UT Southwestern, Dept. of Cell Biology, Dallas, TX 75390.

⁶ To whom correspondence should be addressed: Dept. of Pharmacology, UT Southwestern Medical Center, 6001 Forest Park Blvd., Dallas, TX 75390-9041. Tel.: 214-645-6122; Fax: 214-645-6124; E-mail: Melanie.Cobb{at}UTSouthwestern.edu.

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