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J. Biol. Chem., Vol. 281, Issue 24, 16821-16832, June 16, 2006

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ERK8 Down-regulates Transactivation of the Glucocorticoid Receptor through Hic-5^*

From the Department of Pediatrics, University of Chicago, Chicago, Illinois 60637-1470

Extracellular signal-regulated kinase 8 (ERK8) is the most recently identified member of the ERK subfamily of MAPKs. Although other members of the ERK subfamily are established regulators of signaling pathways involved in cell growth and/or differentiation, less is known about ERK8. To understand the cellular function of ERK8, a yeast two-hybrid screen of a human lung library was performed to identify binding partners. One binding partner identified was Hic-5 (also known as ARA55), a multiple LIM domain containing protein implicated in focal adhesion signaling and the regulation of specific nuclear receptors, including the androgen receptor and the glucocorticoid receptor (GR). Co-immunoprecipitation experiments in mammalian cells confirmed the interaction between Hic-5 and both ERK8 and its rodent ortholog ERK7. The C-terminal region of ERK8 was not required for the interaction. Although the LIM3 and LIM4 domains of Hic-5 were sufficient and required for this interaction, the specific zinc finger motifs in these domains were not. Transcriptional activation reporter assays revealed that ERK8 can negatively regulate transcriptional co-activation of androgen receptor and GR by Hic-5 in a kinase-independent manner. Knockdown of endogenous ERK8 in human airway epithelial cells enhanced dexamethasone-stimulated transcriptional activity of endogenous GR. Transcriptional regulation of GR and interaction with its ligand binding domain by ERK8 were dependent on the presence of Hic-5. These results provide the first physiological function for human ERK8 as a negative regulator of human GR, acting through Hic-5, and suggest a broader role for ERK8 in the regulation of nuclear receptors beyond estrogen receptor .

Received for publication, November 21, 2005 , and in revised form, April 17, 2006.

^* This work was supported in part by National Institutes of Health Grant HL073132 (to M. K. A.). 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 Both authors contributed equally to this work.

² Present address: the Whitehead Institute, Cambridge, MA 02142.

³ Supported in part by National Institutes of Health Training Grant HL07605.

⁴ To whom correspondence should be addressed: Dept. of Pediatrics, University of Chicago, 5841 S. Maryland Ave., MC4064, Chicago, IL 60637-1470. Tel.: 773-702-9659; Fax: 773-702-4041; E-mail: mabe{at}peds.bsd.uchicago.edu.

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