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Papers In Press, published online ahead of print April 18, 2006
Pediatrics, University of Chicago, Chicago, IL 60637
Corresponding Author: mabe{at}peds.bsd.uchicago.edu
Extracellular signal-regulated kinase 8 (ERK8) is the most recently identified member of the ERK subfamily of MAP kinases. While 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 (AR) 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. While 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 AR and GR
J. Biol. Chem, 10.1074/jbc.M512418200
Submitted on November 21, 2005
Revised on April 17, 2006
Accepted on April 18, 2006
ERK8 down-regulates transactivation of the glucocorticoid receptor through Hic-5
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 was 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 ER.
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