ERK8 down-regulates transactivation of the glucocorticoid receptor through Hic-5

Matthew P. Saelzler, Christy C. Spackman, Yuru Liu, Lesly C. Martinez, Jeremy P. Harris, Mark K. Abe

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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 GRα 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 GRα 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 GRα, acting through Hic-5, and suggest a broader role for ERK8 in the regulation of nuclear receptors beyond estrogen receptor α.

Original languageEnglish (US)
Pages (from-to)16821-16832
Number of pages12
JournalJournal of Biological Chemistry
Volume281
Issue number24
DOIs
StatePublished - Jun 16 2006
Externally publishedYes

Fingerprint

Glucocorticoid Receptors
Transcriptional Activation
Down-Regulation
Androgen Receptors
Cytoplasmic and Nuclear Receptors
LIM Domain Proteins
Chemical activation
human ERK8 protein
Focal Adhesions
Zinc Fingers
Cell growth
Immunoprecipitation
Cell Communication
Estrogen Receptors
Yeast
Dexamethasone
Zinc
Rodentia
Assays
Phosphotransferases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

ERK8 down-regulates transactivation of the glucocorticoid receptor through Hic-5. / Saelzler, Matthew P.; Spackman, Christy C.; Liu, Yuru; Martinez, Lesly C.; Harris, Jeremy P.; Abe, Mark K.

In: Journal of Biological Chemistry, Vol. 281, No. 24, 16.06.2006, p. 16821-16832.

Research output: Contribution to journalArticle

Saelzler, Matthew P. ; Spackman, Christy C. ; Liu, Yuru ; Martinez, Lesly C. ; Harris, Jeremy P. ; Abe, Mark K. / ERK8 down-regulates transactivation of the glucocorticoid receptor through Hic-5. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 24. pp. 16821-16832.
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