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 GRalpha 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 GRalpha 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 GRalpha, acting through Hic-5, and suggest a broader role for ERK8 in the regulation of nuclear receptors beyond estrogen receptor alpha.
Highlights
Since the identification of ERK1 and ERK2, additional ERK5 family members have been identified and extensively studied
We cloned ERK7 and ERK8 as the last identified members of the ERK subfamily of MAPKs containing a TEY activation motif, but a physiologic role has not been identified to date
In this study we identify the nuclear receptor co-activator Hic-5 as a binding partner of ERK8
Summary
Since the identification of ERK1 and ERK2, additional ERK5 family members have been identified and extensively studied. ERK1 and ERK2 are classically activated by growth factors and mediate signals leading to proliferation or differentiation of most cell types [1, 2] These founding members of the ERK subfamily of MAPKs have a characteristic threonine-glutamine-tyrosine (TEY) motif that requires dual phosphorylation of the threonine and tyrosine residues for full kinase activity. Overexpression of ERK7 was found to reduce cell growth independent of kinase activity but dependent on its C-terminal region [15]. ER␣ is a member of the nuclear receptor superfamily of transcription factors Additional members of this family include the androgen receptor (AR), the glucocorticoid receptor ␣ (GR␣), the mineralocorticoid receptor, the progesterone receptor, the thyroid receptor, the retinoic acid receptors, and the peroxisome proliferator-activated receptor-␥ (PPAR␥). The co-activation function of Hic-5 is dependent on one or more of its LIM domains, which are cysteine- and/or histidinerich regions that resemble zinc fingers
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