Abstract
ERK8 (MAPK15) is a large MAP kinase already implicated in the regulation of the functions of different nuclear receptors and in cellular proliferation and transformation. Here, we identify ERRα as a novel ERK8-interacting protein. As a consequence of such interaction, ERK8 induces CRM1-dependent translocation of ERRα to the cytoplasm and inhibits its transcriptional activity. Also, we identify in ERK8 two LXXLL motifs, typical of agonist-bound nuclear receptor corepressors, as necessary features for this MAP kinase to interact with ERRα and to regulate its cellular localization and transcriptional activity. Ultimately, we demonstrate that ERK8 is able to counteract, in immortalized human mammary cells, ERRα activation induced by the EGF receptor pathway, often deregulated in breast cancer. Altogether, these results reveal a novel function for ERK8 as a bona fide ERRα corepressor, involved in control of its cellular localization by nuclear exclusion, and suggest a key role for this MAP kinase in the regulation of the biological activities of this nuclear receptor.
Highlights
Mitogen-activated protein (MAP) kinases are a family of proline-directed serine/threonine kinases expressed in all eukaryotic cells, from yeast to human, and involved in key signaling pathways regulating cell proliferation, differentiation, apoptosis, and stress response [1, 2]
In this paper we demonstrate that ERK8, a member of the MAP kinase family of proteins, is a bona fide ERR␣ corepressor, able to modulate the subcellular localization and activity of this nuclear receptor
Our data support a model in which ERK8 binds to ERR␣, inhibits both its basal and stimulated activity, and induces its localization to the cytoplasm (Fig. 8)
Summary
ER␣, estrogen receptor ␣; ERE, estrogen response element; LMB, leptomycin B; ERRE, ERR response element; SFRE, SF-1 response element; PGC1␣, peroxisome proliferator-activated receptor-␥ coactivator-1␣; EGFR, epidermal growth factor receptor; TRITC, tetramethylrhodamine isothiocyanate. ERK8 as an ERR␣ Corepressor receptor-␥ coactivator-1␣ (PGC1␣), a powerful coactivator that controls its role in cellular functions such as oxidative phosphorylation, mitochondrial biogenesis, and respiration [20, 21]. Evidence of ERR␣ roles in human malignancies, especially in breast cancer, is rapidly accumulating [22,23,24,25,26]. The EGF receptor and ErbB2 signaling pathways regulate ERR␣ transcriptional activity, leading to its hyperphosphorylation and enhancing its DNA binding [27, 28]. The possibility to modulate ERR␣ activity is currently regarded as a valuable approach to target breast cancer as well as other aggressive human malignancies [23,24,25]
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