title: Extracellular signal-regulated kinase 8 (ERK8) controls estrogen-related receptor α (ERRα) cellular localization and inhibits its transcriptional activity.
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.
authors.affiliation: From the Istituto Toscano Tumori-Core Research Laboratory, Signal Transduction Unit, Siena,; the Università degli Studi di Siena, and.
authors.forename: Matteo
authors.initials: M
authors.lastname: Rossi
authors.affiliation: From the Istituto Toscano Tumori-Core Research Laboratory, Signal Transduction Unit, Siena,; the Università degli Studi di Siena, and.
authors.forename: David
authors.initials: D
authors.lastname: Colecchia
authors.affiliation: Istituto di Endocrinologia e Oncologia Sperimentale, CNR, Napoli.
authors.forename: Carlo
authors.initials: C
authors.lastname: Iavarone
authors.affiliation: From the Istituto Toscano Tumori-Core Research Laboratory, Signal Transduction Unit, Siena.
authors.forename: Angela
authors.initials: A
authors.lastname: Strambi
authors.affiliation: the CEINGE-Biotecnologie Avanzate, Napoli.
authors.forename: Federica
authors.initials: F
authors.lastname: Piccioni
authors.affiliation: the CEINGE-Biotecnologie Avanzate, Napoli,; the Dipartimento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli, Napoli, and.
authors.forename: Arturo
authors.initials: A
authors.lastname: Verrotti di Pianella
authors.affiliation: From the Istituto Toscano Tumori-Core Research Laboratory, Signal Transduction Unit, Siena,; Istituto di Endocrinologia e Oncologia Sperimentale, CNR, Napoli,; the Istituto di Fisiologia Clinica, Sede di Siena, CNR, Siena, Italy. Electronic address: mario.chiariello@ittumori.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Chiariello
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D020816:Amino Acid Motifs; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D000097606:Exportin 1 Protein; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D000097606:Exportin 1 Protein; D000097983:ERRalpha Estrogen-Related Receptor; C456320:MAPK15 protein, human