title: MAP kinase mediates growth factor-induced nuclear translocation of estrogen receptor alpha.
abstract: In addition to mediating the classical transcriptional effects of estrogen, estrogen receptors (ERs) are now known to regulate gene expression in the absence of estrogen by ligand-independent activation pathways, and to mediate the rapid, non-genomic effects of estrogen as well. ERs have been shown to associate with the cell membrane, and recent studies demonstrate that this subpopulation of membrane-associated ER mediates the rapid effects of estrogen. To date, however, little is known regarding the pathways that regulate the distribution of the ER between the nuclear and membrane fractions. In the current study, we demonstrate membrane localization of transiently transfected ERalpha in human vascular smooth muscle cells, and translocation of ERalpha from the membrane to the nucleus in response to both estrogen-dependent and estrogen-independent stimulation. Mutational analyses identified serine 118 as the critical residue regulating nuclear localization following estrogen-independent stimulation, but not following estrogen stimulation. Induction of nuclear localization of ERalpha by estrogen-independent, but not estrogen-dependent stimulation was blocked by both pharmacologic and genetic inhibition of mitogen-activated protein (MAP) kinase activation. Furthermore, constitutive activation of MAP kinase resulted in nuclear translocation of ERalpha. These overexpression studies support that MAP kinase-mediated phosphorylation of ERalpha induces nuclear localization of the ER in response to estrogen-independent, but not estrogen-dependent stimulation, demonstrating stimulus-specific molecular pathways regulate the nuclear localization of the ER. These findings identify a previously unrecognized pathway that regulates the intracellular localization of the ER, and represent the first demonstration that the distribution of the ER between membrane and nuclear compartments is regulated by physiologic stimuli.
authors.affiliation: Molecular Cardiology Research Institute, Department of Medicine, and Division of Cardiology, New England Medical Center Hospitals, Tufts University School of Medicine, 750 Washington Street, P.O. Box 80, 02111, Boston, MA, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Heather
authors.initials: H
authors.lastname: Ebling
authors.forename: Jens
authors.initials: J
authors.lastname: Mittler
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Baur
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
mesh_terms: D021581:Active Transport, Cell Nucleus; D019943:Amino Acid Substitution; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D015870:Gene Expression; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D017354:Point Mutation; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D047628:Estrogen Receptor alpha; D008164:Luminescent Proteins; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases