MAP kinase mediates growth factor-induced nuclear translocation of estrogen receptor α

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. nongenomic 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-ativated 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. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.