title: Ligand-independent phosphorylation of the glucocorticoid receptor integrates cellular stress pathways with nuclear receptor signaling.
abstract: Glucocorticoids are stress hormones that maintain homeostasis through gene regulation mediated by nuclear receptors. We have discovered that other cellular stressors are integrated with glucocorticoid signaling through a new hormone-independent phosphorylation site, Ser134, on the human glucocorticoid receptor (GR). Ser134 phosphorylation is induced by a variety of stress-activating stimuli in a p38 mitogen-activated protein kinase (MAPK)-dependent manner. Cells expressing a mutant glucocorticoid receptor incapable of phosphorylation at Ser134 (S134A-GR) had significantly altered hormone-dependent genome-wide transcriptional responses and associated hormone-mediated cellular functions. The phosphorylation of Ser134 significantly increased the association of the GR with the zeta isoform of the 14-3-3 class of signaling proteins (14-3-3zeta) on chromatin promoter regions, resulting in a blunted hormone-dependent transcriptional response of select genes. These data argue that the phosphorylation of Ser134 acts as a molecular sensor on the GR, monitoring the level of cellular stress to redirect glucocorticoid-regulated signaling through altered 14-3-3zeta cofactor binding and promoter recruitment. This posttranslational modification allows prior cellular stress signals to dictate the transcriptional response to glucocorticoids.
authors.affiliation: Molecular Endocrinology Group, Laboratory of Signal Transduction, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Amy Jo
authors.initials: AJ
authors.lastname: Galliher-Beckley
authors.forename: Jason Grant
authors.initials: JG
authors.lastname: Williams
authors.forename: John Anthony
authors.initials: JA
authors.lastname: Cidlowski
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047468:Immunoprecipitation; D008024:Ligands; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010766:Phosphorylation; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D005938:Glucocorticoids; D007093:Imidazoles; D008024:Ligands; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D012694:Serine; D003907:Dexamethasone; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580