Ligand-independent phosphorylation of the glucocorticoid receptor integrates cellular stress pathways with nuclear receptor signaling

Mol Cell Biol. 2011 Dec;31(23):4663-75. doi: 10.1128/MCB.05866-11. Epub 2011 Sep 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Amino Acid Sequence
  • Cell Line, Tumor
  • Dexamethasone / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Glucocorticoids / pharmacology
  • Glucocorticoids / physiology
  • Humans
  • Imidazoles / pharmacology
  • Immunoprecipitation
  • Ligands
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Mutation, Missense
  • Phosphorylation
  • Protein Binding
  • Pyridines / pharmacology
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Serine / metabolism
  • Signal Transduction*
  • Stress, Physiological*
  • Transcription, Genetic
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • 14-3-3 Proteins
  • Glucocorticoids
  • Imidazoles
  • Ligands
  • Pyridines
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Glucocorticoid
  • Serine
  • Dexamethasone
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580