Modulation of glucocorticoid receptor function via phosphorylation

Ann N Y Acad Sci. 2004 Jun;1024:86-101. doi: 10.1196/annals.1321.007.


The glucocorticoid receptor (GR) is phosphorylated at multiple serine residues in a hormone-dependent manner. It has been suggested that GR phosphorylation affects turnover, subcellular trafficking, or the transcriptional regulatory functions of the receptor, yet the contribution of individual GR phosphorylation sites to the modulation of GR activity remains enigmatic. This review critically evaluates the literature on GR phosphorylation and presents more recent work on the mechanism of GR phosphorylation from studies using antibodies that recognize GR only when it is phosphorylated. In addition, we present support for the notion that GR phosphorylation modifies protein-protein interactions, which can stabilize the hypophosphorylated form of the receptor in the absence of ligand, as well as facilitate transcriptional activation by the hyperphosphorylation of GR via cofactor recruitment upon ligand binding. Finally, we propose that GR phosphorylation also participates in the nongenomic activation of cytoplasmic signaling pathways evoked by GR. Thus, GR phosphorylation is a versatile mechanism for modulating and integrating multiple receptor functions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27
  • Humans
  • Mice
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism
  • Rats
  • Receptors, Glucocorticoid / chemistry
  • Receptors, Glucocorticoid / metabolism*
  • Transcriptional Activation
  • Tumor Suppressor Proteins / metabolism


  • Cdkn1b protein, mouse
  • Cdkn1b protein, rat
  • Cell Cycle Proteins
  • Receptors, Glucocorticoid
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Protein Kinases
  • Phosphoprotein Phosphatases