Rho family Guanine nucleotide exchange factor Brx couples extracellular signals to the glucocorticoid signaling system

J Biol Chem. 2006 Apr 7;281(14):9118-26. doi: 10.1074/jbc.M509339200. Epub 2006 Feb 8.


Glucocorticoids regulate many crucial biologic functions through their cytoplasmic/nuclear glucocorticoid receptors (GR). Excess, deficiency, or alteration in tissue sensitivity to glucocorticoids has been associated with major causes of human morbidity and mortality. Brx, a cytoplasmic Rho family guanine nucleotide exchange factor, binds to and influences the activity of several nuclear hormone receptors. We examined the functional and molecular interactions between GR and Brx. The glucocorticoid sensitivity of lymphocytes obtained from mice haplo-insufficient for Brx was significantly decreased. Conversely, GR-mediated transcriptional activity of a glucocorticoid response element (GRE)-mediated glucocorticoid-responsive promoter was enhanced by Brx in a guanine nucleotide exchange factor domain-dependent fashion. Brx interacted with GR, forming a ternary complex with RhoA. In a chromatin immunoprecipitation assay, Brx and RhoA were co-precipitated with GREs only in the presence of ligand-activated GR. Extracellularly administered lysophosphatidic acid, which activates its signaling cascade through a specific membrane GTP-binding protein (G-protein)-coupled receptor in a G-protein alpha(13)-, Brx-, and RhoA-dependent fashion, enhanced GR transcriptional activity, whereas depletion of endogenous Brx attenuated this effect. These findings suggest that glucocorticoid signaling and, hence, the tissue sensitivity to glucocorticoids, may be coupled to extracellular signals via Brx and small G-proteins. Nuclear Brx might act as a local GRE-GR-transcriptosome activator by mediating the effect of small G-proteins on glucocorticoid-regulated genes.

Publication types

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

MeSH terms

  • A Kinase Anchor Proteins
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Chlorocebus aethiops
  • Glucocorticoids / metabolism*
  • Guanine Nucleotide Exchange Factors / physiology*
  • HeLa Cells
  • Humans
  • Kidney / cytology
  • Lymphocytes / physiology
  • Mice
  • Minor Histocompatibility Antigens
  • Monomeric GTP-Binding Proteins / metabolism
  • Plasmids
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Receptors, Glucocorticoid / biosynthesis*
  • Receptors, Glucocorticoid / physiology*
  • Signal Transduction*
  • Transcription, Genetic
  • Transfection
  • rho GTP-Binding Proteins / metabolism


  • A Kinase Anchor Proteins
  • AKAP13 protein, human
  • Adaptor Proteins, Signal Transducing
  • Glucocorticoids
  • Guanine Nucleotide Exchange Factors
  • Minor Histocompatibility Antigens
  • Proto-Oncogene Proteins
  • Receptors, Glucocorticoid
  • Monomeric GTP-Binding Proteins
  • rho GTP-Binding Proteins