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

Tomoshige Kino, Emanuel Souvatzoglou, Evangelia Charmandari, Takamasa Ichijo, Paul Driggers, Chantal Mayers, Anton Alatsatianos, Irini Manoli, Heiner Westphal, George P. Chrousos, James H. Segars

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Abstract

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 α13-, 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.

Original languageEnglish
Pages (from-to)9118-9126
Number of pages9
JournalJournal of Biological Chemistry
Volume281
Issue number14
DOIs
Publication statusPublished - 7 Apr 2006

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kino, T., Souvatzoglou, E., Charmandari, E., Ichijo, T., Driggers, P., Mayers, C., Alatsatianos, A., Manoli, I., Westphal, H., Chrousos, G. P., & Segars, J. H. (2006). Rho family guanine nucleotide exchange factor Brx couples extracellular signals to the glucocorticoid signaling system. Journal of Biological Chemistry, 281(14), 9118-9126. https://doi.org/10.1074/jbc.M509339200