Rho family Guanine nucleotide exchange factor Brx couples extracellular signals to the glucocorticoid signaling system.
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.
Pediatric Endocrinology Section, Reproductive Biology and Medicine Branch, NICHD, National Institutes of Health, Bethesda Maryland 20892, USA. kinot@mail.nih.gov
Tomoshige
T
Kino
Emanuel
E
Souvatzoglou
Evangelia
E
Charmandari
Takamasa
T
Ichijo
Paul
P
Driggers
Chantal
C
Mayers
Anton
A
Alatsatianos
Irini
I
Manoli
Heiner
H
Westphal
George P
GP
Chrousos
James H
JH
Segars
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002522:Chlorocebus aethiops; D005938:Glucocorticoids / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008214:Lymphocytes / Q000502:physiology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D010957:Plasmids; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D048868:Adaptor Proteins, Signal Transducing; D005938:Glucocorticoids; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D011518:Proto-Oncogene Proteins; D011965:Receptors, Glucocorticoid; D020559:Monomeric GTP-Binding Proteins; D020741:rho GTP-Binding Proteins