A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins.
We have identified a new first step in the hormonal activation of the glucocorticoid receptor (GR). Rather than causing immediate dissociation of the cytoplasmic GR heterocomplex, binding of hormone-induced substitution of one immunophilin (FKBP51) for another (FKBP52), and concomitant recruitment of the transport protein dynein while leaving Hsp90 unchanged. Immunofluorescence and fractionation revealed hormone-induced translocation of the hormone-generated GR-Hsp90-FKBP52-dynein complex from cytoplasm to nucleus, a step that precedes dissociation of the complex within the nucleus and conversion of GR to the DNA-binding form. Taken as a whole, these studies identify immunophilin interchange as the earliest known event in steroid receptor signaling and provide the first evidence of differential roles for FKBP51 and FKBP52 immunophilins in the control of steroid receptor subcellular localization and transport.
Davies
Todd H
TH
Department of Pharmacology, Medical College of Ohio, Toledo, Ohio 43614, USA.
Ning
Yang-Min
YM
Sánchez
Edwin R
ER
D021581:Active Transport, Cell Nucleus; D000818:Animals; D015153:Blotting, Western; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004398:Dyneins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism* / Q000502:physiology; D000099159:Tacrolimus Binding Protein 5
D004398:Dyneins; D018841:HSP90 Heat-Shock Proteins; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C403485:tacrolimus binding protein 4