A novel FK506-like binding protein interacts with the glucocorticoid receptor and regulates steroid receptor signaling.
FKBP-like (FKBPL) protein is a novel immunophilin-like protein that plays a role in the cellular stress response. Its three tetratricopeptide repeat motifs are homologous to the heat shock protein 90 interaction sites of other immunophilins that have roles in steroid hormone receptor signaling. In this study, using biomolecular complementation and coimmunoprecipitation techniques, we show that FKBPL also colocalizes and interacts with the components of the heat shock protein 90-glucocorticoid receptor (GR) complex and demonstrate that the PPIase domain of FKBPL is important for the interaction between this complex and the dynein motor protein, dynamitin. Treatment of DU145 cells with the GR ligand, dexamethasone, induced a rapid and coordinated translocation of both GR and FKBPL to the nucleus; this response was perturbed when FKBPL was knocked down with a targeted small interfering RNA. Furthermore, overexpression of FKBPL increased GR protein levels and transactivation of a luciferase reporter gene in response to dexamethasone in DU145 cells. However, these responses were cell line dependent. In summary, these data suggest that FKBPL can be classed as a new member of the FKBP protein family with a role in steroid receptor complexes and signaling.
McKeen
Hayley D
HD
School of Pharmacy, Queen's University, Belfast BT9 7BL, Northern Ireland.
McAlpine
Kerry
K
Valentine
Andrea
A
Quinn
Derek J
DJ
McClelland
Keeva
K
Byrne
Christopher
C
O'Rourke
Martin
M
Young
Sheila
S
Scott
Christopher J
CJ
McCarthy
Helen O
HO
Hirst
David G
DG
Robson
Tracy
T
D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D020104:Immunophilins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D022021:Tacrolimus Binding Proteins; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
C400101:FKBPL protein, human; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins