title: FKBP51 reciprocally regulates GRα and PPARγ activation via the Akt-p38 pathway.
abstract: FK506-binding protein 51 (FKBP51) is a negative regulator of glucocorticoid receptor-α (GRα), although the mechanism is unknown. We show here that FKBP51 is also a chaperone to peroxisome proliferator-activated receptor-γ (PPARγ), which is essential for activity, and uncover the mechanism underlying this differential regulation. In COS-7 cells, FKBP51 overexpression reduced GRα activity at a glucocorticoid response element-luciferase reporter, while increasing PPARγ activity at a peroxisome proliferator response element reporter. Conversely, FKBP51-deficient (knockout) (51KO) mouse embryonic fibroblasts (MEFs) showed elevated GRα but reduced PPARγ activities compared with those in wild-type MEFs. Phosphorylation is known to exert a similar pattern of reciprocal modulation of GRα and PPARγ. Knockdown of FKBP51 in 3T3-L1 preadipocytes increased phosphorylation of PPARγ at serine 112, a phospho-residue that inhibits activity. In 51KO cells, elevated phosphorylation of GRα at serines 220 and 234, phospho-residues that promote activity, was observed. Because FKBP51 is an essential chaperone to the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase, Akt signaling was investigated. Elevated Akt activation and increased activation of p38 kinase, a downstream target of Akt that phosphorylates GRα and PPARγ, were seen in 51KO MEFs, causing activation and inhibition, respectively. Inactivation of p38 with PD169316 reversed the effects of FKBP51 deficiency on GRα and PPARγ activities and reduced PPARγ phosphorylation. Last, loss of FKBP51 caused a shift of PPARγ from cytoplasm to nucleus, as previously shown for GRα. A model is proposed in which FKBP51 loss reciprocally regulates GRα and PPARγ via 2 complementary mechanisms: activation of Akt-p38-mediated phosphorylation and redistribution of the receptors to the nucleus for direct targeting by p38.
authors.affiliation: Center for Diabetes and Endocrine Research (L.A.S., T.D.H., S.S.G., S.M.N., E.R.S.), Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614; and Herman B. Wells Center for Pediatric Research (W.S.), Section of Pediatric Cardiology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Lance A
authors.initials: LA
authors.lastname: Stechschulte
authors.forename: Terry D
authors.initials: TD
authors.lastname: Hinds
authors.forename: Simona S
authors.initials: SS
authors.lastname: Ghanem
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Sanchez
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D007328:Insulin / Q000502:physiology; D020935:MAP Kinase Signaling System; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000502:physiology*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D007328:Insulin; D047495:PPAR gamma; D051057:Proto-Oncogene Proteins c-akt; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C411470:glucocorticoid receptor alpha