| First Author | Stechschulte LA | Year | 2014 |
| Journal | Mol Endocrinol | Volume | 28 |
| Issue | 8 | Pages | 1254-64 |
| PubMed ID | 24933248 | Mgi Jnum | J:216240 |
| Mgi Id | MGI:5608547 | Doi | 10.1210/me.2014-1023 |
| Citation | Stechschulte LA, et al. (2014) FKBP51 reciprocally regulates GRalpha and PPARgamma activation via the Akt-p38 pathway. Mol Endocrinol 28(8):1254-64 |
| abstractText | FK506-binding protein 51 (FKBP51) is a negative regulator of glucocorticoid receptor-alpha (GRalpha), although the mechanism is unknown. We show here that FKBP51 is also a chaperone to peroxisome proliferator-activated receptor-gamma (PPARgamma), which is essential for activity, and uncover the mechanism underlying this differential regulation. In COS-7 cells, FKBP51 overexpression reduced GRalpha activity at a glucocorticoid response element-luciferase reporter, while increasing PPARgamma activity at a peroxisome proliferator response element reporter. Conversely, FKBP51-deficient (knockout) (51KO) mouse embryonic fibroblasts (MEFs) showed elevated GRalpha but reduced PPARgamma activities compared with those in wild-type MEFs. Phosphorylation is known to exert a similar pattern of reciprocal modulation of GRalpha and PPARgamma. Knockdown of FKBP51 in 3T3-L1 preadipocytes increased phosphorylation of PPARgamma at serine 112, a phospho-residue that inhibits activity. In 51KO cells, elevated phosphorylation of GRalpha 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 GRalpha and PPARgamma, were seen in 51KO MEFs, causing activation and inhibition, respectively. Inactivation of p38 with PD169316 reversed the effects of FKBP51 deficiency on GRalpha and PPARgamma activities and reduced PPARgamma phosphorylation. Last, loss of FKBP51 caused a shift of PPARgamma from cytoplasm to nucleus, as previously shown for GRalpha. A model is proposed in which FKBP51 loss reciprocally regulates GRalpha and PPARgamma via 2 complementary mechanisms: activation of Akt-p38-mediated phosphorylation and redistribution of the receptors to the nucleus for direct targeting by p38. |
