Phosphorylation of Farnesoid X Receptor by Protein Kinase C Promotes Its Transcriptional Activity
Open Access
- 1 November 2008
- journal article
- research article
- Published by The Endocrine Society in Molecular Endocrinology
- Vol. 22 (11), 2433-2447
- https://doi.org/10.1210/me.2008-0092
Abstract
The farnesoid X receptor (FXR, NR1H4) belongs to the nuclear receptor superfamily and is activated by bile acids such as chenodeoxycholic acid, or synthetic ligands such as GW4064. FXR is implicated in the regulation of bile acid, lipid, and carbohydrate metabolism. Posttranslational modifications regulating its activity have not been investigated yet. Here, we demonstrate that calcium-dependent protein kinase C (PKC) inhibition impairs ligand-mediated regulation of FXR target genes. Moreover, in a transactivation assay, we show that FXR transcriptional activity is modulated by PKC. Furthermore, phorbol 12-myristate 13-acetate , a PKC activator, induces the phosphorylation of endogenous FXR in HepG2 cells and PKCα phosphorylates in vitro FXR in its DNA-binding domain on S135 and S154. Mutation of S135 and S154 to alanine residues reduces in cell FXR phosphorylation. In contrast to wild-type FXR, mutant FXRS135AS154A displays an impaired PKCα-induced transactivation and a decreased ligand-dependent FXR transactivation. Finally, phosphorylation of FXR by PKC promotes the recruitment of peroxisomal proliferator-activated receptor γ coactivator 1α. In conclusion, these findings show that the phosphorylation of FXR induced by PKCα directly modulates the ability of agonists to activate FXR.Keywords
This publication has 67 references indexed in Scilit:
- Atypical Protein Kinase C Regulates Dual Pathways for Degradation of the Oncogenic Coactivator SRC-3/AIB1Molecular Cell, 2008
- The farnesoid X receptor induces fetuin-B gene expression in human hepatocytesBiochemical Journal, 2007
- Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesisProceedings of the National Academy of Sciences of the United States of America, 2007
- Farnesoid X receptor is essential for normal glucose homeostasisJCI Insight, 2006
- Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasisCell Metabolism, 2005
- Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1Biochemical and Biophysical Research Communications, 2005
- Identification of membrane-type receptor for bile acids (M-BAR)Biochemical and Biophysical Research Communications, 2002
- Serine 157, a Retinoic Acid Receptor α Residue Phosphorylated by Protein Kinase C in Vitro, Is Involved in RXR·RARα Heterodimerization and Transcriptional ActivityPublished by Elsevier BV ,1999
- Modulation of protein kinase C by taurolithocholic acid in isolated rat hepatocytesHepatology, 1999
- The effects of bile acids on phospholipase c activity in extracts of normal human colon mucosa and primary colon tumorsMolecular Carcinogenesis, 1994