title: Phosphorylation of Farnesoid X Receptor at Serine 154 Links Ligand Activation With Degradation.
abstract: Comparison of 11 human nuclear receptor amino acid sequences revealed a conserved phosphorylation motif within their DNA-binding domains as an intramolecular signal that regulates proteolytic degradation. Nuclear receptors use this signal to either degrade or proscribe degradation through either the proteasome or nonproteasome pathways. A phosphomimetic farnesoid X receptor (FXR) S154D mutant neither bound to nor trans-activated an FXR-response element-driven reporter gene and was rapidly degraded in COS-1 cells. Ectopically expressed FXR had increased Ser154 phosphorylation in COS-1 cells after ligand treatment, and knock-down of the nuclear vaccinia-related kinase 1 (VRK1) greatly reduced this phosphorylation. FXR was phosphorylated at Ser154 in the nucleus of centrilobular hepatocytes only in ligand-treated mice. Thus, FXR Ser154 phosphorylation is a rheostat for activation and subsequent degradation that controls receptor levels and activity.
authors: Pharmacogenetics Section (T.H., S.A., T.S., M.N.), Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; and Laboratory of Metabolism (S.T., F.J.G.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors: Takuyu
authors: T
authors: Hashiguchi
authors: Pharmacogenetics Section (T.H., S.A., T.S., M.N.), Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; and Laboratory of Metabolism (S.T., F.J.G.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors: Shingo
authors: S
authors: Arakawa
authors: Pharmacogenetics Section (T.H., S.A., T.S., M.N.), Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; and Laboratory of Metabolism (S.T., F.J.G.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors: Shogo
authors: S
authors: Takahashi
authors: Pharmacogenetics Section (T.H., S.A., T.S., M.N.), Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; and Laboratory of Metabolism (S.T., F.J.G.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors: Frank J
authors: FJ
authors: Gonzalez
authors: Pharmacogenetics Section (T.H., S.A., T.S., M.N.), Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; and Laboratory of Metabolism (S.T., F.J.G.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors: Tatsuya
authors: T
authors: Sueyoshi
authors: Pharmacogenetics Section (T.H., S.A., T.S., M.N.), Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; and Laboratory of Metabolism (S.T., F.J.G.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors: Masahiko
authors: M
authors: Negishi
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000596:Amino Acids; D004268:DNA-Binding Proteins; D008024:Ligands; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D012694:Serine; D000099150:Receptor, Farnesoid X-Activated