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Phosphorylation of Farnesoid X Receptor at Serine 154 Links Ligand Activation With Degradation.

Authors
  • Hashiguchi, Takuyu1
  • Arakawa, Shingo1
  • Takahashi, Shogo1
  • Gonzalez, Frank J1
  • Sueyoshi, Tatsuya1
  • Negishi, Masahiko1
  • 1 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.
Type
Published Article
Journal
Molecular Endocrinology
Publisher
The Endocrine Society
Publication Date
Oct 01, 2016
Volume
30
Issue
10
Pages
1070–1080
Identifiers
PMID: 27571290
Source
Medline
License
Unknown

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.

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