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Phosphorylation of farnesoid X receptor at serine 154 links ligand activation with degradation

Molecular Endocrinology, ISSN: 1944-9917, Vol: 30, Issue: 10, Page: 1070-1080
2016
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Article Description

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.

Bibliographic Details

Hashiguchi, Takuyu; Arakawa, Shingo; Takahashi, Shogo; Gonzalez, Frank J; Sueyoshi, Tatsuya; Negishi, Masahiko

The Endocrine Society

Biochemistry, Genetics and Molecular Biology

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