Match!

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

Published on Aug 29, 2016in Molecular Endocrinology3.628
· DOI :10.1210/ME.2016-1105
Takuyu Hashiguchi2
Estimated H-index: 2
(NIH: National Institutes of Health),
Shingo Arakawa1
Estimated H-index: 1
(NIH: National Institutes of Health)
+ 3 AuthorsMasahiko Negishi64
Estimated H-index: 64
(NIH: National Institutes of Health)
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.
  • References (26)
  • Citations (11)
📖 Papers frequently viewed together
78 Citations
97 Citations
119 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References26
Newest
#1Takeshi Hori (NIH: National Institutes of Health)H-Index: 2
#2Rick Moore (NIH: National Institutes of Health)H-Index: 14
Last. Masahiko Negishi (NIH: National Institutes of Health)H-Index: 64
view all 3 authors...
Nuclear receptor constitutive androstane receptor (CAR, NR1I3), which regulates hepatic drug and energy metabolisms as well as cell growth and death, is sequestered in the cytoplasm as its inactive form phosphorylated at threonine 38. CAR activators elicit dephosphorylation, and nonphosphorylated CAR translocates into the nucleus to activate its target genes. CAR was previously found to require p38 mitogen-activated protein kinase (MAPK) to transactivate the cytochrome P450 2B (CYP2B) genes. Her...
10 CitationsSource
#1Wen Zhou (UM: University of Miami)H-Index: 14
#2Sathish Srinivasan (UM: University of Miami)H-Index: 3
Last. Joyce M. Slingerland (UM: University of Miami)H-Index: 57
view all 4 authors...
ERα, SKP2 and E2F-1 form a feed forward loop driving late ERα targets and G1 cell cycle progression
18 CitationsSource
#1Hui Yang (UMB: University of Maryland, Baltimore)H-Index: 4
#2Brandy Garzel (UMB: University of Maryland, Baltimore)H-Index: 3
Last. Hongbing Wang (UMB: University of Maryland, Baltimore)H-Index: 21
view all 6 authors...
Metformin is currently the most widely used drug for the treatment of type 2 diabetes. Mechanistically, metformin interacts with many protein kinases and transcription factors that alter the expression of numerous downstream target genes governing lipid metabolism, cell proliferation, and drug metabolism. The constitutive androstane receptor (CAR, NR1i3), a known xenobiotic sensor, has recently been recognized as a novel signaling molecule, in that its activation could be regulated by protein ki...
28 CitationsSource
#1Sawako Shindo (NIH: National Institutes of Health)H-Index: 2
#2Rick Moore (NIH: National Institutes of Health)H-Index: 14
Last. Masahiko Negishi (NIH: National Institutes of Health)H-Index: 64
view all 4 authors...
14 CitationsSource
#1Keisuke Watanabe (Tohoku University)H-Index: 2
#2Kaori Sakurai (Tohoku University)H-Index: 1
Last. Kouichi Yoshinari (Tohoku University)H-Index: 28
view all 5 authors...
Abstract CYP3A4 is a major drug-metabolizing enzyme in humans, whose expression levels show large inter-individual variations and are associated with several factors such as genetic polymorphism, physiological and disease status, diet and xenobiotic exposure. Nuclear receptor pregnane X receptor (PXR) is a key transcription factor for the xenobiotic-mediated transcription of CYP3A4. In this study, we have investigated a possible involvement of liver X receptor α (LXRα), a critical regulator of c...
24 CitationsSource
#1Shingo Mutoh (NIH: National Institutes of Health)H-Index: 3
#2Mack Sobhany (NIH: National Institutes of Health)H-Index: 10
Last. Masahiko Negishi (NIH: National Institutes of Health)H-Index: 64
view all 7 authors...
119 CitationsSource
#1Sawako Shindo (NIH: National Institutes of Health)H-Index: 2
#2Tsutomu Sakuma (NIH: National Institutes of Health)H-Index: 1
Last. James Squires (NIH: National Institutes of Health)H-Index: 1
view all 4 authors...
Estrogen receptor α (ERα) can be phosphorylated at various residues, one of which is serine 212 in the DNA binding domain. The majority of human nuclear receptors conserves, as a motif, this serine residue within their DNA binding domain. Among these nuclear receptors, phosphorylation of the corresponding threonine 38 in the nuclear receptor CAR is essential for determining its activity [9]. Here, we have investigated the role of phosphorylated serine 212 in the regulation of ERα activity by com...
9 CitationsSource
#1Muralidharan Anbalagan (Tulane University)H-Index: 10
#2B. P. Huderson (Tulane University)H-Index: 4
Last. Brian G. Rowan (Tulane University)H-Index: 28
view all 4 authors...
Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor...
133 CitationsSource
The nuclear constitutive active/androstane receptor (CAR) is inactivated and sequestered in the cytoplasm when Thr-38 is phosphorylated. Here, we have demonstrated that activated ERK1/2 interacts with phosphorylated CAR to repress dephosphorylation of Thr-38. The phosphorylation-dependent interaction between CAR and ERK1/2 was examined by co-immunoprecipitation experiments of ectopically expressed FLAG-tagged CAR T38A and CAR T38D mutants with endogenous phospho-ERK1/2 in Huh-7 cells. Phospho-ER...
46 CitationsSource
#1Guodong Li (KU: University of Kansas)H-Index: 13
#2Ann M. Thomas (KU: University of Kansas)H-Index: 13
Last. Grace L. Guo (KU: University of Kansas)H-Index: 28
view all 6 authors...
As a unique nuclear receptor with only ligand-binding but no DNA-binding domain, small heterodimer partner (SHP) interacts with many transcription factors to inhibit their function. However, the regulation of SHP expression is not well understood. SHP is highly expressed in the liver, and previous studies have shown farnesoid X receptor (FXR) highly induces SHP by binding to a FXR response element (FXRRE) in the promoter of the Nr0b2 gene, which encodes SHP. The FXR-SHP pathway is critical in ma...
33 CitationsSource
Cited By11
Newest
#1Kosuke Yokobori (NIH: National Institutes of Health)
#1Kosuke Yokobori (RTP: Research Triangle Park)
Last. Masahiko Negishi (RTP: Research Triangle Park)H-Index: 14
view all 4 authors...
Vaccinia-related kinase 1 (VRK1) is a chromatin-associated Ser-Thr kinase that regulates numerous down-stream factors including DNA repair as well as stress factors c-Jun and p53. Both c-Jun and p53 are phosphorylated at Ser63 and Thr18, respectively, in response to low glucose (40 mg/dL of medium) but not high glucose (140 mg/dL of medium) in human hepatoma-derived Huh-7 cells. Here, we have determined the molecular mechanism by which VRK1 phosphorylates these residues in response to glucose in...
Source
#1Muluneh Fashe (NIH: National Institutes of Health)H-Index: 4
#2Takuyu Hashiguchi (NIH: National Institutes of Health)H-Index: 2
Last. Tatsuya SueyoshiH-Index: 3
view all 4 authors...
We have previously shown that the RORα phosphorylation plays a pivotal role in Sult1e1 gene regulation within mouse liver. Here, we found serine 100 phosphorylated RORα orchestrates CAR and HNF4α to induce CYP2B6 by phenobarbital (PB) in human primary hepatocytes (HPH). RORα knockdown using small interfering RNAs (siRNAs) suppressed CYP2B6 mRNAs in HPH, while transient expression of RORα in COS-1 cells activated CYP2B6 promoter activity in reporter assays. Through chromatin immunoprecipitation (...
Source
#1Elena Martín-Doncel (University of Salamanca)H-Index: 3
#2Ana M. Rojas (CSIC: Spanish National Research Council)H-Index: 22
Last. Pedro A. Lazo (University of Salamanca)H-Index: 37
view all 4 authors...
Very rare polymorphisms in the human VRK1 (vaccinia-related kinase 1) gene have been identified in complex neuromotor phenotypes associated to spinal muscular atrophy (SMA), pontocerebellar hypoplasia (PCH), microcephaly, amyotrophic lateral sclerosis (ALS) and distal motor neuron dysfunctions. The mechanisms by which these VRK1 variant proteins contribute to the pathogenesis of these neurological syndromes are unknown. The syndromes are manifested when both of these rare VRK1 polymorphic allele...
4 CitationsSource
#1Tatsuya Sueyoshi (NIH: National Institutes of Health)H-Index: 33
#2Tsutomu Sakuma (NIH: National Institutes of Health)H-Index: 1
Last. Masahiko Negishi (NIH: National Institutes of Health)H-Index: 64
view all 8 authors...
Retinoid X receptor α (RXRα) has a conserved phosphorylation motif at threonine 162 (humans) and threonine 167 (mice) within the DNA-binding domain. Here we have generated RXRα knock-in mice (RxrαT167A) bearing a single mutation of Thr 167 to alanine and examined the roles of Thr 167 in the regulation of energy metabolism within adipose, muscle, and liver tissues. RxrαT167A mice exhibited down-regulation of metabolic pathways converting glucose to fatty acids, such as acetyl-CoA carboxylase in t...
1 CitationsSource
#1Vittoria Massafra (UU: Utrecht University)H-Index: 5
#2Roberto PellicciariH-Index: 55
Last. Saskia W.C. van Mil (UU: Utrecht University)H-Index: 22
view all 4 authors...
Abstract Bile acids are amphipathic molecules that were previously known to serve as fat solubilizers in the intestine in postprandial conditions. In the last two decades, bile acids have been recognized as signaling molecules regulating energy metabolism pathways via, amongst others, the farnesoid X receptor (FXR). Upon bile acid activation, FXR controls expression of genes involved in bile acid, lipid, glucose and amino acid metabolism. In addition, FXR activation has been shown to limit the i...
22 CitationsSource
#1Muluneh Fashe (NIH: National Institutes of Health)H-Index: 4
#2Takuyu Hashiguchi (NIH: National Institutes of Health)H-Index: 2
Last. Masahiko Negishi (NIH: National Institutes of Health)H-Index: 64
view all 5 authors...
: The estrogen sulfotransferase SULT1E1 sulfates and inactivates estrogen, which is reactivated via desulfation by steroid sulfatase, thus regulating estrogen homeostasis. Phenobarbital (PB), a clinical sedative, activates Sult1e1 gene transcription in mouse livers. Here, the molecular mechanism by which the nuclear receptors CAR, which is targeted by PB, and RORα communicate through phosphorylation to regulate Sult1e1 activation has been studied. RORα, a basal activity repressor of the Sult1e1 ...
2 CitationsSource
#1Ignacio Campillo-Marcos (University of Salamanca)H-Index: 3
#2Pedro A. Lazo (University of Salamanca)H-Index: 37
DNA damage causes a local distortion of chromatin that triggers the sequential processes that participate in specific DNA repair mechanisms. This initiation of the repair response requires the involvement of a protein whose activity can be regulated by histones. Kinases are candidates to regulate and coordinate the connection between a locally altered chromatin and the response initiating signals that lead to identification of the type of lesion and the sequential steps required in specific DNA ...
9 CitationsSource
#1Hagit Shapiro (Weizmann Institute of Science)H-Index: 19
#2Aleksandra A. Kolodziejczyk (Weizmann Institute of Science)H-Index: 16
Last. Eran Elinav (Weizmann Institute of Science)H-Index: 58
view all 4 authors...
: Bile acids (BAs) are cholesterol-derived metabolites that facilitate the intestinal absorption and transport of dietary lipids. Recently, BAs also emerged as pivotal signaling molecules controlling glucose, lipid, and energy metabolism by binding to the nuclear hormone farnesoid X receptor (FXR) and Takeda G protein receptor 5 (TGR5) in multiple organs, leading to regulation of intestinal incretin secretion, hepatic gluconeogenesis, glycogen synthesis, energy expenditure, inflammation, and gut...
70 CitationsSource
#1Ryota Shizu (NIH: National Institutes of Health)H-Index: 6
#2Makoto Osabe (NIH: National Institutes of Health)H-Index: 9
Last. Masahiko Negishi (NIH: National Institutes of Health)H-Index: 64
view all 6 authors...
: The nuclear receptor CAR (NR1I3) regulates hepatic drug and energy metabolism as well as cell fate. Its activation can be a critical factor in drug-induced toxicity and the development of diseases, including diabetes and tumors. CAR inactivates its constitutive activity by phosphorylation at threonine 38. Utilizing receptor for protein kinase 1 (RACK1) as the regulatory subunit, protein phosphatase 2A (PP2A) dephosphorylates threonine 38 to activate CAR. Here we demonstrate that CAR undergoes ...
16 CitationsSource
#1Oscar Chávez-Talavera (Pasteur Institute)H-Index: 4
#2Anne Tailleux (Pasteur Institute)H-Index: 33
Last. Bart Staels (Pasteur Institute)H-Index: 136
view all 4 authors...
Bile acids are signaling molecules that coordinately regulate metabolism and inflammation via the nuclear farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in bile acid, lipid and carbohydrate metabolism, energy expenditure, and inflammation by acting predominantly in enterohepatic tissues, but also in peripheral organs. In this review, w...
160 CitationsSource