Glucose elicits serine/threonine kinase VRK1 to phosphorylate nuclear pregnane X receptor as a novel hepatic gluconeogenic signal

Saki Gotoh, Yuu Miyauchi, Rick Moore, Masahiko Negishi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Low glucose stimulated phosphorylation of pregnane X receptor (PXR) at Ser350 in correlation with an increased gluconeogenesis in human hepatoma-derived HepG2 cells. Only glucose, but neither insulin nor glucagon, stimulated this phosphorylation. Here, serine/threonine kinase, vaccinia related kinase 1 (VRK1)-mediated phosphorylation of PXR is now defined as this glucose-elicited novel signal. In low glucose conditions, VRK1 directly phosphorylates PXR at Ser350, enabling PO3-PXR to scaffold protein phosphatase PP2Cα. This PP2Cα dephosphorylates serine/threonine kinase 2 (SGK2) at Thr193. This dephosphorylation dissociates SGK2 from and actives the phosphoenolpyruvate carboxykinase 1 (PCK1) gene as phosphorylated SGK2 binds and represses the gene. Conversely, VRK1 self-represses its activity to phosphorylate PXR through cyclin-dependent kinase 2 (CDK2) in high glucose conditions, resulting in the repression of the PCK1 gene. This PXR phosphorylation was also observed in fasting mouse livers. Thus, the VRK1-CDK2-PXR-PP2Cα-SGK2 pathway can be a novel physiological cell signaling that regulates gluconeogenesis in response to glucose.

Original languageEnglish
Pages (from-to)200-209
Number of pages10
JournalCellular Signalling
Volume40
DOIs
Publication statusPublished - Dec 1 2017
Externally publishedYes

Fingerprint

Vaccinia
Protein-Serine-Threonine Kinases
Phosphotransferases
Glucose
Liver
Phosphorylation
Cyclin-Dependent Kinase 2
Phosphoenolpyruvate
Gluconeogenesis
Genes
Phosphoprotein Phosphatases
Hep G2 Cells
pregnane X receptor
Glucagon
Hepatocellular Carcinoma
Fasting
Insulin

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Glucose elicits serine/threonine kinase VRK1 to phosphorylate nuclear pregnane X receptor as a novel hepatic gluconeogenic signal. / Gotoh, Saki; Miyauchi, Yuu; Moore, Rick; Negishi, Masahiko.

In: Cellular Signalling, Vol. 40, 01.12.2017, p. 200-209.

Research output: Contribution to journalArticle

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