Proteomics

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DYRK1B phosphorylates FOXO1 to promote hepatic gluconeogenesis


ABSTRACT: Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), a member of the CMGC group of kinase, is associated with metabolic syndrome. However, the molecular mechanisms involved remain elusive. In this study, we demonstrate that Dyrk1b expression is induced in liver by fasting and in diabetic mice. Using both in vivo and in vitro studies, we show that DYRK1B promotes hepatic gluconeogenesis and glucose intolerance. Liver-specific Dyrk1b conditional knockout mice were protected from diet-induced hyperglycemia. Mechanistically, DYRK1B interacts with and phosphorylates FOXO1, primarily at Thr467/Ser468, which is essential for its nuclear localization. Additionally, DYRK1B inhibits AKT mediated FOXO1 phosphorylation at Thr24 and Ser256, thereby enhancing its nuclear retention. DYRK1B mediated phosphorylation enhances the expression of gluconeogenic genes and promotes gluconeogenesis. Further, a pharmacological inhibitor of DYRK1B significantly reduced blood glucose levels in diabetic mice. Collectively, these findings offer new insights into DYRK1B’s role in the glucose metabolism and identify it as a new therapeutic target for treating diabetes.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Cell Culture

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Shanshan Li  

LAB HEAD: Cheng Hu

PROVIDER: PXD052214 | Pride | 2025-05-07

REPOSITORIES: Pride

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Publications

DYRK1B phosphorylates FOXO1 to promote hepatic gluconeogenesis.

Li Shanshan S   Huang Kai K   Xu Chu C   Zhang Hong H   Wang Xiao X   Zhang Rong R   Lu Yan Y   Mohan Man M   Hu Cheng C  

Nucleic acids research 20250401 8


Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B), a member of the CMGC group of kinases, is linked to metabolic syndrome, though the underlying molecular mechanisms remain unclear. In this study, we show that Dyrk1b expression is induced in the liver by fasting and in diabetic mice. Through both in vivo and in vitro experiments, we demonstrate that DYRK1B promotes hepatic gluconeogenesis and glucose intolerance. Liver-specific Dyrk1b conditional knockout mice were protected  ...[more]

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