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Per-Arnt-Sim Kinase Regulates Pancreatic Duodenal Homeobox-1 Protein Stability via Phosphorylation of Glycogen Synthase Kinase 3β in Pancreatic β-Cells
Ist Teil von
The Journal of biological chemistry, 2013-08, Vol.288 (34), p.24825-24833
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2013
Quelle
MEDLINE
Beschreibungen/Notizen
In pancreatic β-cells, glucose induces the binding of the transcription factor pancreatic duodenal homeobox-1 (PDX-1) to the insulin gene promoter to activate insulin gene transcription. At low glucose levels, glycogen synthase kinase 3β (GSK3β) is known to phosphorylate PDX-1 on C-terminal serine residues, which triggers PDX-1 proteasomal degradation. We previously showed that the serine/threonine Per-Arnt-Sim domain-containing kinase (PASK) regulates insulin gene transcription via PDX-1. However, the mechanisms underlying this regulation are unknown. In this study, we aimed to identify the role of PASK in the regulation of PDX-1 phosphorylation, protein expression, and stability in insulin-secreting cells and isolated rodent islets of Langerhans. We observed that glucose induces a decrease in overall PDX-1 serine phosphorylation and that overexpression of WT PASK mimics this effect. In vitro, PASK directly phosphorylates GSK3β on its inactivating phosphorylation site Ser9. Overexpression of a kinase-dead (KD), dominant negative version of PASK blocks glucose-induced Ser9 phosphorylation of GSK3β. Accordingly, GSK3β Ser9 phosphorylation is reduced in islets from pask-null mice. Overexpression of WT PASK or KD GSK3β protects PDX-1 from degradation and results in increased PDX-1 protein abundance. Conversely, overexpression of KD PASK blocks glucose-induction of PDX-1 protein. We conclude that PASK phosphorylates and inactivates GSK3β, thereby preventing PDX-1 serine phosphorylation and alleviating GSK3β-mediated PDX-1 protein degradation in pancreatic β-cells.
Background: The enzyme PASK regulates the expression of PDX-1 and insulin in pancreatic β-cells via unknown mechanisms.
Results: PASK enhances PDX-1 protein stability via phosphorylation of GSK3β on Ser9.
Conclusion: PASK regulates insulin gene expression at least in part through inactivation of GSK3β and stabilization of PDX-1 protein.
Significance: We identified GSK3β as a novel target of PASK in the regulation of pancreatic β-cell function.