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Dual Role of Phosphofructokinase-2/Fructose Bisphosphatase-2 in Regulating the Compartmentation and Expression of Glucokinase in Hepatocytes

¹ School of Clinical Medical Sciences, Division of Diabetes, University of Newcastle upon Tyne, Newcastle upon Tyne, U.K
² Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota

Hepatic glucokinase is regulated by a 68-kDa regulatory protein (GKRP) that is both an inhibitor and nuclear receptor for glucokinase. We tested the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) in regulating glucokinase compartmentation in hepatocytes. PFK2 catalyzes formation or degradation of the regulator of glycolysis fructose 2,6-bisphosphate (fructose 2,6-P₂), depending on its phosphorylation state (ser-32), and is also a glucokinase-binding protein. Incubation of hepatocytes at 25 mmol/l glucose causes translocation of glucokinase from the nucleus to the cytoplasm and an increase in fructose 2,6-P₂. Glucagon caused phosphorylation of PFK2-ser-32, lowered the fructose 2,6-P₂ concentration, and inhibited glucose-induced translocation of glucokinase. These effects of glucagon were reversed by expression of a kinase-active PFK2 mutant (S32A/H258A) that overrides the suppression of fructose 2,6-P₂ but not by overexpression of wild-type PFK2. Overexpression of PFK2 potentiated glucokinase expression in hepatocytes transduced with an adenoviral vector–encoding glucokinase by a mechanism that does not involve stabilization of glucokinase protein from degradation. It is concluded that PFK2 has a dual role in regulating glucokinase in hepatocytes: it potentiates glucokinase protein expression by posttranscriptional mechanisms and favors its cytoplasmic compartmention. Thus, it acts in a complementary mechanism to GKRP, which also regulates glucokinase protein expression and compartmentation.

Abbreviations: Ad-LGK, adenovirus-encoding rat liver glucokinase; Ad-PFK2-DM, adenovirus encoding PFK2-DM; Ad-PFK2-WT, adenovirus encoding PFK2-WT; GKRP, glucokinase regulatory protein; fructose 2,6-P₂, fructose-2,6-bisphosphate; MEM, minimum essential medium; PFK2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PFK2-DM, PFK2-S32A/H258A; PFK-WT, wild-type PFK2

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