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Dual role of phosphofructokinase-2/fructose bisphosphatase-2 in regulating the compartmentation and expression of glucokinase in hepatocytes

Lookup NU author(s): Victoria Payne, Dr Catherine Arden, Professor Loranne Agius

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Abstract

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. © 2005 by the American Diabetes Association.


Publication metadata

Author(s): Payne VA, Arden C, Wu C, Lange AJ, Agius L

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2005

Volume: 54

Issue: 7

Pages: 1949-1957

Print publication date: 01/07/2005

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association

URL: http://dx.doi.org/10.2337/diabetes.54.7.1949

DOI: 10.2337/diabetes.54.7.1949

PubMed id: 15983194


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