Nuclear Location of the Regulatory Protein of Glucokinase in Rat Liver and Translocation of the Regulator to the Cytoplasm in Response to High Glucose

Toyoda, Yusuke; Miwa, Ichitomo; Satake, Sayuri; Anai, Motonobu; Oka, Yoshitomo

doi:10.1006/bbrc.1995.2488

Cited by 62 publications

(62 citation statements)

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“…This critical issue will have to be resolved by cell-based approaches. Regulation and nuclear localization of glucokinase in the hepatocytes is achieved by GKRP, a competitive inhibitor with respect to glucose (9,10). We therefore investigated the regulation of the mutants G72R, S263P, and G264S GST-glucokinase by human GKRP.…”

Section: Discussionmentioning

confidence: 99%

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From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation

Sagen

Odili²,

Bjørkhaug³

et al. 2006

Diabetes

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Glucokinase functions as a glucose sensor in pancreatic ␤-cells and regulates hepatic glucose metabolism. A total of 83 probands were referred for a diagnostic screening of mutations in the glucokinase (GCK) gene. We found 11 different mutations (V62A, G72R, L146R, A208T, M210K, Y215X, S263P, E339G, R377C, S453L, and IVS5 ؉ 1G>C) in 14 probands. Functional characterization of recombinant glutathionyl S-transferase-G72R glucokinase showed slightly increased activity, whereas S263P and G264S had near-normal activity. The other point mutations were inactivating. S263P showed marked thermal instability, whereas the stability of G72R and G264S differed only slightly from that of wild type. G72R and M210K did not respond to an allosteric glucokinase activator (GKA) or the hepatic glucokinase regulatory protein (GKRP). Mutation analysis of the role of glycine at position 72 by substituting E, F, K, M, S, or Q showed that G is unique since all these mutants had very low or no activity and were refractory to GKRP and GKA. Structural analysis provided plausible explanations for the drug resistance of G72R and M210K. Our study provides further evidence that protein instability in combination with loss of control by a putative endogenous activator and GKRP could be involved in the development of hyperglycemia in maturity-onset diabetes of the young, type 2. Furthermore, based on data obtained on G264S, we propose that other and still unknown mechanisms participate in the regulation of glucokinase.

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Section: Discussionmentioning

confidence: 99%

“…Reversible nuclear sequestration and inhibition of glucokinase is accomplished by binding to GKRP, whereas free active glucokinase is shuttled back to the cytosol in response to increased glucose levels in blood and in hepatocytes (10). It is still questionable whether GKRP is expressed and functional in pancreatic ␤-cells (11)(12)(13).…”

mentioning

confidence: 99%

From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation

Sagen

Odili²,

Bjørkhaug³

et al. 2006

Diabetes

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show abstract

“…37). 163,164 The normal full-length form of this liver-specific protein is 69 kDa; it regulates both the amount, the activity and the subcellular localization of glucokinase by anchoring it to the nucleus or to mitochondria, [165][166][167][168] and is itself regulated by fructose phosphates. 163 GKRP is thus a binding protein capable of recognizing soluble proteins and carbohydrates as well as cellular structural elements, and a fragment with retained binding capacity may well contribute to the binding properties of sequestering phagophores.…”

Section: Autophagosomal Membrane Proteinsmentioning

confidence: 99%

Proteomic Analysis of Membrane-Associated Proteins from Rat Liver Autophagosomes

Øverbye¹,

Fengsrud²,

Seglen³

2007

Autophagy

143

117

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“…In addition, glucokinase activity depends on the glucokinase regulatory protein (GKRP), which inhibits glucokinase and controls its intracellular distribution (1). At low glucose concentrations, glucokinase is bound to GKRP in the nucleus and translocates to the cytoplasm when glucose concentrations increase (2)(3)(4). The interaction between glucokinase and GKRP is modulated by fructose 6-phosphate (Fru-6-P) and fructose 1-phosphate (Fru-1-P), which promote the association or dissociation of the two proteins, respectively (5).…”

mentioning

confidence: 99%

5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

et al. 2006

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AMP-activated protein kinase (AMPK) controls glucose uptake and glycolysis in muscle. Little is known about its role in liver glucose uptake, which is controlled by glucokinase. We report here that 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR), metformin, and oligomycin activated AMPK and inhibited glucose phosphorylation and glycolysis in rat hepatocytes. In vitro experiments demonstrated that this inhibition was not due to direct phosphorylation of glucokinase or its regulatory protein by AMPK. By contrast, AMPK phosphorylated liver 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase without affecting activity. Inhibitors of the endothelial nitric oxide synthase, stress kinases, and phosphatidylinositol 3-kinase pathways did not counteract the effects of AICAR, metformin, or oligomycin, suggesting that these signaling pathways were not involved. Interestingly, the inhibitory effect on glucose phosphorylation of these well-known AMPK activators persisted in primary cultured hepatocytes from newly engineered mice lacking both liver ␣ 1 and ␣ 2 AMPK catalytic subunits, demonstrating that this effect was clearly not mediated by AMPK. Finally, AICAR, metformin, and oligomycin were found to inhibit the glucose-induced translocation of glucokinase from the nucleus to the cytosol by a mechanism that could be related to the decrease in intracellular ATP concentrations observed in these conditions. Diabetes 55: [865][866][867][868][869][870][871][872][873][874] 2006

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Nuclear Location of the Regulatory Protein of Glucokinase in Rat Liver and Translocation of the Regulator to the Cytoplasm in Response to High Glucose

Cited by 62 publications

References 0 publications

From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation

From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation

Proteomic Analysis of Membrane-Associated Proteins from Rat Liver Autophagosomes

5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase–Independent Effect on Glucokinase Translocation

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