Disease relevance of GCKR

• We conclude that V62M may cause hyperglycemia by a complex defect of GCK regulation involving instability in combination with loss of control by a putative endogenous activator and/or GKRP [1].
• Our goal was to investigate whether mutations in the GKRP gene were associated with obesity [2].
• In contrast, moderate activating mutation A456V nearly abolishes the GKRP inhibition (76-fold increase in K(i)) but causes only mild hypoglycemia [3].

High impact information on GCKR

• In addition, we show that GCKR positively affects the beta-catenin pathway in B cells [4].
• Reduction of GCKR expression inhibits Wnt3a-induced phosphorylation of GSK3beta at serine 9 and decreases the accumulation of cytosolic beta-catenin [4].
• On the other hand, compound A did not bind to glucose-unbound GK or GKRP-associated GK [5].
• Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP [5].
• 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 [6].

Biological context of GCKR

• Characterization of P1 and YAC clones containing GCKR shows it to consist of 19 exons spanning 27 kb [7].
• By SSCP screening, a common polymorphic sequence variant has been defined within exon 15 of human GCKR, at nt 1400 of the cDNA [7].
• RT-PCR, RACE, and RNase protection experiments defined a transcriptional start site for GCKR 66 bp upstream of the initiation codon, but provided no evidence for islet cell specific alternative splicing in the rat [7].
• A new microsatellite polymorphism was used to place the GCKR-KHK locus between D2S305 and D2S165 on the genetic map [8].
• Co-localization of the ketohexokinase and glucokinase regulator genes to a 500-kb region of chromosome 2p23 [8].

Anatomical context of GCKR

• Glucokinase regulatory protein may interact with glucokinase in the hepatocyte nucleus [9].
• AIMS/HYPOTHESIS: Glucokinase regulatory protein (GKRP) controls the activity of glucokinase in liver but possibly also in some areas of the central nervous system, suggesting that it could play a role in body mass control [2].
• This hitherto unknown new protein factor may have the function of a glucokinase regulatory protein in the pancreatic beta-cell, which may regulate glucokinase enzyme activity in a glucose-dependent manner [10].
• Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP [5].
• In situ hybridization studies revealed the presence of glucokinase regulatory protein mRNA, the highest number of positive cells being found in the paraventricular nucleus of the hypothalamus [11].

Associations of GCKR with chemical compounds

• The inhibition of GCK by GCKR is relieved by the binding of fructose-1-phosphate (F-1-P) to GCKR [8].
• Mutation Arg518Gln, replacing a conserved residue, led to a marked decrease in the affinity of GKRP for both fructose 6-phosphate and fructose 1-phosphate and to a destabilization of GKRP [2].
• Novel polymorphisms in the GCKR gene and their influence on glucose and insulin levels in a Danish twin population [12].
• 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 [6].
• Inhibition by Stearoyl CoA and glucokinase regulatory protein and thermal stability were assayed for all mutants kinetically similar to wild-type glucokinase [13].
• We also suggest an additive effect of GCK and GCKR risk alleles on [corrected] serum insulin release [14].

Other interactions of GCKR

• V62M GCK does not respond to RO0281675, nor does it respond to the hepatic glucokinase regulatory protein (GKRP) [1].

Analytical, diagnostic and therapeutic context of GCKR

• Northern blot analyses revealed that this binding protein was not identical to the well-known liver glucokinase regulatory protein [10].

References