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Gene Review

GCKR  -  glucokinase (hexokinase 4) regulator

Homo sapiens

Synonyms: FGQTL5, GKRP, Glucokinase regulator, Glucokinase regulatory protein
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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


Anatomical context of GCKR


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


Analytical, diagnostic and therapeutic context of GCKR


  1. Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young. Gloyn, A.L., Odili, S., Zelent, D., Buettger, C., Castleden, H.A., Steele, A.M., Stride, A., Shiota, C., Magnuson, M.A., Lorini, R., d'Annunzio, G., Stanley, C.A., Kwagh, J., van Schaftingen, E., Veiga-da-Cunha, M., Barbetti, F., Dunten, P., Han, Y., Grimsby, J., Taub, R., Ellard, S., Hattersley, A.T., Matschinsky, F.M. J. Biol. Chem. (2005) [Pubmed]
  2. Mutations in the glucokinase regulatory protein gene in 2p23 in obese French caucasians. Veiga-da-Cunha, M., Delplanque, J., Gillain, A., Bonthron, D.T., Boutin, P., Van Schaftingen, E., Froguel, P. Diabetologia (2003) [Pubmed]
  3. Biochemical basis of glucokinase activation and the regulation by glucokinase regulatory protein in naturally occurring mutations. Heredia, V.V., Carlson, T.J., Garcia, E., Sun, S. J. Biol. Chem. (2006) [Pubmed]
  4. The mitogen-activated protein kinase kinase kinase kinase GCKR positively regulates canonical and noncanonical Wnt signaling in B lymphocytes. Shi, C.S., Huang, N.N., Harrison, K., Han, S.B., Kehrl, J.H. Mol. Cell. Biol. (2006) [Pubmed]
  5. An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism. Futamura, M., Hosaka, H., Kadotani, A., Shimazaki, H., Sasaki, K., Ohyama, S., Nishimura, T., Eiki, J., Nagata, Y. J. Biol. Chem. (2006) [Pubmed]
  6. From clinicogenetic studies of maturity-onset diabetes of the young to unraveling complex mechanisms of glucokinase regulation. Sagen, J.V., Odili, S., Bjørkhaug, L., Zelent, D., Buettger, C., Kwagh, J., Stanley, C., Dahl-Jørgensen, K., de Beaufort, C., Bell, G.I., Han, Y., Grimsby, J., Taub, R., Molven, A., Søvik, O., Njølstad, P.R., Matschinsky, F.M. Diabetes (2006) [Pubmed]
  7. Organization of the human glucokinase regulator gene GCKR. Hayward, B.E., Dunlop, N., Intody, S., Leek, J.P., Markham, A.F., Warner, J.P., Bonthron, D.T. Genomics (1998) [Pubmed]
  8. Co-localization of the ketohexokinase and glucokinase regulator genes to a 500-kb region of chromosome 2p23. Hayward, B.E., Fantes, J.A., Warner, J.P., Intody, S., Leek, J.P., Markham, A.F., Bonthron, D.T. Mamm. Genome (1996) [Pubmed]
  9. Glucokinase regulatory protein may interact with glucokinase in the hepatocyte nucleus. Brown, K.S., Kalinowski, S.S., Megill, J.R., Durham, S.K., Mookhtiar, K.A. Diabetes (1997) [Pubmed]
  10. Metabolic regulation, activity state, and intracellular binding of glucokinase in insulin-secreting cells. Tiedge, M., Steffeck, H., Elsner, M., Lenzen, S. Diabetes (1999) [Pubmed]
  11. Evidence that glucokinase regulatory protein is expressed and interacts with glucokinase in rat brain. Alvarez, E., Roncero, I., Chowen, J.A., Vázquez, P., Blázquez, E. J. Neurochem. (2002) [Pubmed]
  12. Novel polymorphisms in the GCKR gene and their influence on glucose and insulin levels in a Danish twin population. Køster, B., Fenger, M., Poulsen, P., Vaag, A., Bentzen, J. Diabet. Med. (2005) [Pubmed]
  13. Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis. Davis, E.A., Cuesta-Muñoz, A., Raoul, M., Buettger, C., Sweet, I., Moates, M., Magnuson, M.A., Matschinsky, F.M. Diabetologia (1999) [Pubmed]
  14. The GCKR rs780094 polymorphism is associated with elevated fasting serum triacylglycerol, reduced fasting and OGTT-related insulinaemia, and reduced risk of type 2 diabetes. Sparsø, T., Andersen, G., Nielsen, T., Burgdorf, K.S., Gjesing, A.P., Nielsen, A.L., Albrechtsen, A., Rasmussen, S.S., Jørgensen, T., Borch-Johnsen, K., Sandbaek, A., Lauritzen, T., Madsbad, S., Hansen, T., Pedersen, O. Diabetologia (2008) [Pubmed]
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