Glucokinase regulatory protein

glucokinase (hexokinase 4) regulator
Identifiers
Symbol GCKR
Entrez 2646
HUGO 4196
OMIM 600842
RefSeq NM_001486
UniProt Q14397
Other data
Locus Chr. 2 p23

The glucokinase regulatory protein (GKRP) also known as glucokinase (hexokinase 4) regulator (GCKR) is a protein produced in hepatocytes (liver cells). GKRP binds and moves glucokinase (GK), thereby controlling both activity and intracellular location[1][2] of this key enzyme of glucose metabolism.[3]

GKRP is a 68 kD protein of 626 amino acids. It is coded for by a 19 exon gene, GCKR, on the short arm of chromosome 2 (2p23). GKRP was discovered by Emile van Schaftingen and reported in 1989[4]

Physiological function

Glucokinase (GK) in liver cells phosphorylates glucose, preparing it for incorporation into glycogen. During periods of ample glucose supply, most GK activity can be found in the peripheral cytoplasm where glycogen synthesis is occurring.[5] As the glucose supply declines during periods of fasting, GK activity in the cytoplasm diminishes. GKRP participates in this modulation of GK activity and location by binding free cytoplasmic GK as glucose levels decline, and moving it into the nucleus, where it is held in reserve in an inactive form.[6] As glucose and insulin levels rise, as during digestion of a meal, GK is released from GKRP and moves back to the cytoplasm, where much of it associates with the bifunctional enzyme.[7]

In hepatocytes of various mammals, GKRP has always been found in molar excess of the amount of GK, but the GKRP:GK ratio varies according to diet, insulin sufficiency, and other factors. Free GKRP shuttles between the nucleus and the cytoplasm. It may be attached to the microfilament cytoskeleton.[8]

GKRP competes with glucose to bind with GK, but inactivates it when bound. In conditions of low glucose, GKRP then pulls the GK into the nucleus. Rising amounts of glucose coming into the hepatocyte prompt the GKRP to rapidly release GK to return to the cytoplasm.

GKRP itself is subject to modulation. Fructose and sorbitol can both be converted to fructose-1-phosphate, which inhibits GKRP and frees GK.[1] Fructose 6-phosphate binds to the same site of GKRP, but enhances the ability of GKRP to bind and inactivate GK. In contrast, phosphorylation of GKRP by AMP-activated protein kinase, induced by elevated levels of AMP, reduces its capacity to inactivate GK.[9]

Presence of GKRP in other organs

A presence and role of GKRP in other organs and tissues beyond the liver remains uncertain. Some researchers have finding small amounts of GKRP, or at least RNA coding for it, in small amounts in certain rat lung cells, in pancreatic islet cells, and in periventricular neurons of the hypothalamus in rats,[10] but physiological function and significance in these organs are unknown.

Species differences

GKRP was originally discovered in rat liver. GKRP was found to serve a similar function in livers of mice and humans as well as other animals.[11] Cats are unusual in lacking GK activity, and have also been found to lack GKRP, though the genes for both GK and GKRP can be identified in the feline genome.[12]

Clinical significance

Many mutant forms of human GK are associated with impaired or amplified insulin secretion or action, resulting in higher or lower blood glucose levels, and either diabetes (MODY2) or hyperinsulinemic hypoglycemia, respectively. Some of these variants have altered interaction with GKRP, which may contribute to the hyperglycemia.[13][14][15][16]

The glucokinase of "knockout mice" who lack GKRP is entirely found in the cytoplasm. They do not respond rapidly to glucose, exhibiting impaired glucose tolerance.[17] Mutations of the GKRP gene (GCKR) in humans have been sought as possible causes of monogenic diabetes (MODY), but no examples have yet been discovered. However, variant forms of GCKR have been found to be associated with small differences in levels of glucose, insulin, triglycerides, C-reactive protein, and higher or lower risks for type 2 diabetes mellitus.[18][19][20][21]

Activators of GK are being investigated as possible medicines for type 2 diabetes. One of the mechanisms of activation may be protection from binding by GKRP.[22]

References

  1. 1 2 Van Schaftingen E (September 1994). "Short-term regulation of glucokinase". Diabetologia. 37 Suppl 2: S43–7. doi:10.1007/bf00400825. PMID 7821739.
  2. ↑ de la Iglesia N, Veiga-da-Cunha M, Van Schaftingen E, Guinovart JJ, Ferrer JC; Veiga-Da-Cunha; Van Schaftingen; Guinovart; Ferrer (August 1999). "Glucokinase regulatory protein is essential for the proper subcellular localisation of liver glucokinase". FEBS Lett. 456 (2): 332–8. doi:10.1016/S0014-5793(99)00971-0. PMID 10456334.
  3. ↑ Iynedjian PB (January 2009). "Molecular physiology of mammalian glucokinase". Cell. Mol. Life Sci. 66 (1): 27–42. doi:10.1007/s00018-008-8322-9. PMC 2780631. PMID 18726182.
  4. ↑ Van Schaftingen E (January 1989). "A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose 1-phosphate". Eur. J. Biochem. 179 (1): 179–84. doi:10.1111/j.1432-1033.1989.tb14538.x. PMID 2917560.
  5. ↑ Jetton TL, Shiota M, Knobel SM, Piston DW, Cherrington AD, Magnuson MA; Shiota; Knobel; Piston; Cherrington; Magnuson (2001). "Substrate-induced nuclear export and peripheral compartmentalization of hepatic glucokinase correlates with glycogen deposition". Int. J. Exp. Diabetes Res. 2 (3): 173–86. doi:10.1155/EDR.2001.173. PMC 2478546. PMID 12369705.
  6. ↑ Shiota C, Coffey J, Grimsby J, Grippo JF, Magnuson MA; Coffey; Grimsby; Grippo; Magnuson (December 1999). "Nuclear import of hepatic glucokinase depends upon glucokinase regulatory protein, whereas export is due to a nuclear export signal sequence in glucokinase". J. Biol. Chem. 274 (52): 37125–30. doi:10.1074/jbc.274.52.37125. PMID 10601273.
  7. ↑ Payne VA, Arden C, Wu C, Lange AJ, Agius L; Arden; Wu; Lange; Agius (July 2005). "Dual role of phosphofructokinase-2/fructose bisphosphatase-2 in regulating the compartmentation and expression of glucokinase in hepatocytes". Diabetes 54 (7): 1949–57. doi:10.2337/diabetes.54.7.1949. PMID 15983194.
  8. ↑ van Schaftingen, E.F., and Veiga da Cunha, M., (2004). "Discovery and role of glucokinase regulatory protein". In M. Matschinsky. in Glucokinase And Glycemic Disease: From Basics to Novel Therapeutics (Frontiers in Diabetes). S. Karger AG (Switzerland). pp. 197–307. ISBN 3-8055-7744-3.
  9. ↑ Mukhtar MH, Payne VA, Arden C; et al. (March 2008). "Inhibition of glucokinase translocation by AMP-activated protein kinase is associated with phosphorylation of both GKRP and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase". Am. J. Physiol. Regul. Integr. Comp. Physiol. 294 (3): R766–74. doi:10.1152/ajpregu.00593.2007. PMID 18199594.
  10. ↑ Alvarez E, Roncero I, Chowen JA, Vázquez P, Blázquez E; Roncero; Chowen; Vázquez; Blázquez (January 2002). "Evidence that glucokinase regulatory protein is expressed and interacts with glucokinase in rat brain". J. Neurochem. 80 (1): 45–53. doi:10.1046/j.0022-3042.2001.00677.x. PMID 11796742.
  11. ↑ Polakof S, Míguez JM, Soengas JL; Míguez; Soengas (February 2009). "A hepatic protein modulates glucokinase activity in fish and avian liver: a comparative study". J. Comp. Physiol. B, Biochem. Syst. Environ. Physiol. 179 (5): 643–52. doi:10.1007/s00360-009-0346-4. PMID 19247671.
  12. ↑ Hiskett EK, Suwitheechon OU, Lindbloom-Hawley S, Boyle DL, Schermerhorn T; Suwitheechon; Lindbloom-Hawley; Boyle; Schermerhorn (March 2009). "Lack of glucokinase regulatory protein expression may contribute to low glucokinase activity in feline liver". Vet. Res. Commun. 33 (3): 227–40. doi:10.1007/s11259-008-9171-6. PMID 18780155.
  13. ↑ Arden C, Trainer A, de la Iglesia N; et al. (July 2007). "Cell biology assessment of glucokinase mutations V62M and G72R in pancreatic beta-cells: evidence for cellular instability of catalytic activity". Diabetes 56 (7): 1773–82. doi:10.2337/db06-1151. PMID 17389332.
  14. ↑ García-Herrero CM, Galán M, Vincent O; et al. (February 2007). "Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity". Diabetologia 50 (2): 325–33. doi:10.1007/s00125-006-0542-7. PMID 17186219.
  15. ↑ Heredia VV, Carlson TJ, Garcia E, Sun S; Carlson; Garcia; Sun (December 2006). "Biochemical basis of glucokinase activation and the regulation by glucokinase regulatory protein in naturally occurring mutations". J. Biol. Chem. 281 (52): 40201–7. doi:10.1074/jbc.M607987200. PMID 17082186.
  16. ↑ Pino MF, Kim KA, Shelton KD; et al. (May 2007). "Glucokinase thermolability and hepatic regulatory protein binding are essential factors for predicting the blood glucose phenotype of missense mutations". J. Biol. Chem. 282 (18): 13906–16. doi:10.1074/jbc.M610094200. PMID 17353190.
  17. ↑ Grimsby J, Coffey JW, Dvorozniak MT; et al. (March 2000). "Characterization of glucokinase regulatory protein-deficient mice". J. Biol. Chem. 275 (11): 7826–31. doi:10.1074/jbc.275.11.7826. PMID 10713097.
  18. ↑ Køster B, Fenger M, Poulsen P, Vaag A, Bentzen J; Fenger; Poulsen; Vaag; Bentzen (December 2005). "Novel polymorphisms in the GCKR gene and their influence on glucose and insulin levels in a Danish twin population". Diabet. Med. 22 (12): 1677–82. doi:10.1111/j.1464-5491.2005.01700.x. PMID 16401311.
  19. ↑ Orho-Melander M, Melander O, Guiducci C; et al. (November 2008). "Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations". Diabetes 57 (11): 3112–21. doi:10.2337/db08-0516. PMC 2570409. PMID 18678614.
  20. ↑ Tam CH, Ma RC, So WY; et al. (March 2009). "Interaction effect of genetic polymorphisms in glucokinase (GCK) and glucokinase regulatory protein (GCKR) on metabolic traits in healthy Chinese adults and adolescents". Diabetes 58 (3): 765–9. doi:10.2337/db08-1277. PMC 2646078. PMID 19073768.
  21. ↑ Bi, M; Kao, WH; Boerwinkle, E; Hoogeveen, RC; Rasmussen-Torvik, LJ; Astor, BC; North, KE; Coresh, J; Köttgen, A (Jul 22, 2010). "Association of rs780094 in GCKR with metabolic traits and incident diabetes and cardiovascular disease: the ARIC Study". PLOS ONE 5 (7): e11690. doi:10.1371/journal.pone.0011690. PMC 2908550. PMID 20661421.
  22. ↑ Futamura M, Hosaka H, Kadotani A; et al. (December 2006). "An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism". J. Biol. Chem. 281 (49): 37668–74. doi:10.1074/jbc.M605186200. PMID 17028192.
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