Glucokinase regulatory protein explained

glucokinase (hexokinase 4) regulator
Hgncid:4196
Symbol:GCKR
Entrezgene:2646
Omim:600842
Refseq:NM_001486
Uniprot:Q14397
Chromosome:2
Arm:p
Band:23

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 or for glycolysis. 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 has a reduced expression and is entirely found in the cytoplasm. The knockout mice 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]

Notes and References

  1. Van Schaftingen E . Short-term regulation of glucokinase . Diabetologia . 37 . S43-7 . September 1994 . Suppl 2 . 7821739 . 10.1007/bf00400825 . free .
  2. de la Iglesia N, Veiga-da-Cunha M, Van Schaftingen E, Guinovart JJ, Ferrer JC . Glucokinase regulatory protein is essential for the proper subcellular localisation of liver glucokinase . FEBS Letters . 456 . 2 . 332–8 . August 1999 . 10456334 . 10.1016/S0014-5793(99)00971-0 . 11923216 . free .
  3. Iynedjian PB . Molecular physiology of mammalian glucokinase . Cellular and Molecular Life Sciences . 66 . 1 . 27–42 . January 2009 . 18726182 . 2780631 . 10.1007/s00018-008-8322-9 .
  4. Van Schaftingen E . A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose 1-phosphate . European Journal of Biochemistry . 179 . 1 . 179–84 . January 1989 . 2917560 . 10.1111/j.1432-1033.1989.tb14538.x .
  5. Jetton TL, Shiota M, Knobel SM, Piston DW, Cherrington AD, Magnuson MA . Substrate-induced nuclear export and peripheral compartmentalization of hepatic glucokinase correlates with glycogen deposition . International Journal of Experimental Diabetes Research . 2 . 3 . 173–86 . 2001 . 12369705 . 2478546 . 10.1155/EDR.2001.173 . free .
  6. Shiota C, Coffey J, Grimsby J, Grippo JF, Magnuson MA . Nuclear import of hepatic glucokinase depends upon glucokinase regulatory protein, whereas export is due to a nuclear export signal sequence in glucokinase . The Journal of Biological Chemistry . 274 . 52 . 37125–30 . December 1999 . 10601273 . 10.1074/jbc.274.52.37125 . free .
  7. Payne VA, Arden C, Wu C, Lange AJ, Agius L . Dual role of phosphofructokinase-2/fructose bisphosphatase-2 in regulating the compartmentation and expression of glucokinase in hepatocytes . Diabetes . 54 . 7 . 1949–57 . July 2005 . 15983194 . 10.2337/diabetes.54.7.1949 . free .
  8. Book: van Schaftingen EF, Veiga da Cunha M . Matschinsky M . in Glucokinase And Glycemic Disease: From Basics to Novel Therapeutics (Frontiers in Diabetes) . S. Karger AG (Switzerland) . 2004 . 197–307 . Discovery and role of glucokinase regulatory protein . 978-3-8055-7744-1 .
  9. Mukhtar MH, Payne VA, Arden C, Harbottle A, Khan S, Lange AJ, Agius L . 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 . American Journal of Physiology. Regulatory, Integrative and Comparative Physiology . 294 . 3 . R766-74 . March 2008 . 18199594 . 10.1152/ajpregu.00593.2007 .
  10. Alvarez E, Roncero I, Chowen JA, Vázquez P, Blázquez E . Evidence that glucokinase regulatory protein is expressed and interacts with glucokinase in rat brain . Journal of Neurochemistry . 80 . 1 . 45–53 . January 2002 . 11796742 . 10.1046/j.0022-3042.2001.00677.x . 46075589 . free .
  11. Polakof S, Míguez JM, Soengas JL . A hepatic protein modulates glucokinase activity in fish and avian liver: a comparative study . Journal of Comparative Physiology B: Biochemical, Systemic, and Environmental Physiology . 179 . 5 . 643–52 . July 2009 . 19247671 . 10.1007/s00360-009-0346-4 . 38796726 .
  12. Hiskett EK, Suwitheechon OU, Lindbloom-Hawley S, Boyle DL, Schermerhorn T . Lack of glucokinase regulatory protein expression may contribute to low glucokinase activity in feline liver . Veterinary Research Communications . 33 . 3 . 227–40 . March 2009 . 18780155 . 10.1007/s11259-008-9171-6 . 11115622 .
  13. Arden C, Trainer A, de la Iglesia N, Scougall KT, Gloyn AL, Lange AJ, Shaw JA, Matschinsky FM, Agius L . 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 . July 2007 . 17389332 . 10.2337/db06-1151 . free .
  14. García-Herrero CM, Galán M, Vincent O, Flández B, Gargallo M, Delgado-Alvarez E, Blázquez E, Navas MA . Functional analysis of human glucokinase gene mutations causing MODY2: exploring the regulatory mechanisms of glucokinase activity . Diabetologia . 50 . 2 . 325–33 . February 2007 . 17186219 . 10.1007/s00125-006-0542-7 . free .
  15. Heredia VV, Carlson TJ, Garcia E, Sun S . Biochemical basis of glucokinase activation and the regulation by glucokinase regulatory protein in naturally occurring mutations . The Journal of Biological Chemistry . 281 . 52 . 40201–7 . December 2006 . 17082186 . 10.1074/jbc.M607987200 . free .
  16. Pino MF, Kim KA, Shelton KD, Lindner J, Odili S, Li C, Collins HW, Shiota M, Matschinsky FM, Magnuson MA . Glucokinase thermolability and hepatic regulatory protein binding are essential factors for predicting the blood glucose phenotype of missense mutations . The Journal of Biological Chemistry . 282 . 18 . 13906–16 . May 2007 . 17353190 . 10.1074/jbc.M610094200 . free .
  17. Grimsby J, Coffey JW, Dvorozniak MT, Magram J, Li G, Matschinsky FM, Shiota C, Kaur S, Magnuson MA, Grippo JF . Characterization of glucokinase regulatory protein-deficient mice . The Journal of Biological Chemistry . 275 . 11 . 7826–31 . March 2000 . 10713097 . 10.1074/jbc.275.11.7826 . free .
  18. Køster B, Fenger M, Poulsen P, Vaag A, Bentzen J . Novel polymorphisms in the GCKR gene and their influence on glucose and insulin levels in a Danish twin population . Diabetic Medicine . 22 . 12 . 1677–82 . December 2005 . 16401311 . 10.1111/j.1464-5491.2005.01700.x . 20786263 . free .
  19. Orho-Melander M, Melander O, Guiducci C, Perez-Martinez P, Corella D, Roos C, Tewhey R, Rieder MJ, Hall J, Abecasis G, Tai ES, Welch C, Arnett DK, Lyssenko V, Lindholm E, Saxena R, de Bakker PI, Burtt N, Voight BF, Hirschhorn JN, Tucker KL, Hedner T, Tuomi T, Isomaa B, Eriksson KF, Taskinen MR, Wahlstrand B, Hughes TE, Parnell LD, Lai CQ, Berglund G, Peltonen L, Vartiainen E, Jousilahti P, Havulinna AS, Salomaa V, Nilsson P, Groop L, Altshuler D, Ordovas JM, Kathiresan S . 6 . 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 . November 2008 . 18678614 . 2570409 . 10.2337/db08-0516 .
  20. Tam CH, Ma RC, So WY, Wang Y, Lam VK, Germer S, Martin M, Chan JC, Ng MC . 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 . March 2009 . 19073768 . 2646078 . 10.2337/db08-1277 .
  21. Bi M, Kao WH, Boerwinkle E, Hoogeveen RC, Rasmussen-Torvik LJ, Astor BC, North KE, Coresh J, Köttgen A . Association of rs780094 in GCKR with metabolic traits and incident diabetes and cardiovascular disease: the ARIC Study . PLOS ONE . 5 . 7 . e11690 . July 2010 . 20661421 . 2908550 . 10.1371/journal.pone.0011690 . 2010PLoSO...511690B . free .
  22. Futamura M, Hosaka H, Kadotani A, Shimazaki H, Sasaki K, Ohyama S, Nishimura T, Eiki J, Nagata Y . An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism . The Journal of Biological Chemistry . 281 . 49 . 37668–74 . December 2006 . 17028192 . 10.1074/jbc.M605186200 . free .

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