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Gene Review

PFKFB3  -  6-phosphofructo-2-kinase/fructose-2,6...

Homo sapiens

Synonyms: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, 6PF-2-K/Fru-2,6-P2ase 3, 6PF-2-K/Fru-2,6-P2ase brain/placenta-type isozyme, IPFK2, PFK/FBPase 3, ...
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Disease relevance of PFKFB3


High impact information on PFKFB3

  • PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate [5].
  • Increased expression of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) enhanced F2,6BP production and, consequently, cellular lactate production [6].
  • In addition, IGF-1 promoted the binding of endogenous PFK-2 to 14-3-3s [7].
  • These findings suggest that PKB-dependent binding of 14-3-3s to phospho-Ser483 of cardiac PFK-2 mediates the stimulation of glycolysis by growth factor [7].
  • When HeLa cells expressing HA-tagged PFK-2 were co-transfected with active PKB or stimulated with IGF-1, HA-PFK-2 was phosphorylated and bound to 14-3-3s [7].

Chemical compound and disease context of PFKFB3

  • A key regulator of glycolytic flux is fructose-2,6-bisphosphate, and its steady state concentration is regulated by the action of different isozymes product of four genes (pfkfb1-4). pfkfb3 has been found in proliferating cells and tumors, being induced by hypoxia [8].
  • Moreover, the thermostability of PFK-2 and the affinity of this enzyme for its substrate fructose 6-phosphate were increased upon transformation by Rous sarcoma virus [9].

Biological context of PFKFB3


Anatomical context of PFKFB3


Associations of PFKFB3 with chemical compounds

  • Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer [10].
  • Inhibition of inducible PFK-2 protein expression decreased the intracellular level of 5-phosphoribosyl-1-pyrophosphate, a product of the pentose phosphate pathway and an important precursor for nucleic acid biosynthesis [13].
  • We recently cloned an inducible isozyme of 6-phosphofructo-2 kinase (iPFK-2) that bears an oncogene-like regulatory element in its mRNA and functions to produce fructose-2,6-bisphosphate, which is a powerful allosteric activator of glycolysis [14].
  • Treatment of human thymocytes with different anti-CD69 monoclonal antibodies (mAbs), in the presence of submitogenic doses of phorbol ester, produced an enhanced release of lactate without significant alterations in Fru 2,6-P2 levels or phosphofructokinase-2 (PFK-2) and pyruvate kinase activities [15].
  • Forced expression of the iPFK-2/PFKFB3 in COS-7 cells resulted in increased glucose uptake and cellular F2,6BP content [16].
  • We then overexpressed PFKFB3 and observed no change in glucose metabolism but rather a marked increase in cell proliferation [17].

Enzymatic interactions of PFKFB3


Other interactions of PFKFB3

  • The basal level of PFKFB-4 protein expression in gastric cancers was much higher as compared to the PFKFB-3 isoenzyme [2].
  • PFKFB3 (iPFK2) is one of four tissue-specific PFKFB isozymes that have been identified to date [11].
  • The heterogeneity of human brain PFK-2/FBPase-2 isoforms is generated by alternative splicing [19].
  • The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) has been identified as an activating binding partner of beta-cell GK, increasing the V(max) value of the enzyme, while the S(0.5) value for glucose remains unchanged [20].
  • Molecular modelling of the PFK-2 domain revealed that, instead, it has the same fold as adenylate kinase [21].

Analytical, diagnostic and therapeutic context of PFKFB3


  1. Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. Minchenko, A., Leshchinsky, I., Opentanova, I., Sang, N., Srinivas, V., Armstead, V., Caro, J. J. Biol. Chem. (2002) [Pubmed]
  2. Hypoxic regulation of PFKFB-3 and PFKFB-4 gene expression in gastric and pancreatic cancer cell lines and expression of PFKFB genes in gastric cancers. Bobarykina, A.Y., Minchenko, D.O., Opentanova, I.L., Moenner, M., Caro, J., Esumi, H., Minchenko, O.H. Acta Biochim. Pol. (2006) [Pubmed]
  3. Insulin induces PFKFB3 gene expression in HT29 human colon adenocarcinoma cells. Riera, L., Manzano, A., Navarro-Sabaté, A., Perales, J.C., Bartrons, R. Biochim. Biophys. Acta (2002) [Pubmed]
  4. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and tumor cell glycolysis. Chesney, J. Current opinion in clinical nutrition and metabolic care. (2006) [Pubmed]
  5. PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate. Okar, D.A., Manzano, A., Navarro-Sabatè, A., Riera, L., Bartrons, R., Lange, A.J. Trends Biochem. Sci. (2001) [Pubmed]
  6. The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle. Benigni, F., Atsumi, T., Calandra, T., Metz, C., Echtenacher, B., Peng, T., Bucala, R. J. Clin. Invest. (2000) [Pubmed]
  7. 14-3-3s regulate fructose-2,6-bisphosphate levels by binding to PKB-phosphorylated cardiac fructose-2,6-bisphosphate kinase/phosphatase. Pozuelo Rubio, M., Peggie, M., Wong, B.H., Morrice, N., MacKintosh, C. EMBO J. (2003) [Pubmed]
  8. 6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia. Obach, M., Navarro-Sabaté, A., Caro, J., Kong, X., Duran, J., Gómez, M., Perales, J.C., Ventura, F., Rosa, J.L., Bartrons, R. J. Biol. Chem. (2004) [Pubmed]
  9. Activation of 6-phosphofructo-2-kinase by pp60v-src is an indirect effect. Marchand, M.J., Maisin, L., Hue, L., Rousseau, G.G. Biochem. J. (1992) [Pubmed]
  10. Phosphorylation of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase/PFKFB3 family of glycolytic regulators in human cancer. Bando, H., Atsumi, T., Nishio, T., Niwa, H., Mishima, S., Shimizu, C., Yoshioka, N., Bucala, R., Koike, T. Clin. Cancer Res. (2005) [Pubmed]
  11. Cloning and chromosomal characterization of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 gene (PFKFB3, iPFK2). Mahlknecht, U., Chesney, J., Hoelzer, D., Bucala, R. Int. J. Oncol. (2003) [Pubmed]
  12. Expression and hypoxia-responsiveness of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 in mammary gland malignant cell lines. Minchenko, O.H., Opentanova, I.L., Ogura, T., Minchenko, D.O., Komisarenko, S.V., Caro, J., Esumi, H. Acta Biochim. Pol. (2005) [Pubmed]
  13. An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect. Chesney, J., Mitchell, R., Benigni, F., Bacher, M., Spiegel, L., Al-Abed, Y., Han, J.H., Metz, C., Bucala, R. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  14. High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Atsumi, T., Chesney, J., Metz, C., Leng, L., Donnelly, S., Makita, Z., Mitchell, R., Bucala, R. Cancer Res. (2002) [Pubmed]
  15. Anti-CD69 antibodies enhance phorbol-dependent glucose metabolism and Ca2+ levels in human thymocytes. Antagonist effect of cyclosporin A. Conde, M., Montaño, R., Moreno-Aurioles, V.R., Ramirez, R., Sanchez-Mateos, P., Sanchez-Madrid, F., Sobrino, F. J. Leukoc. Biol. (1996) [Pubmed]
  16. Expression of Inducible 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase/PFKFB3 Isoforms in Adipocytes and Their Potential Role in Glycolytic Regulation. Atsumi, T., Nishio, T., Niwa, H., Takeuchi, J., Bando, H., Shimizu, C., Yoshioka, N., Bucala, R., Koike, T. Diabetes (2005) [Pubmed]
  17. Nuclear targeting of 6-phosphofructo-2-kinase (PFKFB3) increases proliferation via cyclin-dependent kinases. Yalcin, A., Clem, B.F., Simmons, A., Lane, A., Nelson, K., Clem, A.L., Brock, E., Siow, D., Wattenberg, B., Telang, S., Chesney, J. J. Biol. Chem. (2009) [Pubmed]
  18. Evaluation of the role of protein kinase Czeta in insulin-induced heart 6-phosphofructo-2-kinase activation. Mouton, V., Vertommen, D., Bertrand, L., Hue, L., Rider, M.H. Cell. Signal. (2007) [Pubmed]
  19. Splice isoforms of ubiquitous 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in human brain. Kessler, R., Eschrich, K. Brain Res. Mol. Brain Res. (2001) [Pubmed]
  20. Glucokinase Regulatory Network in Pancreatic {beta}-Cells and Liver. Baltrusch, S., Tiedge, M. Diabetes (2006) [Pubmed]
  21. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Rider, M.H., Bertrand, L., Vertommen, D., Michels, P.A., Rousseau, G.G., Hue, L. Biochem. J. (2004) [Pubmed]
  22. Molecular cloning, expression, and chromosomal localization of a ubiquitously expressed human 6-phosphofructo-2-kinase/ fructose-2, 6-bisphosphatase gene (PFKFB3). Manzano, A., Rosa, J.L., Ventura, F., Pérez, J.X., Nadal, M., Estivill, X., Ambrosio, S., Gil, J., Bartrons, R. Cytogenet. Cell Genet. (1998) [Pubmed]
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