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PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2)

Written2014-03Ana Rodríguez-García, Pere Fontova, Helga Simon, Anna Manzano, Ramon Bartrons, Àurea Navarro-Sabaté
Departament de Ciencies Fisiologiques II, Campus de Bellvitge, Universitat de Barcelona, Feixa Llarga s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain

(Note : for Links provided by Atlas : click)


Alias (NCBI)PFK-2/FBPase-2
LocusID (NCBI) 5208
Atlas_Id 52100
Location 1q32.2  [Link to chromosome band 1q32]
Location_base_pair Starts at 207053275 and ends at 207077817 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping PFKFB2.png]
Local_order The human PFKFB2 gene is located on the chromosome 1 at position 1q31-q32.2 (GeneCards) (Fig. 1).
  Figure 1. Localization of human PFKFB2 gene.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
APOA2 (1q23.3)::PFKFB2 (1q32.2)PFKFB2 (1q32.2)::DDHD1 (14q22.1)PFKFB2 (1q32.2)::PFKFB2 (1q32.2)


  Figure 2. Schematic representation of the location of PFKFB2 gene in chromosome 1 and its structural organization. Description of the exon/intron splice junctions. Exon sequences are shown in vertical bars numbered 1-15. The sequences of 060825 and 060825-2 correspond to variant 1 and variant 2, respectively (NCBI).
Description The human PFKFB2 is composed of 15 exons spanning 22617 bp (GenBank: AJ005577.1). This gene has 9 transcripts; two of them have been reported to codify a protein and three contain an open reading frame, but no protein has been identified. The transcripts are derived from different promoters and vary only in non-coding sequences at the 5' end. Therefore, the resulting proteins differ in their C-terminal amino acid sequence (Heine-Suñer et al., 1998). The main products of the gene correspond to mRNAs of 7073 bp and 3529 bp for the variant 1 (isoform a; NM_006212.2) and variant 2 (isoform b; NM_001018053.1), respectively (Fig. 2). The isoform b differs in the 3' UTR and the coding region compared to isoform a. The resulting isoform b is shorter and has a distinct C-terminus compared to isoform a. However, it is not known how these different 5' ends are related to the three mRNAs (H1, H2 and H4) that encode the isoform a or the H3 mRNA that encodes the isoform b. None of these mRNAs are strictly heart-specific.
The overall gene structure of the human PFKFB2 gene has exons clustered into three groups. The first group contains exons 1 and 2 that are different from those in other PFKFB2 genes and contain the ATG initiation codon in exon 2. The second group contains exons 3-8 coding for the PFK-2 domain and the third group contains exons 8-15 coding for the FBPase-2 domain and a carboxy-terminal regulatory domain. Gene structure, exon-intron organization, as well as intron sizes, are similar to those of the rat and bovine homologous genes.
Transcription The human PFKFB2 coding sequence consists of 1518 bp for isoform a and 1416 bp for isoform b from the start codon to the stop codon, although the immature transcript forms contain 7904 bp and 3494 bp, respectively. Multiple alternatively spliced transcript variants have been described for this gene (Ensembl: OTTHUMG00000036033).
Pseudogene No pseudogene of PFKFB2 is known.


Description PFKFB2 is a homodimeric protein of 505 amino acids for isoform a and 471 for isoform b with a deduced molecular mass of 58 kDa and 54 kDa, respectively.
PFKFB2 is an enzyme of PFKFB family, as it shares different structure and function with the others isoenzymes. PFKFB2 has two distinct catalytic sites in each subunit: one for the 6-phosphofruto-2-kinase (PFK-2) activity and the other for the fructose-2,6-bisphosphatase (FBPase-2) activity (El-Maghrabi et al., 1982; Pilkis et al., 1995; Okar et al., 2001). The sequence of the catalytic core is highly conserved, whereas the N-terminal and C-terminal regions show more divergence (Rider et al., 2004).
PFK-2/FBPase-2 activities control fructose-2,6-bisphosphate (Fru-2,6-P2) synthesis and degradation, regulating the rate of glucose metabolism. More information about PFKFB2 protein can be found in Uniprot O60825.
Expression PFKFB2 protein is expressed mainly in heart, although expression is also found in other tissues at lesser extent (Minchenko et al., 2002). Moreover, it is expressed in different cancer cell lines such as T-lymph Jurkat, K562 erythroleukemia, liver HepG2, lung A549, colon RKO, bone U2OS, brain GAMG, prostate LnCap, cervix HeLa and breast MCF7. All this information can be found in GeneCards (sections proteins and expression).
According to the RNAseq database, this gene can also be expressed in thyroid, brain, kidney, skeletal muscle, ovary, testis and others.
Localisation PFKFB2 protein is active in the cytosol.
  Figure 3. PFKFB2 activities and function in the glycolytic pathway in heart during hypoxia.
Function This enzyme regulates the concentration of Fru-2,6-P2 through the two catalytic domains. PFK-2 domain catalyzes the synthesis of Fru-2,6-P2, using fructose-6-phosphate (Fru-6-P) and adenosine-5-triphosphate (ATP) as substrates; FBPase-2 domain catalyzes the degradation of Fru-2,6-P2 into Fru-6-P and inorganic phosphate (Pi). These two mutually opposing catalytic activities are controlled by different mechanisms such that each activity is predominant in a given physiological condition. In detail, the reactions catalyzed are:
Kinase catalytic activity: ATP + D-fructose-6-phosphate ⇔ ADP + beta-D-fructose-2,6-bisphosphate
Phosphatase catalytic activity: Beta-D-fructose-2,6-bisphosphate + H2O ⇔ D-fructose-6-phosphate + phosphate
The rate of glycolytic flux is controlled at different levels and by different mechanisms: substrate availability, enzyme concentrations, allosteric effectors and covalent modifications on regulatory enzymes. One of the critically modulated steps is that catalyzed by 6-phosphofructo-1-kinase (PFK-1), in which Fru-2,6-P2 is the most powerful allosteric activator (Van Schaftingen, 1987; Okar and Lange, 1999; Rider et al., 2004). Fru-2,6-P2 relieves ATP inhibition and acts synergistically with adenosine monophosphate (AMP), inhibiting fructose 1,6-bisphosphatase (Fru-1,6-Pase) (Van Schaftingen, 1987). These properties confer to this metabolite a key role in the control of Fru-6-P/Fru-1,6-P2 substrate cycle and hence critically regulates carbohydrate metabolism (Fig. 3).
In vertebrates, there are four different PFKFB genes (PFKFB1, PFKFB2, PFKFB3 and PFKFB4), which encode the PFK-2/FBPase-2 isoenzymes. Each of these enzymes has been originally identified in different mammalian tissues: PFKFB1 in liver and skeletal muscle, PFKFB2 in heart, PFKFB3 in brain, adipose tissue and proliferating cells, and PFKFB4 in testis (Okar et al., 2004; Rider et al., 2004). However, all four are widely expressed throughout the adult organism. These isoenzymes show differences in their distribution and kinetic properties in response to allosteric effectors, hormonal, and growth factors signals (Okar et al., 2001). PFKFB2 enzyme is overexpressed in different cancer cells like melanoma, prostate, pancreatic, gastric and mammary gland cells (Minchenko et al., 2005a; Minchenko et al., 2005b; Bobarykina et al., 2006). For more information about PFKFB genes see: PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3) and PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4).

PFKFB2 is an essential enzyme for the regulation of glycolysis in heart. PFKFB2 is multisite-phosphorylated, integrating signaling from many pathways via protein kinase cascades to a single molecule, Fru-2,6-P2, to stimulate glycolysis.
The human PFKFB2 protein contains the Ser 29, Ser 466, Thr 475 and Ser 483 residues that regulate the activity of the enzyme. These residues are located in its C-terminal domain and can be phosphorylated by protein kinases such as AMPK, 3-phosphoinositide-dependent kinase-1 (PDK-1), cAMP-dependent protein kinase (protein kinase A; PKA), protein kinase B (PKB; also known as Akt), p70 ribosomal S6 kinase (S6K1), and mitogen-activated protein kinase 1 (MAPK-1). Phosphorylation of PFKFB2 results in the activation of the enzyme, increasing Vmax of PFK-2 activity. The variations in PFK-2 activity, however, appear to be different with the phosphorylation by the different kinases (Marsin et al., 2000; Rider et al., 2004).
In perfused rat hearts, it has been shown that the concentration of Fru-2,6-P2 is raised by increasing the work load, after hypoxia or stimulation with adrenalin or insulin (Hue et al., 1982; Rider and Hue, 1984; Depre et al., 1993; Deprez et al., 1997). This activation is probably mediated by the phosphorylation of three conserved residues (Ser 466, Thr 475 and Ser 483) by specific protein kinases (Depre et al., 1993; Deprez et al., 1997).
Insulin stimulates glycolysis in heart by a combination of an increase in glucose transport and activation of PFKFB2 (Depré et al., 1998; Hue et al., 2002). Two serine residues, Ser 466 ad Ser 483 can be phosphorylated in vitro by PKB in response to insulin resulting from a 2-fold increase in both Vmax and affinity for Fru-6-P, one of the substrates of PFK-2 (Lefebvre et al., 1996; Deprez et al., 1997).
Rat heart PFKFB2 is activated by insulin in vivo through a 2-fold increase in Vmax with no change in Km for Fru-6-P (Rider and Hue, 1984). Moreover, it has been shown that the insulin-induced activation of PFKFB2 was blocked by wortmannin, a PI3K inhibitor, but was insensitive to rapamycin or PD098059, which prevent the activation of p70S6K and the MAPK cascade, respectively (Lefebvre et al., 1996). These results suggest that PI3K, but not p70S6K, is involved in the activation of PFKFB2 in response to insulin. New in vitro and in vivo experiments show that SGK3 is not required for insulin-induced heart PFK-2 activation and this effect is likely mediated by PKBα (Mouton et al., 2010). Moreover, it has been proposed that 14-3-3s, that have been implicated in promoting cell survival (Masters et al., 2002), bind to PFK-2 at Ser 483 when it is phosphorylated by PKB in vitro in response to insulin or in cells that are stimulated with IGF-1 or transfected with active forms of PKB, mediating the stimulation of glycolysis by growth factors (Pozuelo et al., 2003).
Glycolysis in heart also increases in response to increased the workload (Depre et al., 1993; Beauloye et al., 2002), rising Fru-2.6-P2 due to the activation of PFKFB2. The increase on workload activates PKB but not p70 S6K and this increase is blocked by wortmannin and is rapamycin-insensitive. Ca/CAMK (Ca2+/calmodulin-activated protein kinase) is which phosphorylates and activates PFKFB2 secondarily to a rise in cytoplasmatic Ca22+ (Depre et al., 1993; Beauloye et al., 2002).
Adrenalin administration in perfused rat hearts suggests that PKA may be responsible for the activation of PFKFB2, which accounts for the increased Fru-2,6-P2 levels (Narabayashi et al.,1985). This hormone promotes PFKFB2 phosphorylation by PKA in the residues already described in vitro, which are Ser 466 and Ser 483. These phosphorylations have an impact on PFK-2 activity, decreasing the Km for Fru-6-P (Kitamura et al., 1988; Rider et al., 1992a; Rider et al., 1992b).
PFKFB2 mRNA is induced in organs exposed to hypoxic conditions. Activation of the AMP-activated protein kinase (AMPK) during ischemia or hypoxia leads to phosphorylation of PFKFB2 at Ser 466 which increases the levels of Fru-2,6-P2 and stimulates glycolysis. PFKFB2 phosphorylation leads to an increase in Vmax with no change in Km for Fru-6-P (Marsin et al., 2000). Other studies have described PFKFB2 as a hypoxia-responsive gene in vivo but the regulation of its expression following hypoxic treatments appears to occur in a cell-specific manner. The mechanism underlying the expression of each isoform in different tissues remains unclear (Minchenko et al., 2002).
Moreover, amino acids increase the synthesis of Fru-2,6-P2 in HeLa and MCF7 cell lines by phosphorylation at PFKFB2 at Ser 483. This activation is mediated by PI3K and PKB. Similar effects on Fru-2,6-P2 metabolism were observed in freshly isolated rat cardiomyocytes treated with amino acids, which indicates that these effects are not restricted to human cancer cells. In these cardiomyocytes, PFKFB2 phosphorylation increases glucose consumption and the production of lactate and ATP (Novellasdemunt et al., 2013).
PFKFB2 is also a substrate of PKC which phosphorylates Ser 84, Ser 466 and Thr 475 (Rider and Hue, 1986; Kitamura et al., 1988; Rider et al., 1992a; Rider et al., 1992b). However, the physiological significance of phosphorylation of Ser 84, Ser 466 and Thr 475 of PFKFB2 by PKC is not completely understood. It seems that phosphorylation of Ser 466 or Thr 475 does not change the enzyme activity. This might be due to the fact that the phosphorylation at Ser 84 possibly counteracts the effects of phosphorylation at the activating C-terminal sites (Kitamura et al., 1988; Rider et al., 1992b).
The mechanism of control of PFKFB2 isoenzyme by phosphorylation is also difficult to explain in the absence of a crystal structure of the phosphorylated isoenzyme. Phosphorylation of Ser 466 and Ser 483 at the C-terminal end of the bovine heart isoenzyme by PKA (Kitamura et al., 1988; Rider et al., 1992a; Rider et al., 1992b; Deprez et al., 1997) and insulin-stimulated protein kinases (Deprez et al., 1997) activates PFK-2 by decreasing Km for Fru-6-P and by increasing the Vmax without affecting FBPase-2. Ser 466 phosphorylation is responsible for the increase in Vmax whereas both phosphorylations are necessary to decrease the Km for Fru-6-P (Bertrand et al., 1999).
Regulatory sequences that account for some of the mechanisms involved in the long-term hormonal control and tissue-specific expression of PFKFB2 have been identified. The 5' flanking sequence of PFKFB2 contains regions that are conserved between the human, bovine and rat genes. In these regions, several potential binding sites for the Sp1, HNF-1 and BHLH (helix-loop-helix) (E boxes) transcription factors and for the GR have been described (Tsuchiya and Uyeda, 1994; Chikri and Rousseau, 1995; Heine-Suñer et al., 1998), but a factor binding to these sites has not been reported.

Chromosomal rearrangements: copy number variants
There are three alterations affecting PFKFB2 genome region described in patients. One of them, the gain of 1:195266734-216326885, shows phenotypic effects such us visual impairment, low-set ears, iris coloboma, intellectual disability, defect in the atrial septum, ventricular septal defect and vertical nystagmus. For more information see DECIPHER.
No syndrome or disease was found in OMIM database.

  Figure 4. Domain organization and phosphorylation of PFKFB2 isoenzyme. The N-terminal PFK-2 domain is shown in violet, the C-terminal FBPase-2 domain is shown in red and the regulatory domains are shown in blue. Phosphorylation sites, the stimuli and the kinases responsible of their phosphorylation are indicated.
Homology Location in the mouse: chromosome 1, 56,89 cM, cytoband E4, 130689043-130729253 bp, complement strand (MGI).
For a comparison of the gene from Homo sapiens, mouse, rat, cattle, chimpanzee, chicken, zebrafish, rhesus macaque and dog see MGI.
Also for all species known gene tree, see Treefam database.
It appears that the use of Fru-2,6-P2 as a regulatory metabolite is a specifically eukaryotic phenomenon. The most plausible hypothesis for the origin of the PFK-2/FBPase-2 would be the fusion of two ancestral genes coding for a kinase functional unit and a phosphohydrolase/mutase unit, respectively. From protein sequence alignments, it is clear that the bisphosphatase activity located in the C-terminal domain of the PFK-2/FBPase-2, the phosphoglycerate mutases (PGAMs) and the acid phosphatase family diverged from a common ancestor (Jedrzejas, 2000; Okar et al., 2001). Alignments of the bisphosphatase domain with PGM and acid phosphatase can be obtained at EBI. On the other hand, PFK-2 domain is related to a superfamily of mononucleotide binding proteins including adenylate kinase (AK) of E. coli., p21 Ras, EF-tu, the mitochondrial ATPase- β-subunits and myosin ATPase, all of them contain the Walker A and B motifs and have a similar fold (Rider et al., 2004).

Orthologs (from BLAST Local Alignment Tool)
Results from BLAST Local Alignment Tool are shown in Figure 5. Only the annotated proteins are reported, the predicted proteins appearing in the local alignment were excluded.
Comparison of the PFKFB2 cDNA sequence with the bovine and rat 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) heart isoforms shows 87-90% nucleotide and 92-95% amino acid identity (Sakata and Uyeda, 1990; Darville et al., 1991).



Note Genomic variants
There are 647 SNP variants described in PFKFB2 (see GeneCards).
The most SNP are found in non coding regions: 418 are presented in introns, 3 in splice donor variant, 107 in 3' UTR and 25 variant within a half kb of the end of gene and others.
Furthermore, 61 SNP are presented with the coding regions. The most of them are missense (31 variants) and also synonymous variants (19 variants) and only one frameshift.
  Figure 6. Histogram of mutations found among the amino acid sequence of PFKFB2 protein. The maximum number of substitutions at any specific genomic region is represented in Y axis. 6-phosphofructo-2-kinase and histidine phosphatase superfamily domains are represented in green and red respectively. From: COSMIC Database.
Somatic 49 somatic mutations in the PFKFB2 gene detected in patient tumor samples are collected in the COSMIC database.
Coding silent substitutions: 20, which represent 40.8% of the mutations described among all patients. Two of them have been found in two patients: c.1008C>G (p.T336T) and c.1419G>A (p.S473S).
Nonsense substitutions: 1, located in c.1051C>T (p.R351*).
Missense substitutions: 23, which represent 46.9% of the mutations described among all patients.
Deletions frameshift: 1, located in c.1044delT (p.F348fs*66).
Insertion frameshift: 1, located in c.703_407insT (p.Q235fs*37).
Deletion inframe: 2, located in c.28_30delAAC (p.N12delN) and in in c.82_84delTGT (p.C28delC).
Unknown mutation: 2, one of them located in c.376-2A>T and the other in c.840+1G>A.
No synonymous substitutions or chromosomal fusions in PFKFB2 gene have been described in any tumor sample.

Implicated in

Entity Various cancers
Oncogenesis Cancer cells energy metabolism is characterized by a high glycolytic rate, which is maintained under aerobic conditions, when compared to non-malignant cells. The concentration of Fru-2,6-P2 is generally increased due to overexpression and activation of PFK-2. Adrenaline, insulin, hypoxia and workload stimulate heart glycolysis by activating PFKFB2, hence producing a subsequent rise in Fru-2,6-P2 concentration (Marsin et al., 2000; Rider et al., 2004).
Hypoxia is an important component of the tumor microenvironment. One key mediator of the hypoxic response in animal cells is the hypoxia-inducible factor (HIF) complex, a transcription factor frequently deregulated in cancer cells that induces the expression of glycolytic genes (Bartrons and Caro, 2007).
In culture cells, hypoxia induces PFKFB2 in HeLa and MCF7 cells. These data demonstrate that PFKFB2 is one of the responsive to hypoxia in vivo, indicating a physiological role in the adaptation of the organism to environmental or localized hypoxia/ischemia. Marsin et al. (2000) showed that AMPK phosphorylates PFKFB2 at Ser 466 in hypoxia conditions and this could contribute to maintain the high glycolytic rate that is a characteristic feature of many tumors.
Entity Acute lymphoblastic leukemia
Note Alterations in glucose metabolism have been implicated in cell death and survival decisions, particularly in the lymphoid lineage (Plas et al., 2002) and in transformed cells (Tennant et al., 2010).
PFKFB2 was identified by microarray analysis of lymphoblasts isolated from glucocorticoid-treated children suffering from ALL (acute lymphoblastic leukemia) as one of the most promising candidate genes as a glucocorticoid (GC)-response gene, since it was regulated in the majority of patients. Its deregulation was proposed to entail disturbances in glucose metabolism which, in turn, have been implicated in cell death induction (Schmidt et al., 2006). These data suggest that cellular metabolism and apoptosis might be intertwined with connections between regulation of cellular bioenergetics and apoptosis. Carlet et al. (2010) demonstrated that both splice variants of PFKFB2 are expressed and specifically induced by GC in malignant lymphoid cells, however, functional analysis of this gene in the human T-ALL cell line model CCRF-CEM revealed that its over-expression does not explain the anti-leukemic effects of GC.
Entity Prostate cancer
Note In the early stages of prostate cancer, the androgen receptor (AR) is one of the key regulators that mediates tumor growth, promoting glucose uptake and anabolic metabolism, and modulates gene expression. Massie et al. (2011), using multiple metabolomic approaches, demonstrated that PFKFB2 is up-regulated as a consequence of the transcriptional changes by AR, with possible control through the AR-CAMKII-AMPK signaling pathway.
Other studies performing microarray analysis, using total RNA isolated from LNCaP cells treated with or without R1881 (methyltreinolone), a synthetic androgen, showed that androgens induce PFKFB2 expression in LNCaP cells (androgen-sensitive human prostate adenocarcinoma cells) by the direct recruitment of the ligand-activated AR to the PFKFB2 promoter. Moreover, depletion of PFKFB2 expression using siRNA (small interfering RNA) or inhibiting the PFK-2 activity with LY294002 (inhibitor of PI3K) treatment resulted in a reduced glucose uptake and lipogenesis, suggesting that the induction of de novo lipid synthesis by androgens requires the transcriptional up-regulation of PFKFB2 in prostate cancer cells (Moon et al., 2011).
Entity Gastric cancer
Note PFKFB2 mRNA expression is increased in malignant gastric tumors as well as the expression of known HIF-1-dependent genes, Glut1 (glucose transporter 1) and VEGF (vascular endothelial growth factor), supporting the HIF-dependent character of the induction of expression of the PFKFB2 (Bobarykina et al., 2006).
Entity Hepatocellular cancer
Note In immuhistochemistry samples of hepatocellular carcinoma, it has been recently found that high expression of MACC1 (metastasis associated in colon cancer 1), a key regulator of the HGF/Met-pathway, correlates with high expression of PFKFB2. This correlation has an effect on TNM stage (classification of malignant tumors), overall survival and Edmondson-Steier classification (Ji et al., 2014).
Entity Papillary thyroid cancer
Note The extent and presentation of papillary thyroid cancer (PTC) in adolescents and young adults (AYAs) is different than in older patients. This difference may be due to several candidate genes that are differentially expressed and which may have important roles in tumor cell biology. One of these genes is PFKFB2 but future functional genomics studies are needed to shed further light on whether a biologic basis exists to account for the disparity in AYA cancer incidence and outcome (Vriens et al., 2011).
Entity Heart diseases
Note In the heart, acute ischemia induces rapid activation of AMPK which phosphorylates Ser 466 leading to a two-fold increase in the Vmax of PFKFB2 (Hue et al., 2002). mRNA analysis indicated that PFKFB2 is expressed at high levels not only in the heart but also in the brain and lungs. However, in vivo experiments showed that hypoxia induce moderate expression in the lung and liver and very strong stimulation in the testis. No induction or even mild inhibition was found in the heart, kidney, brain and skeletal muscle. Myocardial ischemia induces a shift to anaerobic metabolism, with a rapid stimulation of glycolysis (Wang et al., 2008).
Tetralogy of Fallot (TOF) is a heart defect in children that results in chronic progressive right ventricular pressure overload and shunt hypoxemia. Western blot, RT-qPCR (real time PCR) and immunohystochemical analysis revealed that PKFB2 expression and mRNA of PFKFB2 increased significantly in TOF patients. Like tumors, under pathological stress conditions, cardiomyocytes gradually come to rely on glycolysis to satisfy their main energy requirements. That is why these results suggest that PFKFB2 plays an important role in certain biological processes related to cardiac remodeling, which occurs in response to chronic hypoxia and long-term pressure overload in TOF patients (Xia et al., 2013).
Glycolysis increases in cognitive heart failure (CHF), cardiac hypertrophy and cardiac ischemia (Neely et al., 1975). Some studies producing mice with chronic and stable elevation of cardiac Fru-2,6-P2 showed significant change in cardiac metabolite concentrations, increased glycolysis, reduced palmitate oxidation and protection of isolated myocytes from hypoxia. Taken together, these results show that PFKFB2 is one of the enzymes that control cardiac glycolysis, producing an increase in Fru-2,6-P2, causing detrimental effects and suggesting that the elevation of glycolysis in failing hearts could be injurious to an already compromised heart (Wang et al., 2008).
Entity Inflammation
Note It has been shown that purified human CD3+ T cells express PFKFB2 (Telang et al., 2012). CCL5 (proinflammatory chemokine) treatment of ex vivo activated human CD3+ T cells induced the activation of the nutrient-sensing kinase AMPK and downstream substrates like PFKFB2, suggesting that both glycolysis and AMPK signaling are required for efficient T cell migration in response to CCL5, relating therefore PFKFB2 with T-cell activation and migration (Chan et al., 2012).
Entity Mental disorders
Note Schizophrenia presents impaired glucose regulation. Stone et al. (2004), using a genome scan, found that PFKFB2 shows linkage with schizophrenia in a multiple sample of subjects (European-American samples). However, it is necessary to replicate these results with other samples and if PFKFB2 contributes on the liability for schizophrenia, its influence is likely to be modest, as most cases of schizophrenia are likely to result from multiple factors.
Entity Growth restriction and development
Note Infants with intrauterine growth restriction (IUGR) have a low weight at birth as a result of pathologic restriction of fetal growth (Wollmann, 1998). cDNA microarrays, RT-qPCR and Western blot analysis revealed that PFKFB2 expression increases in placentas from pregnancies with IUGR causing hypoglycemia. However, further studies have to be performed in order to elucidate the role of PFKFB2 in glucose metabolism on IUGR placenta (Lee et al., 2010).


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MACC1 expression correlates with PFKFB2 and survival in hepatocellular carcinoma.
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Asian Pac J Cancer Prev. 2014;15(2):999-1003.
PMID 24568531
Phosphorylation of myocardial fructose-6-phosphate,2-kinase: fructose-2,6-bisphosphatase by cAMP-dependent protein kinase and protein kinase C. Activation by phosphorylation and amino acid sequences of the phosphorylation sites.
Kitamura K, Kangawa K, Matsuo H, Uyeda K.
J Biol Chem. 1988 Nov 15;263(32):16796-801.
PMID 2846551
Placental gene expression is related to glucose metabolism and fetal cord blood levels of insulin and insulin-like growth factors in intrauterine growth restriction.
Lee MH, Jeon YJ, Lee SM, Park MH, Jung SC, Kim YJ.
Early Hum Dev. 2010 Jan;86(1):45-50. doi: 10.1016/j.earlhumdev.2010.01.001. Epub 2010 Jan 27.
PMID 20106611
Signaling pathway involved in the activation of heart 6-phosphofructo-2-kinase by insulin.
Lefebvre V, Mechin MC, Louckx MP, Rider MH, Hue L.
J Biol Chem. 1996 Sep 13;271(37):22289-92.
PMID 8798384
Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia.
Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF, Van den Berghe G, Carling D, Hue L.
Curr Biol. 2000 Oct 19;10(20):1247-55.
PMID 11069105
The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis.
Massie CE, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L, Warren A, Scott H, Madhu B, Sharma N, Bon H, Zecchini V, Smith DM, Denicola GM, Mathews N, Osborne M, Hadfield J, Macarthur S, Adryan B, Lyons SK, Brindle KM, Griffiths J, Gleave ME, Rennie PS, Neal DE, Mills IG.
EMBO J. 2011 May 20;30(13):2719-33. doi: 10.1038/emboj.2011.158.
PMID 21602788
Survival-promoting functions of 14-3-3 proteins.
Masters SC, Subramanian RR, Truong A, Yang H, Fujii K, Zhang H, Fu H.
Biochem Soc Trans. 2002 Aug;30(4):360-5. (REVIEW)
PMID 12196095
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 Feb 22;277(8):6183-7. Epub 2001 Dec 14.
PMID 11744734
Expression and hypoxia-responsiveness of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 in mammary gland malignant cell lines.
Minchenko OH, Opentanova IL, Ogura T, Minchenko DO, Komisarenko SV, Caro J, Esumi H.
Acta Biochim Pol. 2005;52(4):881-8. Epub 2005 Jul 11.
PMID 16025159
Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells.
Moon JS, Jin WJ, Kwak JH, Kim HJ, Yun MJ, Kim JW, Park SW, Kim KS.
Biochem J. 2011 Jan 1;433(1):225-33. doi: 10.1042/BJ20101104.
PMID 20958264
Heart 6-phosphofructo-2-kinase activation by insulin requires PKB (protein kinase B), but not SGK3 (serum- and glucocorticoid-induced protein kinase 3).
Mouton V, Toussaint L, Vertommen D, Gueuning MA, Maisin L, Havaux X, Sanchez-Canedo C, Bertrand L, Dequiedt F, Hemmings BA, Hue L, Rider MH.
Biochem J. 2010 Oct 15;431(2):267-75. doi: 10.1042/BJ20101089.
PMID 20687898
Regulation of phosphofructokinase in perfused rat heart. Requirement for fructose 2,6-bisphosphate and a covalent modification.
Narabayashi H, Lawson JW, Uyeda K.
J Biol Chem. 1985 Aug 15;260(17):9750-8.
PMID 3160703
Effect of coronary blood flow on glycolytic flux and intracellular pH in isolated rat hearts.
Neely JR, Whitmer JT, Rovetto MJ.
Circ Res. 1975 Dec;37(6):733-41.
PMID 156
Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) isoenzyme by amino acids.
Novellasdemunt L, Tato I, Navarro-Sabate A, Ruiz-Meana M, Mendez-Lucas A, Perales JC, Garcia-Dorado D, Ventura F, Bartrons R, Rosa JL.
J Biol Chem. 2013 Apr 12;288(15):10640-51. doi: 10.1074/jbc.M113.455998. Epub 2013 Mar 2.
PMID 23457334
Fructose-2,6-bisphosphate and control of carbohydrate metabolism in eukaryotes.
Okar DA, Lange AJ.
Biofactors. 1999;10(1):1-14. (REVIEW)
PMID 10475585
PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2,6-bisphosphate.
Okar DA, Manzano A, Navarro-Sabate A, Riera L, Bartrons R, Lange AJ.
Trends Biochem Sci. 2001 Jan;26(1):30-5. (REVIEW)
PMID 11165514
6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: a metabolic signaling enzyme.
Pilkis SJ, Claus TH, Kurland IJ, Lange AJ.
Annu Rev Biochem. 1995;64:799-835. (REVIEW)
PMID 7574501
Homeostatic control of lymphocyte survival: potential origins and implications.
Plas DR, Rathmell JC, Thompson CB.
Nat Immunol. 2002 Jun;3(6):515-21. (REVIEW)
PMID 12032565
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 BH, Morrice N, MacKintosh C.
EMBO J. 2003 Jul 15;22(14):3514-23.
PMID 12853467
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis.
Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L.
Biochem J. 2004 Aug 1;381(Pt 3):561-79. (REVIEW)
PMID 15170386
Activation of rat heart phosphofructokinase-2 by insulin in vivo.
Rider MH, Hue L.
FEBS Lett. 1984 Oct 29;176(2):484-8.
PMID 6237934
The two forms of bovine heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase result from alternative splicing.
Rider MH, Vandamme J, Lebeau E, Vertommen D, Vidal H, Rousseau GG, Vandekerckhove J, Hue L.
Biochem J. 1992 Jul 15;285 ( Pt 2):405-11.
PMID 1322130
Evidence for new phosphorylation sites for protein kinase C and cyclic AMP-dependent protein kinase in bovine heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase.
Rider MH, van Damme J, Vertommen D, Michel A, Vandekerckhove J, Hue L.
FEBS Lett. 1992 Sep 28;310(2):139-42.
PMID 1327869
Bovine heart fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase: complete amino acid sequence and localization of phosphorylation sites.
Sakata J, Uyeda K.
Proc Natl Acad Sci U S A. 1990 Jul;87(13):4951-5.
PMID 2164212
Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia.
Schmidt S, Rainer J, Riml S, Ploner C, Jesacher S, Achmuller C, Presul E, Skvortsov S, Crazzolara R, Fiegl M, Raivio T, Janne OA, Geley S, Meister B, Kofler R.
Blood. 2006 Mar 1;107(5):2061-9. Epub 2005 Nov 17.
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Evidence for linkage between regulatory enzymes in glycolysis and schizophrenia in a multiplex sample.
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Am J Med Genet B Neuropsychiatr Genet. 2004 May 15;127B(1):5-10.
PMID 15108172
Small molecule inhibition of 6-phosphofructo-2-kinase suppresses t cell activation.
Telang S, Clem BF, Klarer AC, Clem AL, Trent JO, Bucala R, Chesney J.
J Transl Med. 2012 May 16;10:95. doi: 10.1186/1479-5876-10-95.
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Clinical and molecular features of papillary thyroid cancer in adolescents and young adults.
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External links


HGNC (Hugo)PFKFB2   8873
Atlas Explorer : (Salamanque)PFKFB2
Entrez_Gene (NCBI)PFKFB2    6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2
GeneCards (Weizmann)PFKFB2
Ensembl hg19 (Hinxton)ENSG00000123836 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000123836 [Gene_View]  ENSG00000123836 [Sequence]  chr1:207053275-207077817 [Contig_View]  PFKFB2 [Vega]
ICGC DataPortalENSG00000123836
Genatlas (Paris)PFKFB2
SOURCE (Princeton)PFKFB2
Genetics Home Reference (NIH)PFKFB2
Genomic and cartography
GoldenPath hg38 (UCSC)PFKFB2  -     chr1:207053275-207077817 +  1q32.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)PFKFB2  -     1q32.1   [Description]    (hg19-Feb_2009)
GoldenPathPFKFB2 - 1q32.1 [CytoView hg19]  PFKFB2 - 1q32.1 [CytoView hg38]
Genome Data Viewer NCBIPFKFB2 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB044805 AF470623 AJ005578 AK125661 AK292883
RefSeq transcript (Entrez)NM_001018053 NM_006212
Consensus coding sequences : CCDS (NCBI)PFKFB2
Gene ExpressionPFKFB2 [ NCBI-GEO ]   PFKFB2 [ EBI - ARRAY_EXPRESS ]   PFKFB2 [ SEEK ]   PFKFB2 [ MEM ]
Gene Expression Viewer (FireBrowse)PFKFB2 [ Firebrowse - Broad ]
GenevisibleExpression of PFKFB2 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5208
GTEX Portal (Tissue expression)PFKFB2
Human Protein AtlasENSG00000123836-PFKFB2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO60825   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO60825  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO60825
Catalytic activity : Enzyme2.7.1.105 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   [ MEROPS ]
Domaine pattern : Prosite (Expaxy)PG_MUTASE (PS00175)   
Domains : Interpro (EBI)6Pfruct_kin    6Phosfructo_kin    His_Pase_superF_clade-1    His_PPase_superfam    P-loop_NTPase    PG/BPGM_mutase_AS   
Domain families : Pfam (Sanger)6PF2K (PF01591)    His_Phos_1 (PF00300)   
Domain families : Pfam (NCBI)pfam01591    pfam00300   
Domain families : Smart (EMBL)PGAM (SM00855)  
Conserved Domain (NCBI)PFKFB2
PDB Europe5HTK   
Structural Biology KnowledgeBase5HTK   
SCOP (Structural Classification of Proteins)5HTK   
CATH (Classification of proteins structures)5HTK   
AlphaFold pdb e-kbO60825   
Human Protein Atlas [tissue]ENSG00000123836-PFKFB2 [tissue]
Protein Interaction databases
IntAct (EBI)O60825
Ontologies - Pathways
Ontology : AmiGO6-phosphofructo-2-kinase activity  6-phosphofructo-2-kinase activity  fructose-2,6-bisphosphate 2-phosphatase activity  protein binding  ATP binding  nucleoplasm  cytosol  cytosol  fructose metabolic process  fructose 2,6-bisphosphate metabolic process  glucose catabolic process  lactate metabolic process  glycolytic process  response to glucose  dephosphorylation  protein kinase binding  positive regulation of insulin secretion  positive regulation of glucokinase activity  carbohydrate phosphorylation  
Ontology : EGO-EBI6-phosphofructo-2-kinase activity  6-phosphofructo-2-kinase activity  fructose-2,6-bisphosphate 2-phosphatase activity  protein binding  ATP binding  nucleoplasm  cytosol  cytosol  fructose metabolic process  fructose 2,6-bisphosphate metabolic process  glucose catabolic process  lactate metabolic process  glycolytic process  response to glucose  dephosphorylation  protein kinase binding  positive regulation of insulin secretion  positive regulation of glucokinase activity  carbohydrate phosphorylation  
REACTOMEO60825 [protein]
REACTOME PathwaysR-HSA-9634600 [pathway]   
NDEx NetworkPFKFB2
Atlas of Cancer Signalling NetworkPFKFB2
Wikipedia pathwaysPFKFB2
Orthology - Evolution
GeneTree (enSembl)ENSG00000123836
Phylogenetic Trees/Animal Genes : TreeFamPFKFB2
Homologs : HomoloGenePFKFB2
Homology/Alignments : Family Browser (UCSC)PFKFB2
Gene fusions - Rearrangements
Fusion : FusionGDB2.7.1.105|   
Fusion : FusionHubAPOA2--PFKFB2    C4BPB--PFKFB2    PFKFB2--DDHD1    PFKFB2--FCN1    PFKFB2--FMO2    PFKFB2--GTF2I    PFKFB2--PFKFB2    PFKFB2--RBM39    PFKFB2--THEMIS2    PPIL2--PFKFB2   
Fusion : QuiverPFKFB2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPFKFB2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PFKFB2
Exome Variant ServerPFKFB2
GNOMAD BrowserENSG00000123836
Varsome BrowserPFKFB2
ACMGPFKFB2 variants
Genomic Variants (DGV)PFKFB2 [DGVbeta]
DECIPHERPFKFB2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisPFKFB2 
ICGC Data PortalPFKFB2 
TCGA Data PortalPFKFB2 
Broad Tumor PortalPFKFB2
OASIS PortalPFKFB2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPFKFB2  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DPFKFB2
Mutations and Diseases : HGMDPFKFB2
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)PFKFB2
DoCM (Curated mutations)PFKFB2
CIViC (Clinical Interpretations of Variants in Cancer)PFKFB2
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry PFKFB2
NextProtO60825 [Medical]
Target ValidationPFKFB2
Huge Navigator PFKFB2 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDPFKFB2
Pharm GKB GenePA33212
Clinical trialPFKFB2
DataMed IndexPFKFB2
PubMed73 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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