Written | 2014-03 | Ana 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 |
Identity |
Other alias | PFK-2/FBPase-2 |
HGNC (Hugo) | PFKFB2 |
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 hg19-Feb_2009) [Mapping PFKFB2.png] |
Local_order | The human PFKFB2 gene is located on the chromosome 1 at position 1q31-q32.2 (GeneCards) (Fig. 1). |
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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) | |
DNA/RNA |
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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. |
Protein |
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. |
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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). Regulation Chromosomal rearrangements: copy number variants |
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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) |
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Mutations |
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. |
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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 |
Note | |
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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