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PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4)

Written2013-04Alexandra Ouertani, Violaine Goidts
German Cancer Research Center (DKFZ), Department of Molecular Genetics, Heidelberg, Germany

(Note : for Links provided by Atlas : click)

Identity

Other aliasPFK/FBPase 4
HGNC (Hugo) PFKFB4
LocusID (NCBI) 5210
Atlas_Id 46519
Location 3p21.31  [Link to chromosome band 3p21]
Location_base_pair Starts at 48555117 and ends at 48594356 bp from pter ( according to hg19-Feb_2009)  [Mapping PFKFB4.png]
Fusion genes
(updated 2016)
PFKFB4 (3p21.31) / MYRIP (3p22.1)SPATA13 (13q12.12) / PFKFB4 (3p21.31)

DNA/RNA

Description PFKFB4 is composed of 14 exons and spans 44332 bp on the minus strand.
Transcription PFKFB4 NM_004567.2 contains 3586 bases and the open reading starts at 114 bases to finish at 1410 bases.
There are nine putative splice variants that are protein coding, as reported in the Ensembl database. Moreover, several splice variants have been reported in rat tissues, as well as in DB-1 melanoma cells. Notably, the PFK-2 core domain is conserved among all splice variants (Minchenko et al., 2005b; Minchenko et al., 2008; Ros and Schulze, 2013).

Protein

Description PFKFB4 consists of 469 residues and has a molecular weight of 54040 Da.
PFKFB4 is one of the four isoforms (PFKFB1-PFKFB2-PFKFB3-PFKFB4) of the bifunctional enzyme PFK2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase), differing in their kinetic and regulatory properties.
The PFK2 enzyme has both kinase and phosphatase activities, producing or degrading fructose-2,6-bisphosphate (Fru-2,6-P2). 6-Phosphofructo-2-kinase (6-PF-2-K) synthesizes Fru-2,6-P2 from fructose-6-phosphate (F6P) and ATP, while fructose-2,6-bisphosphatase (Fru-2,6-P2ase) hydrolyzes Fru-2,6-P2 to form F6P and inorganic phosphate (Pi). Fru-2,6-P2 is a rate-limiting enzyme product and an important control point in glycolysis and gluconeogenesis via its stimulatory effect on phosphofructokinase 1 (PFK1) activity and its inhibitory effect on fructose-1,6-bisphosphatase (Fru-1,6-P2ase) (Pilkis et al., 1996).
The mammalian PFKFB4 gene encodes an isozyme originally identified as a homodimer in the testis (Sakata et al., 1991; Manzano et al., 1999; Gomez et al., 2005).
The enzyme is divided into two functional domains (Figure 1): the N-terminal catalytic domain in which the 6-PF-2-K activity is found, and the C-terminal domain that houses the Fru-2,6-P2ase activity.
 
  Figure 1: Schematic representation of the structure of the bifunctional isozyme PFKFB4. The different potential sites were defined by mutagenesis or by structural similarity to other mononucleotide binding proteins and phosphoglucomutases (Hasemann et al., 1996; Yuen et al., 1999a; Yuen et al., 1999b; Tominaga et al., 1993; Uyeda et al., 1997).
Expression PFKFB4 is expressed in testis and at specific times during sperm maturation (Gomez et al., 2009). A recent report showed that 5α-androstan-17β-ol-3-one, inducing the paracrine secretion of FGF-2 by Sertoli cells could modulate the expression of PFKFB isozymes during spermatogenesis (Gomez et al., 2012). Moreover, it was demonstrated that hypoxia, as well as glucose level, strongly regulate PFKFB4 mRNA and protein expression levels in different cancer cell lines from prostate and liver (Minchenko et al., 2004; Li et al., 2012; Ros et al., 2012). Recent studies have showed the cancer-specific overexpression of PFKFB4 in astrocytoma (Goidts et al., 2012).
Localisation PFKFB4 is found in the cytosol.
 
Function PFKFB4 is a bifunctional isozyme harboring two domains that function within a homodimeric protein complex. It synthesizes and degrades Fru-2,6-P2 as described in the equations above (Figure 2) (Sakata et al., 1991).
The first reaction (kinase) taking place at the N-terminal side of the protein transfers the phosphate from ATP to F-6-P by a sequential-ordered mechanism. The biphosphatase reaction, which is located in the C-terminal domain, proceeds via a covalent phosphohistidine intermediate at position H257 (Figure 1) formed upon reaction with F-2,6-P2. The steady state concentration of F-2,6-P2 is determined by the balance between these opposing reactions. The kinase:biphosphatase activity ratio is different for all four isoforms (Okar et al., 2001). Indeed, the K:B ratio of the human PFKFB4 is approximately of 1 while PFKFB3 harbors a significantly higher ratio (740:1). These differences mainly reside on the effect of several glycolytic metabolites or post-translational modifications.
Fru-2,6-P2 is a powerful allosteric activator of phosphofructokinase 1 (PFK-1), the enzyme that controls one of the most critical steps of glycolysis (Wu et al., 2006). However, Fru-2,6-P2 not only controls the PFK-1 reaction but also the reverse reaction in the gluconeogenic pathway by inhibiting fructose 1,6-bisphosphatase (FBPase-1) (Figure 3).
 
  Figure 3: Overview of the function of PFK2. 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases (PFK-2/FBPase-2) regulates the production of F-2,6-P2 which controls the production of F-1,6-P2 by activating or inhibiting PFK1.
Homology There are four PFK2 isoenzymes in mammals encoded by four different genes (PFKFB1-PFKFB4). Although the different isoforms present a high sequence homology of their core domain, there are differences in their regulatory and kinetic properties, probably due to the structural variations in the N- and C-terminal regions (Ros and Schulze, 2013).
From protein sequence alignments, it appears that the bisphosphatase activity is homologous to the phosphoglycerate mutases (PGMs) and the acid phosphatase family. The N-terminal PFK-2 domain is homologous to several nucleotide binding proteins, such as the NMP kinase (nucleoside-monophosphate kinase) (Bazan et al., 1989; Hasemann et al., 1996; Okar et al., 2001).

Mutations

Somatic 18 different missense somatic mutations have been reported in different tumor samples, such as lung, liver, colon or breast cancer (Sjoeblom et al., 2006; Forbes et al., 2011).

Implicated in

Note
  
Entity Non-muscle invasive bladder cancer (NMIBC)
Note PFKFB4 mRNA and protein expression was investigated in NMBIC samples.
Prognosis Recurrence free survival time was significantly reduced in patients with elevated PFKFB4 mRNA levels, whereas PFKFB4 protein levels did not correlate with differences in time to tumor recurrence. The time of progression free survival was significantly shorter in patients with increased PFKFB4 mRNA or protein expression levels (Yun et al., 2012).
  
  
Entity Breast cancer
Note PFKFB4 was showed to be highly expressed in solid malignant tumors of the breast compared to non-malignant tissue (Minchenko et al., 2005a).
In several breast cancer cell lines (BT549, MCF7, MDA-MB468, SKBR3, TD47), PFKFB4 expression was increased upon exposure to hypoxia (Minchenko et al., 2005a, Minchenko et al., 2005c).
  
  
Entity Glioma
Note PFKFB4 mRNA and protein expression was showed to be increased in three different glioblastoma stem-like cell lines, but not in normal brain cells. shRNA mediated knockdown of PFKFB4 in glioma stem-like cell lines led to increased apoptosis (Goidts et al., 2012), while no phenotypic effect could be seen in PFKFB4-silenced normal neural stem cells. These results suggested a cancer-specific function of PFKFB4 in glioblastoma.
Prognosis Glioblastoma patients with tumors with higher than average PFKFB4 expression showed a significantly shorter overall survival time, compared to patients with lower than average PFKFB4 expression. Furthermore, PFKFB4 mRNA expression correlated with glioma tumors grade (Goidts et al., 2012).
Oncogenesis Glioblastoma stem-like cells, thought to be responsible for chemo- and radiotherapy resistance, are resilient against hypoxic conditions in the tumor microenvironment under which the hypoxia inducible factor 1α (HIF1α), a transcription factor, is triggered. HIF1α activates transcription of PFKFB4 leading to higher glycolysis and production rates of lactate and ATP, essential for the survival of these cells. Silencing of PFKFB4 was showed to decrease significantly ATP and lactate levels, leading to the phosphorylation/activation of the AMPK (adenosine monophosphate-activated protein kinase).
  
  
Entity Colon cancer
Note mRNA expression of PFKFB4 was significantly increased in colon solid malignant tumors in comparison to non-malignant tissue (Minchenko et al., 2005a).
  
  
Entity Gastric cancer
Note In gastric cancer tissue, PFKFB4 mRNA expression was increased compared to the nonmalignant counterpart (Bobarykina et al., 2006).
PFKFB4 mRNA expression was found to be low in the gastric cancer cell lines MKN45 and NUGC3. Protein expression levels differed from low to highly expressed, but low protein levels were increased under hypoxic conditions (Bobarykina et al., 2006).
  
  
Entity Liver cancer
Note In a hepatic cancer cell line (huh-7), sulforaphane-induced apoptosis resulted in decreased PFKFB4 protein expression and glucose consumption. PFKFB4 expression was increased again under hypoxic conditions, due to the HIF1α transcription factor being induced and activating PFKFB4 transcription (Jeon et al., 2011).
Moreover, PFKFB4 expression was suggested to be controlled by HO-2 (Heme oxygenase 2) in the hepatic cancer cell line HepG2 (Li et al., 2012).
  
  
Entity Pancreatic cancer
Note Low levels of PFKFB4 mRNA and protein expression were found in the pancreatic cancer cell line Pank1, but expression was induced on both levels under hypoxia (Bobarykina et al., 2006).
  
  
Entity Prostate cancer
Note In 3 different prostate cancer cell lines (DU145, LNCaP, PC3), PFKFB4 expression was higher than in the noncancer cell line RWPE1 (Ros et al., 2012).
Silencing of PFKFB4 in xenografted prostate cancer tumors in vivo (60% reduction in PFKFB4 mRNA levels) resulted in significant reduction of the tumor size and an increased number of cells with apoptotic morphology. Tumor growth was positively correlated to PFKFB4 mRNA expression (Ros et al., 2012).
Oncogenesis PFKFB4 was accumulated upon siRNA mediated silencing of PFKFB4 in prostate cancer cell lines, leading to reduced cell survival. These findings suggest an enhanced phosphatase activity in prostate cancer cells, important for their survival. Additionally, depletion of PFKFB4 decreased the concentration of NADPH, a pentose phosphate pathway metabolite required for de novo synthesis of fatty acids and the maintenance of the antioxidant GSH, leading to increased levels of reactive oxygen species (Ros et al., 2012).
  

Bibliography

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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 AY, Minchenko DO, Opentanova IL, Moenner M, Caro J, Esumi H, Minchenko OH.
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RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival.
Goidts V, Bageritz J, Puccio L, Nakata S, Zapatka M, Barbus S, Toedt G, Campos B, Korshunov A, Momma S, Van Schaftingen E, Reifenberger G, Herold-Mende C, Lichter P, Radlwimmer B.
Oncogene. 2012 Jul 5;31(27):3235-43. doi: 10.1038/onc.2011.490. Epub 2011 Nov 7.
PMID 22056879
 
Sertoli-secreted FGF-2 induces PFKFB4 isozyme expression in mouse spermatogenic cells by activation of the MEK/ERK/CREB pathway.
Gomez M, Manzano A, Figueras A, Vinals F, Ventura F, Rosa JL, Bartrons R, Navarro-Sabate A.
Am J Physiol Endocrinol Metab. 2012 Sep 15;303(6):E695-707. doi: 10.1152/ajpendo.00381.2011. Epub 2012 Jul 17.
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Switches in 6-phosphofructo-2-kinase isoenzyme expression during rat sperm maturation.
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Biochem Biophys Res Commun. 2009 Sep 18;387(2):330-5. doi: 10.1016/j.bbrc.2009.07.021. Epub 2009 Jul 10.
PMID 19595670
 
The crystal structure of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase reveals distinct domain homologies.
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Sulforaphane induces apoptosis in human hepatic cancer cells through inhibition of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase4, mediated by hypoxia inducible factor-1-dependent pathway.
Jeon YK, Yoo DR, Jang YH, Jang SY, Nam MJ.
Biochim Biophys Acta. 2011 Oct;1814(10):1340-8. doi: 10.1016/j.bbapap.2011.05.015. Epub 2011 May 25.
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Coordinated expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 and heme oxygenase 2: evidence for a regulatory link between glycolysis and heme catabolism.
Li B, Takeda K, Ishikawa K, Yoshizawa M, Sato M, Shibahara S, Furuyama K.
Tohoku J Exp Med. 2012;228(1):27-41.
PMID 22892400
 
Cloning, expression and chromosomal localization of a human testis 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene.
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Alternative splice variants of rat 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase-4 mRNA.
Minchenko DO, Mykhalchenko VG, Tsuchihara K, Kanehara S, Yavorovsky OP, Zavgorodny IV, Paustovsky YO, Komisarenko SV, Esumi H, Minchenko OH.
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Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 gene via hypoxia-inducible factor-1alpha activation.
Minchenko O, Opentanova I, Minchenko D, Ogura T, Esumi H.
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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. 2005c;52(4):881-8. Epub 2005 Jul 11.
PMID 16025159
 
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
 
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PMID 7574501
 
Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival.
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Citation

This paper should be referenced as such :
Ouertani, A ; Goidts, V
PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(10):699-703.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PFKFB4ID46519ch3p21.html


External links

Nomenclature
HGNC (Hugo)PFKFB4   8875
Cards
AtlasPFKFB4ID46519ch3p21
Entrez_Gene (NCBI)PFKFB4  5210  6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4
Aliases
GeneCards (Weizmann)PFKFB4
Ensembl hg19 (Hinxton)ENSG00000114268 [Gene_View]  chr3:48555117-48594356 [Contig_View]  PFKFB4 [Vega]
Ensembl hg38 (Hinxton)ENSG00000114268 [Gene_View]  chr3:48555117-48594356 [Contig_View]  PFKFB4 [Vega]
ICGC DataPortalENSG00000114268
TCGA cBioPortalPFKFB4
AceView (NCBI)PFKFB4
Genatlas (Paris)PFKFB4
WikiGenes5210
SOURCE (Princeton)PFKFB4
Genetics Home Reference (NIH)PFKFB4
Genomic and cartography
GoldenPath hg19 (UCSC)PFKFB4  -     chr3:48555117-48594356 -  3p22-p21   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PFKFB4  -     3p22-p21   [Description]    (hg38-Dec_2013)
EnsemblPFKFB4 - 3p22-p21 [CytoView hg19]  PFKFB4 - 3p22-p21 [CytoView hg38]
Mapping of homologs : NCBIPFKFB4 [Mapview hg19]  PFKFB4 [Mapview hg38]
OMIM605320   
Gene and transcription
Genbank (Entrez)AF108765 AK298732 AK299097 AK312623 AY707863
RefSeq transcript (Entrez)NM_001317134 NM_001317135 NM_001317136 NM_001317137 NM_001317138 NM_004567
RefSeq genomic (Entrez)NC_000003 NC_018914 NT_022517 NW_004929309
Consensus coding sequences : CCDS (NCBI)PFKFB4
Cluster EST : UnigeneHs.476217 [ NCBI ]
CGAP (NCI)Hs.476217
Alternative Splicing GalleryENSG00000114268
Gene ExpressionPFKFB4 [ NCBI-GEO ]   PFKFB4 [ EBI - ARRAY_EXPRESS ]   PFKFB4 [ SEEK ]   PFKFB4 [ MEM ]
Gene Expression Viewer (FireBrowse)PFKFB4 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5210
GTEX Portal (Tissue expression)PFKFB4
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ16877   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ16877  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ16877
Splice isoforms : SwissVarQ16877
Catalytic activity : Enzyme2.7.1.105 [ Enzyme-Expasy ]   2.7.1.1052.7.1.105 [ IntEnz-EBI ]   2.7.1.105 [ BRENDA ]   2.7.1.105 [ KEGG ]   
PhosPhoSitePlusQ16877
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)PFKFB4
DMDM Disease mutations5210
Blocks (Seattle)PFKFB4
SuperfamilyQ16877
Human Protein AtlasENSG00000114268
Peptide AtlasQ16877
HPRD05613
IPIIPI00220070   IPI00924970   IPI00922340   IPI01009778   IPI00927537   IPI00925149   IPI00925359   IPI00478618   IPI00925881   IPI00926077   
Protein Interaction databases
DIP (DOE-UCLA)Q16877
IntAct (EBI)Q16877
FunCoupENSG00000114268
BioGRIDPFKFB4
STRING (EMBL)PFKFB4
ZODIACPFKFB4
Ontologies - Pathways
QuickGOQ16877
Ontology : AmiGO6-phosphofructo-2-kinase activity  6-phosphofructo-2-kinase activity  fructose-2,6-bisphosphate 2-phosphatase activity  ATP binding  cytosol  fructose metabolic process  fructose 2,6-bisphosphate metabolic process  dephosphorylation  carbohydrate phosphorylation  carbohydrate phosphorylation  canonical glycolysis  
Ontology : EGO-EBI6-phosphofructo-2-kinase activity  6-phosphofructo-2-kinase activity  fructose-2,6-bisphosphate 2-phosphatase activity  ATP binding  cytosol  fructose metabolic process  fructose 2,6-bisphosphate metabolic process  dephosphorylation  carbohydrate phosphorylation  carbohydrate phosphorylation  canonical glycolysis  
Pathways : KEGGFructose and mannose metabolism    HIF-1 signaling pathway   
REACTOMEQ16877 [protein]
REACTOME Pathways70171 [pathway]   
NDEx NetworkPFKFB4
Atlas of Cancer Signalling NetworkPFKFB4
Wikipedia pathwaysPFKFB4
Orthology - Evolution
OrthoDB5210
GeneTree (enSembl)ENSG00000114268
Phylogenetic Trees/Animal Genes : TreeFamPFKFB4
HOVERGENQ16877
HOGENOMQ16877
Homologs : HomoloGenePFKFB4
Homology/Alignments : Family Browser (UCSC)PFKFB4
Gene fusions - Rearrangements
Fusion : MitelmanPFKFB4/MYRIP [3p21.31/3p22.1]  
Fusion: TCGAPFKFB4 3p21.31 MYRIP 3p22.1 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPFKFB4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PFKFB4
dbVarPFKFB4
ClinVarPFKFB4
1000_GenomesPFKFB4 
Exome Variant ServerPFKFB4
ExAC (Exome Aggregation Consortium)PFKFB4 (select the gene name)
Genetic variants : HAPMAP5210
Genomic Variants (DGV)PFKFB4 [DGVbeta]
DECIPHER (Syndromes)3:48555117-48594356  ENSG00000114268
CONAN: Copy Number AnalysisPFKFB4 
Mutations
ICGC Data PortalPFKFB4 
TCGA Data PortalPFKFB4 
Broad Tumor PortalPFKFB4
OASIS PortalPFKFB4 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPFKFB4  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPFKFB4
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PFKFB4
DgiDB (Drug Gene Interaction Database)PFKFB4
DoCM (Curated mutations)PFKFB4 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PFKFB4 (select a term)
intoGenPFKFB4
NCG5 (London)PFKFB4
Cancer3DPFKFB4(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605320   
Orphanet
MedgenPFKFB4
Genetic Testing Registry PFKFB4
NextProtQ16877 [Medical]
TSGene5210
GENETestsPFKFB4
Huge Navigator PFKFB4 [HugePedia]
snp3D : Map Gene to Disease5210
BioCentury BCIQPFKFB4
ClinGenPFKFB4
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5210
Chemical/Pharm GKB GenePA33214
Clinical trialPFKFB4
Miscellaneous
canSAR (ICR)PFKFB4 (select the gene name)
Other databasehttp://www.phosphosite.org/homeAction.do
Probes
Litterature
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