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PFKFB4 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 [ Homo sapiens (human) ]

Gene ID: 5210, updated on 3-Apr-2024

Summary

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Official Symbol
PFKFB4provided by HGNC
Official Full Name
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4provided by HGNC
Primary source
HGNC:HGNC:8875
See related
Ensembl:ENSG00000114268 MIM:605320; AllianceGenome:HGNC:8875
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Summary
The protein encoded by this gene is one of four bifunctional kinase/phosphatases that regulate the concentration of the glycolytic byproduct fructose-2,6-bisphosphate (F2,6BP). The encoded protein is highly expressed in cancer cells and is induced by hypoxia. This protein is essential to the survival of cancer cells under conditions of hypoxia, because it increases the amount of F2,6BP and ATP at a time when the cell cannot produce much of them. This finding suggests that this protein may be a good target for disruption in cancer cells, hopefully imperiling their survival. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]
Expression
Broad expression in testis (RPKM 10.5), small intestine (RPKM 8.0) and 18 other tissues See more
Orthologs
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Genomic context

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See PFKFB4 in Genome Data Viewer
Location:
3p21.31
Exon count:
21
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 3 NC_000003.12 (48517684..48563136, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 3 NC_060927.1 (48546648..48592093, complement)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 3 NC_000003.11 (48555117..48598562, complement)

Chromosome 3 - NC_000003.12Genomic Context describing neighboring genes Neighboring gene ATRIP-TREX1 readthrough Neighboring gene ATR interacting protein Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48507557-48508438 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48508439-48509318 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48509460-48510226 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19831 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48513959-48514818 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19833 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48515680-48516539 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19834 Neighboring gene three prime repair exonuclease 1 Neighboring gene shisa family member 5 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14332 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14333 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48542139-48542692 Neighboring gene MPRA-validated peak4641 silencer Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:48587865-48588528 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:48588529-48589190 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48589191-48589854 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48589855-48590516 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19835 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19836 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48596699-48597640 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 19837 Neighboring gene microRNA 6823 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48605535-48606482 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:48607079-48607628 Neighboring gene collagen type VII alpha 1 chain Neighboring gene urocortin 2 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48625763-48626466 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48626467-48627168 Neighboring gene microRNA 711 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:48638465-48638965 Neighboring gene ubiquinol-cytochrome c reductase core protein 1 Neighboring gene small nucleolar RNA, H/ACA box 94

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. PFKFB4 Is a Metabolic Driver of HCC Progression and Chemoresistance Through ROS Mitigation. Olaizola P, et al. Cell Mol Gastroenterol Hepatol, 2023. PMID 36963434, Free PMC Article
  2. PFKFB4 Drives the Oncogenicity in TP53-Mutated Hepatocellular Carcinoma in a Phosphatase-Dependent Manner. Kam CS, et al. Cell Mol Gastroenterol Hepatol, 2023. PMID 36806581, Free PMC Article
  3. Loss of PFKFB4 induces cell cycle arrest and glucose metabolism inhibition by inactivating MEK/ERK/c-Myc pathway in cervical cancer cells. Wu Y, et al. J Obstet Gynaecol, 2022 Aug. PMID 35659173
  4. PFKFB4 is overexpressed in clear-cell renal cell carcinoma promoting pentose phosphate pathway that mediates Sunitinib resistance. Feng C, et al. J Exp Clin Cancer Res, 2021 Sep 30. PMID 34593007, Free PMC Article
  5. Expression of Alternative Splice Variants of 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase-4 in Normoxic and Hypoxic Melanoma Cells. Trojan SE, et al. Int J Mol Sci, 2021 Aug 17. PMID 34445551, Free PMC Article

See all (67) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Transforming growth factor beta1 upregulates 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-4 expression in A549 and MCF-10A cells.
    Title: Transforming growth factor β1 upregulates 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-4 expression in A549 and MCF-10A cells.
  2. THOC3 interacts with YBX1 to promote lung squamous cell carcinoma progression through PFKFB4 mRNA modification.
    Title: THOC3 interacts with YBX1 to promote lung squamous cell carcinoma progression through PFKFB4 mRNA modification.
  3. PFKFB4 Drives the Oncogenicity in TP53-Mutated Hepatocellular Carcinoma in a Phosphatase-Dependent Manner.
    Title: PFKFB4 Drives the Oncogenicity in TP53-Mutated Hepatocellular Carcinoma in a Phosphatase-Dependent Manner.
  4. PFKFB4 Is a Metabolic Driver of HCC Progression and Chemoresistance Through ROS Mitigation.
    Title: PFKFB4 Is a Metabolic Driver of HCC Progression and Chemoresistance Through ROS Mitigation.
  5. Loss of PFKFB4 induces cell cycle arrest and glucose metabolism inhibition by inactivating MEK/ERK/c-Myc pathway in cervical cancer cells.
    Title: Loss of PFKFB4 induces cell cycle arrest and glucose metabolism inhibition by inactivating MEK/ERK/c-Myc pathway in cervical cancer cells.
  6. Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis.
    Title: Phosphorylation of PFKFB4 by PIM2 promotes anaerobic glycolysis and cell proliferation in endometriosis.
  7. PFKFB4 modulated by miR-195-5p can boost the malignant progression of cervical cancer cells.
    Title: PFKFB4 modulated by miR-195-5p can boost the malignant progression of cervical cancer cells.
  8. PFKFB4 interacts with ICMT and activates RAS/AKT signaling-dependent cell migration in melanoma.
    Title: PFKFB4 interacts with ICMT and activates RAS/AKT signaling-dependent cell migration in melanoma.
  9. Hypoxia-inducible CircPFKFB4 Promotes Breast Cancer Progression by Facilitating the CRL4(DDB2) E3 Ubiquitin Ligase-mediated p27 Degradation.
    Title: Hypoxia-inducible CircPFKFB4 Promotes Breast Cancer Progression by Facilitating the CRL4(DDB2) E3 Ubiquitin Ligase-mediated p27 Degradation.
  10. PFKFB4 is overexpressed in clear-cell renal cell carcinoma promoting pentose phosphate pathway that mediates Sunitinib resistance.
    Title: PFKFB4 is overexpressed in clear-cell renal cell carcinoma promoting pentose phosphate pathway that mediates Sunitinib resistance.
Submit: New GeneRIF Correction See all GeneRIFs (40)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

EBI GWAS Catalog

Description
A genome-wide association study identifies a novel locus at 6q22.1 associated with ulcerative colitis.
EBI GWAS Catalog
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.
EBI GWAS Catalog

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables 6-phosphofructo-2-kinase activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables 6-phosphofructo-2-kinase activity NAS
Non-traceable Author Statement
more info
 PubMed 
enables ATP binding IEA
Inferred from Electronic Annotation
more info
  
enables fructose-2,6-bisphosphate 2-phosphatase activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
Process Evidence Code Pubs
involved_in carbohydrate phosphorylation IEA
Inferred from Electronic Annotation
more info
  
involved_in fructose 2,6-bisphosphate metabolic process IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in fructose metabolic process IEA
Inferred from Electronic Annotation
more info
  
Component Evidence Code Pubs
is_active_in cytosol IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in cytosol TAS
Traceable Author Statement
more info
  

General protein information

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Preferred Names
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4
Names
6PF-2-K/Fru-2,6-P2ase 4
6PF-2-K/Fru-2,6-P2ase testis-type isozyme
PFK/FBPase 4
bifunctional enzyme with kinase and biphosphatase activities
NP_001304063.1
NP_001304064.1
NP_001304065.1
NP_001304066.1
NP_001304067.1
NP_004558.1
XP_011532131.1
XP_016862103.1
XP_016862104.1
XP_016862105.1
XP_016862106.1
XP_024309363.1
XP_047304256.1
XP_047304257.1
XP_047304258.1
XP_047304259.1
XP_047304260.1
XP_054202802.1
XP_054202803.1
XP_054202804.1
XP_054202805.1
XP_054202806.1
XP_054202807.1
XP_054202808.1
XP_054202809.1
XP_054202810.1
XP_054202811.1
XP_054202812.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

  1. NM_001317134.2 → NP_001304063.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform a

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (a).
    Source sequence(s)
    AC134772, AY714243, BC010269
    UniProtKB/TrEMBL
    B2R6L2
    Conserved Domains (3) summary
    pfam00300
    Location:281 → 464
    His_Phos_1; Histidine phosphatase superfamily (branch 1)
    pfam01591
    Location:64 → 278
    6PF2K; 6-phosphofructo-2-kinase
    pfam13671
    Location:70 → 225
    AAA_33; AAA domain

  2. NM_001317135.2 → NP_001304064.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform c

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) lacks an alternate coding exon in the 5' end and uses an alternate in-frame splice junction compared to variant 1. The resulting isoform (c) has a shorter and distinct N-terminus and lacks an alternate internal segment compared to isoform a.
    Source sequence(s)
    AY707863, BC010269
    Consensus CDS
    CCDS82770.1
    UniProtKB/TrEMBL
    B2R6L2, Q66S35
    Related
    ENSP00000388394.1, ENST00000416568.5
    Conserved Domains (2) summary
    pfam01591
    Location:30 → 249
    6PF2K; 6-phosphofructo-2-kinase
    pfam00300
    Location:252 → 431
    His_Phos_1; Histidine phosphatase superfamily (branch 1)

  3. NM_001317136.2 → NP_001304065.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform d

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) uses an alternate first exon in place of the first two exons compared to variant 1. The resulting isoform (d) has a shorter and distinct N-terminus compared to isoform a.
    Source sequence(s)
    AK298732, BC010269
    UniProtKB/TrEMBL
    B2R6L2, B7Z5C3
    Conserved Domains (3) summary
    pfam00300
    Location:241 → 424
    His_Phos_1; Histidine phosphatase superfamily (branch 1)
    pfam01591
    Location:24 → 238
    6PF2K; 6-phosphofructo-2-kinase
    pfam13671
    Location:30 → 185
    AAA_33; AAA domain

  4. NM_001317137.2 → NP_001304066.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform e

    Status: REVIEWED

    Description
    Transcript Variant: This variant (5) lacks an alternate coding exon in the 5' end and lacks an alternate in-frame exon compared to variant 1. The resulting isoform (e) has a shorter and distinct N-terminus and lacks an alternate internal segment compared to isoform a.
    Source sequence(s)
    AY756064, BC010269
    Consensus CDS
    CCDS82769.1
    UniProtKB/TrEMBL
    B2R6L2
    Related
    ENSP00000373240.2, ENST00000383734.6
    Conserved Domains (2) summary
    cd07067
    Location:252 → 402
    HP_PGM_like; Histidine phosphatase domain found in phosphoglycerate mutases and related proteins, mostly phosphatases; contains a His residue which is phosphorylated during the reaction
    pfam01591
    Location:30 → 249
    6PF2K; 6-phosphofructo-2-kinase

  5. NM_001317138.2 → NP_001304067.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform f

    Status: REVIEWED

    Description
    Transcript Variant: This variant (6) lacks an alternate exon in the 5' end and contains another alternate internal exon compared to variant 1. The resulting isoform (f) is shorter at the N-terminus compared to isoform a.
    Source sequence(s)
    AY756063, BC010269
    UniProtKB/TrEMBL
    Q5XLC3
    Conserved Domains (2) summary
    pfam00300
    Location:61 → 244
    His_Phos_1; Histidine phosphatase superfamily (branch 1)
    cl17190
    Location:1 → 58
    NK; Nucleoside/nucleotide kinase (NK) is a protein superfamily consisting of multiple families of enzymes that share structural similarity and are functionally related to the catalysis of the reversible phosphate group transfer from nucleoside triphosphates ...

  6. NM_004567.4 → NP_004558.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform b

    See identical proteins and their annotated locations for NP_004558.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) lacks an alternate coding exon in the 5' end compared to variant 1. The resulting isoform (b) has a shorter and distinct N-terminus compared to isoform a.
    Source sequence(s)
    BC010269, DB069657
    Consensus CDS
    CCDS2771.1
    UniProtKB/Swiss-Prot
    Q16877, Q5S3G5, Q5XLC2, Q64EX5
    UniProtKB/TrEMBL
    B2R6L2
    Related
    ENSP00000232375.3, ENST00000232375.8
    Conserved Domains (2) summary
    pfam01591
    Location:30 → 249
    6PF2K; 6-phosphofructo-2-kinase
    pfam00300
    Location:252 → 438
    His_Phos_1; Histidine phosphatase superfamily (branch 1)

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000003.12 Reference GRCh38.p14 Primary Assembly

    Range
    48517684..48563136 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_011533829.3 → XP_011532131.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X2

    UniProtKB/TrEMBL
    B2R6L2
    Conserved Domains (3) summary
    pfam00300
    Location:254 → 437
    His_Phos_1; Histidine phosphatase superfamily (branch 1)
    pfam01591
    Location:37 → 251
    6PF2K; 6-phosphofructo-2-kinase
    pfam13671
    Location:43 → 198
    AAA_33; AAA domain

  2. XM_047448304.1 → XP_047304260.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X9

  3. XM_017006617.2 → XP_016862106.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X6

    UniProtKB/TrEMBL
    B2R6L2

  4. XM_047448301.1 → XP_047304257.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X7

  5. XM_017006616.2 → XP_016862105.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X5

    UniProtKB/TrEMBL
    B2R6L2

  6. XM_047448302.1 → XP_047304258.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

  7. XM_047448300.1 → XP_047304256.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X3

  8. XM_017006615.2 → XP_016862104.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X4

    UniProtKB/TrEMBL
    B2R6L2

  9. XM_017006614.2 → XP_016862103.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X1

    UniProtKB/TrEMBL
    B2R6L2

  10. XM_047448303.1 → XP_047304259.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

  11. XM_024453595.2 → XP_024309363.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

    UniProtKB/TrEMBL
    B2R6L2
    Conserved Domains (2) summary
    pfam01591
    Location:1 → 215
    6PF2K; 6-phosphofructo-2-kinase
    pfam00300
    Location:218 → 404
    His_Phos_1; Histidine phosphatase superfamily (branch 1)

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060927.1 Alternate T2T-CHM13v2.0

    Range
    48546648..48592093 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054346828.1 → XP_054202803.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X2

  2. XM_054346837.1 → XP_054202812.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X9

  3. XM_054346832.1 → XP_054202807.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X6

  4. XM_054346833.1 → XP_054202808.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X7

  5. XM_054346831.1 → XP_054202806.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X5

  6. XM_054346834.1 → XP_054202809.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

  7. XM_054346829.1 → XP_054202804.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X3

  8. XM_054346830.1 → XP_054202805.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X4

  9. XM_054346827.1 → XP_054202802.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X1

  10. XM_054346836.1 → XP_054202811.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

  11. XM_054346835.1 → XP_054202810.1  6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 isoform X8

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
Q16877.6 GenPept UniProtKB/Swiss-Prot:Q16877

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