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PKM (pyruvate kinase isoenzyme type M2)

Identity

Other namesPKM2
CTHBP
OIP3
PK2
PK3
PKM
TCB
THBP1
HGNC (Hugo) PKM
LocusID (NCBI) 5315
Location 15q23
Location_base_pair Starts at 72491370 and ends at 72523727 bp from pter ( according to hg19-Feb_2009)

DNA/RNA

Note Pyruvate kinase isoenzyme type M2 (alias M2-PK, alias PKM2) is one of four pyruvate kinase isoenzymes which differ widely in their occurrence according to the type of tissue, their kinetic characteristics and regulation mechanisms. The three other pyruvate kinase isoenzymes are type M1, type L and type R. The PKM-gene encodes for pyruvate kinase isoenzyme type M2 as well as pyruvate kinase isoenzyme type M1.
 
  Exon/intron structure of the PKM gene and the PKM1 and PKM2 mRNAs derived by alternative splicing.
Description The human PKM gene is 32,315 kb long and consists of 12 exons and 11 introns.
Transcription Pyruvate kinase isoenzymes type M1 and type M2 are different splicing products of the PKM gene (exon 9 for M1-PK and exon 10 for M2-PK). Both mRNAs are 1593 base pairs long and differ from another within 160 nucleotide residues from 1143-1303. The PKM gene is induced by hormones, mitogenic pathways and nutrients. The thyroid gland hormone triiodothyronine (T3) induces PKM gene expression in rat pituitary cells and the monomeric form of the PKM protein has been identified as T3-receptor. Interleukin 2 stimulates PKM transcription in proliferating thymocytes, resulting in increased PKM2 mRNA and protein levels in the S phase of the cell cycle. In NIH3T3 L1 adipocytes PKM gene expression is induced by insulin. Evidence for a role of hypoxia, and the key nutrients glucose and glutamine, in the regulation of PKM gene expression has also been reported. The regulation of the PKM gene at the promoter level is, however, not well understood. The PKM gene contains putative DNA-consensus binding sites for the transcription factors Sp1 and Sp3 (GC-boxes) and Sp1/Sp3-dependent stimulation of PKM gene transcription has been demonstrated. The GC-boxes appear to also play a role in glucose-dependent PKM-gene induction. A carbohydrate-response element (ChoRE), which integrates regulation of many glycolytic genes in response to changes in glucose concentration, has not yet been precisely localized in the PKM promoter region. However, putative consensus DNA-binding elements for USF (Upstream stimulating factor), a transcription factor which is involved in glucose-response, HIF-1alpha (Hypoxia-inducible factor) and the oncogenic transcription factor Myc are present within the PKM promoter region. The USF-box (5'-CACGTG-3'), the HIF-1alpha DNA-binding consensus element (5'-RCGTG-3') as well as the MYC consensus element (E-box; 5'-CACGTG-3') match the consensus core DNA-binding sites (5'-CACGTG-3') of the ChoRE. However, direct evidence for a role of these transcription factors in the stimulation of PKM gene expression has bot been obtained.
Pseudogene No Pseudogenes.

Protein

Note In various references pyruvate kinase isoenzyme type M2 (abbreviations M2-PK or PKM2) has been termed type III, type A, type B, type K or type K4.
 
  Molecular structure of the human PKM2 protein. NLS = nuclear localization signal.
Description Each monomer of PKM2 consists of 531 amino acids and can be subdivided into four domains: the N-domain (aa 1-43), the A-domain (aa 44-116 and 219-389), the B-domain (aa 117-218) and the C-domain (aa 390-531). The molecular weight of the M2-PK monomer is 58 kD. In contrast to the other PK isoenzymes which are characterized by a tetrameric quaternary structure, M2-PK occurs in a tetrameric as well as dimeric form. The dimeric form of M2-PK is the result of intracellular contact between the A-domain of two monomers. The tetrameric form occurs by association of the interface of the C-domains of two dimers. The C-domain contains 44 amino acids of the 56 amino acid stretch (aa 378-434) which differs between M1 and M2-PK-isoenzymes and is responsible for the different kinetic characteristics and regulation mechanisms found for M1 and M2-PK, i.e. fructose 1,6-P2 activation and interaction with different oncoproteins. The cleft formed between the A- and B-domain is the location of the active site of the enzyme. The C-domain (aa 393-531) comprises an inducible nuclear translocation signal.
Expression Pyruvate kinase isoenzyme type M2 is expressed in some differentiated tissues, such as lung, fat tissue, retina, pancreatic islets as well as in all cells with a high rate of nucleic acid synthesis, which include all proliferating cells, such as normal proliferating cells, embryonic cells, adult stem cells and especially tumor cells. In healthy tissues all pyruvate kinase isoenzymes consist of four subunits whereby hybrids of the different forms can also occur. Hybrids between M1 and M2-PK were found in the oesophagus and the stomach. L-PK and M2-PK hybrids were found in the jejunum, colon and rectum. During differentiation of embryonic cells M2-PK is progressively replaced by the respective tissue specific isoenzyme. Conversely, during tumorigenesis the tissue specific isoenzymes disappear and M2-PK is expressed.
Localisation Pyruvate kinase type M2 is found predominantly in the cytosol and to a minor extent in the nucleus. Cytosolic M2-PK is associated with other glycolytic enzymes, i.e. hexokinase, glyceraldehyde 3-P dehydrogenase, phosphoglycerate kinase, phosphoglyceromutase, enolase and lactate dehydrogenase in a so-called glycolytic enzyme complex.
Function Pyruvate kinase (ATP: pyruvate O2-phosphotransferase; EC 2.7.1.40) catalyzes the last step within glycolysis, the dephosphorylation of phosphoenolpyruvate (PEP) to pyruvate while producing one mole of ATP per mole of PEP. Depending upon the tetramer to dimer ratio M2-PK plays a bi-functional role within tumor metabolism. The tetrameric form of M2-PK favors the degradation of glucose to pyruvate and lactate with regeneration of energy due to a high affinity to its substrate PEP. The dimeric form is characterized by a low PEP affinity and is nearly inactive at physiological PEP concentrations. This leads to an expansion of all phosphometabolites above the pyruvate kinase reaction and an increased channeling of glucose carbons into synthetic processes, i.e. DNA, phospholipid and amino acid synthesis. Tumor cells contain high levels of dimeric M2-PK, which has therefore been termed │Tumor M2-PK▓.
The M2-PK tetramer to dimer ratio fluctuates in tumor cells depending upon the concentrations of signal metabolites. High fructose 1,6-P2 levels induce the association of the inactive dimeric form of M2-PK to the highly active tetrameric form. When FBP levels drop below a critical value the tetrameric form dissociates to the dimeric form. Dimerization of M2-PK is induced by direct interaction with different oncoproteins, i.e. pp60v-src, A-Raf and HPV-16 E7. The importance of M2-PK for oncogenesis is further underlined by the impairment of the oncogenic activity of activated A-Raf (gag-A-Raf) by a kinase-dead mutant of M2-PK and the enhancement of the transforming activity of gag-A-Raf by ectopically expressed wild type M2-PK. Similarly, a knockdown of M2-PK expression by short hairpin RNA and replacement with M1-PK led to a reduction in tumor growth rate. Peptide aptamers which specifically bind to M2-PK and not to the 96% homologous PK isoenzyme type M1 were found to avoid re-association of M2-PK to the tetrameric form thereby reducing ATP levels and decelerating tumor cell proliferation.
Recent work has shown that the binding of cytosolic promyelocytic leukemia (PML) tumor suppressor protein to M2-PK leads to inhibition of the activity of the tetrameric form of M2-PK which results in a suppression of lactate production. The interaction of M2-PK with HERC-1, PKCdelta and tumor endothelial marker TEM8 has also been reported; however, the physiological functions of these findings are not yet well understood.
Regarding the function of M2-PK in the nucleus both pro-proliferative, but also pro-apoptotic stimuli have been described. Thus, interleukin-3-induced nuclear translocation of M2-PK stimulated cell proliferation, whereas nuclear translocation of M2-PK induced by TT232, H2O2 or UV-irradiation was linked to the induction of caspase independent programmed cell death. Nuclear M2-PK was found to participate in the phosphorylation of histone H1 by direct phosphate transfer from PEP to histone H1. Furthermore, M2-PK was shown to interact with Oct-4 and stimulates transactivation by the transcription factor; however, the functional consequences of these findings have not been elucidated.
The interaction between PKM2 with gonococcal Opa proteins points to a physiological role of M2-PK in bacterial pathogenesis.
Homology It is assumed that M1 and M2-PK diverged shortly before the evolution of fish. The pyruvate kinase amino acid sequence is highly conserved. The homology between human M1-PK and human M2-PK is 96%. Comparison of the M2-PK amino acid sequence between different species revealed the following homologies: human and rat: 93%; human and mus musculus: 93 %; rat and mus musculus 98%; human and S. cerevisiae: 50%.

Mutations

Note There is one report which describes a missense mutation and a frame shift mutation in exon 10 of the M gene in three B-lymphoblastoid cell lines established from three Bloom syndrome patients. Exon 10 encodes for the intersubunit contact domain of the M2-PK protein. These mutations have a dominant negative effect leading to inactivation of M2-PK. However, the relevance of these mutations has not yet been determined.

Implicated in

Note M2-PK is overexpressed in all tumor entities thus far investigated, such as gastrointestinal tumors, melanoma, tumors of the lung, breast, prostate, ovary and cervix. Tumor M2-PK, the dimeric form of M2-PK, is released from tumors into the blood, and pleural fluid and from tumors of the lower gastrointestinal tract also into the stool of tumor patients. The amount of Tumor M2-PK in plasma and stool was found to correlate with staging and may be used for early detection of tumors and follow up studies during therapy. For some tumor entities correlations with certain oncoprotein expressions have been described.
  
Entity Renal cell carcinoma
Disease The term renal cell carcinoma (RCC) comprises different histological types whereby the clear cell renal cell carcinoma is the most common histologic variant, accounting for approximately 70% of all cases. Estimated incidences rank RCC as the 13th most common malignancy in men and 15th in women. In addition to sporadic forms, hereditary forms of RCC also occur, e.g. in a high proportion of patients with von Hippel-Lindau disease (VHL).
Oncogenesis In patients with von Hippel-Lindau disease and in a high percentage of tumors from patients with sporadic clear cell RCC, one inherited allele of the VHL gene - a master regulator of HIF (hypoxia-inducible factor) - is mutated and the second allele is deleted. VHL mutations lead to a pseudo-hypoxic state with overproduction of HIF-1a. The PKM promotor contains a binding site for HIF-1. Hypoxia correlates with an increase in PKM2 mRNA.
  
Entity Tumors of the uterine cervix
Disease Cervical carcinoma is the 2nd most common cancer in women worldwide. It originates for the most part from the transformation zone of the cervix. The histologic morphology is predominantly of the squamous cell type.
Oncogenesis Chronic infection with human papillomavirus (HPV) plays a major aetiological role in the evolution of cervical carcinomas. The products of the oncogenes E6 and E7 from HPV 16 are able to form stable complexes with cellular proteins thereby modifying or inactivating their normal functions. It has been shown that the E7 protein physically interacts with and stabilizes the dimeric form of PKM2.
  
Entity Gastric carcinoma
Note In different gastric carcinoma cell lines cisplatin resistance was found to correlate with low M2-PK protein levels and activities. Lowering of M2-PK expression through antisense transfection increased cisplatin resistance.
Disease Stomach cancer is the 4th most common cancer worldwide. Helicobacter pylori infection appears to play a pivotal aetiological role in the induction of the intestinal type of gastric carcinoma, whereby its action is probably indirect by provoking an inflammatory response. Thus, gastritis is usually the first step in cancer induction and may lead to multifocal atrophic gastritis followed by intestinal metaplasia as an important precursor lesion.
  
Entity Colon and rectum cancer
Disease Colorectal cancers rank 4th in frequency in men and 3rd in women. Most carcinomas develop from adenomas, which constitute their precursor lesion. These adenomas may occur sporadically or as part of a polyposis syndrome. More than ninety percent of all large bowel tumors are ordinary adenocarcinomas.
Oncogenesis Inactivating mutations of the adenomatous polyposis coli (APC) gene is an early event and a key molecular step in adenoma formation. Further progression to colon cancer is a multistep process wherein multiple alterations may be relevant, e.g. mutations in the DCC, k-ras, and/or p53 genes; loss of heterozygosity; and DNA methylations. A recent report described the coexistence of mutational activation of the k-ras gene and HPV high risk types infection in colon cancer. It has been shown that the HPV-16 E7 protein, which cooperates with ras in cell transformation, directly binds to PKM2, thereby inducing and stabilizing the dimeric form of this isoenzyme.
  

External links

Nomenclature
HGNC (Hugo)PKM   9021
Cards
AtlasPKM2ID41728ch15q22
Entrez_Gene (NCBI)PKM  5315  pyruvate kinase, muscle
GeneCards (Weizmann)PKM
Ensembl (Hinxton)ENSG00000067225 [Gene_View]  chr15:72491370-72523727 [Contig_View]  PKM [Vega]
ICGC DataPortalENSG00000067225
AceView (NCBI)PKM
Genatlas (Paris)PKM
WikiGenes5315
SOURCE (Princeton)NM_001206796 NM_001206797 NM_001206798 NM_001206799 NM_002654 NM_182470 NM_182471
Genomic and cartography
GoldenPath (UCSC)PKM  -  15q23   chr15:72491370-72523727 -  15q23   [Description]    (hg19-Feb_2009)
EnsemblPKM - 15q23 [CytoView]
Mapping of homologs : NCBIPKM [Mapview]
OMIM179050   
Gene and transcription
Genbank (Entrez)AF025439 AK092369 AK222927 AK294315 AK297951
RefSeq transcript (Entrez)NM_001206796 NM_001206797 NM_001206798 NM_001206799 NM_002654 NM_182470 NM_182471
RefSeq genomic (Entrez)AC_000147 NC_000015 NC_018926 NT_010194 NW_001838218 NW_004929398
Consensus coding sequences : CCDS (NCBI)PKM
Cluster EST : UnigeneHs.534770 [ NCBI ]
CGAP (NCI)Hs.534770
Alternative Splicing : Fast-db (Paris)GSHG0010563
Alternative Splicing GalleryENSG00000067225
Gene ExpressionPKM [ NCBI-GEO ]     PKM [ SEEK ]   PKM [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP14618 (Uniprot)
NextProtP14618  [Medical]
With graphics : InterProP14618
Splice isoforms : SwissVarP14618 (Swissvar)
Catalytic activity : Enzyme2.7.1.40 [ Enzyme-Expasy ]   2.7.1.402.7.1.40 [ IntEnz-EBI ]   2.7.1.40 [ BRENDA ]   2.7.1.40 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)PYRUVATE_KINASE (PS00110)   
Domains : Interpro (EBI)Pyr_Knase    Pyrv/PenolPyrv_Kinase-like_dom    Pyrv_Knase-like_insert_dom    Pyrv_Knase_a/b    Pyrv_Knase_AS    Pyrv_Knase_brl    Pyrv_Knase_C    Pyrv_Knase_insert_dom   
Related proteins : CluSTrP14618
Domain families : Pfam (Sanger)PK (PF00224)    PK_C (PF02887)   
Domain families : Pfam (NCBI)pfam00224    pfam02887   
DMDM Disease mutations5315
Blocks (Seattle)P14618
PDB (SRS)1T5A    1ZJH    3BJF    3BJT    3G2G    3GQY    3GR4    3H6O    3ME3    3SRD    3SRF    3SRH    3U2Z    4B2D    4FXF    4FXJ    4G1N    4JPG   
PDB (PDBSum)1T5A    1ZJH    3BJF    3BJT    3G2G    3GQY    3GR4    3H6O    3ME3    3SRD    3SRF    3SRH    3U2Z    4B2D    4FXF    4FXJ    4G1N    4JPG   
PDB (IMB)1T5A    1ZJH    3BJF    3BJT    3G2G    3GQY    3GR4    3H6O    3ME3    3SRD    3SRF    3SRH    3U2Z    4B2D    4FXF    4FXJ    4G1N    4JPG   
PDB (RSDB)1T5A    1ZJH    3BJF    3BJT    3G2G    3GQY    3GR4    3H6O    3ME3    3SRD    3SRF    3SRH    3U2Z    4B2D    4FXF    4FXJ    4G1N    4JPG   
Human Protein AtlasENSG00000067225
Peptide AtlasP14618
HPRD01529
IPIIPI00479186   IPI00220644   IPI00604528   IPI00847989   IPI01018161   IPI00910979   IPI01018212   
Protein Interaction databases
DIP (DOE-UCLA)P14618
IntAct (EBI)P14618
FunCoupENSG00000067225
BioGRIDPKM
InParanoidP14618
Interologous Interaction database P14618
IntegromeDBPKM
STRING (EMBL)PKM
Ontologies - Pathways
Ontology : AmiGOmagnesium ion binding  pyruvate kinase activity  protein binding  ATP binding  nucleus  cytoplasm  mitochondrion  cytosol  cytosol  plasma membrane  cilium  carbohydrate metabolic process  glucose metabolic process  glycolytic process  glycolytic process  programmed cell death  phosphorylation  MHC class II protein complex binding  potassium ion binding  small molecule metabolic process  poly(A) RNA binding  extracellular vesicular exosome  
Ontology : EGO-EBImagnesium ion binding  pyruvate kinase activity  protein binding  ATP binding  nucleus  cytoplasm  mitochondrion  cytosol  cytosol  plasma membrane  cilium  carbohydrate metabolic process  glucose metabolic process  glycolytic process  glycolytic process  programmed cell death  phosphorylation  MHC class II protein complex binding  potassium ion binding  small molecule metabolic process  poly(A) RNA binding  extracellular vesicular exosome  
Pathways : KEGGGlycolysis / Gluconeogenesis    Purine metabolism    Pyruvate metabolism    Type II diabetes mellitus    Viral carcinogenesis   
REACTOMEP14618 [protein]
REACTOME PathwaysREACT_111217 Metabolism [pathway]
Protein Interaction DatabasePKM
Wikipedia pathwaysPKM
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)PKM
SNP (GeneSNP Utah)PKM
SNP : HGBasePKM
Genetic variants : HAPMAPPKM
1000_GenomesPKM 
ICGC programENSG00000067225 
CONAN: Copy Number AnalysisPKM 
Somatic Mutations in Cancer : COSMICPKM 
Mutations and Diseases : HGMDPKM
OMIM179050   
MedgenPKM
GENETestsPKM
Disease Genetic AssociationPKM
Huge Navigator PKM [HugePedia]  PKM [HugeCancerGEM]
Genomic VariantsPKM  PKM [DGVbeta]
Exome VariantPKM
dbVarPKM
ClinVarPKM
snp3D : Map Gene to Disease5315
General knowledge
Homologs : HomoloGenePKM
Homology/Alignments : Family Browser (UCSC)PKM
Phylogenetic Trees/Animal Genes : TreeFamPKM
Chemical/Protein Interactions : CTD5315
Chemical/Pharm GKB GenePA33353
Clinical trialPKM
Cancer Resource (Charite)ENSG00000067225
Other databases
Probes
Litterature
PubMed196 Pubmed reference(s) in Entrez
CoreMinePKM
iHOPPKM

Bibliography

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PMID 4424631
 
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Discovery of a metabolic pathway mediating glucose-induced desensitiziation of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance.
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PMID 2002019
 
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Hypoxia regulates ▀-enolase and pyruvate kinase-M promoters by modulating Sp1/Sp3 binding to a conserved GC element.
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Expression of hypoxia-inducible genes in tumor cells.
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Using the yeast two-hybrid system to identify human epithelial cell proteins that bind gonococcal Opa proteins: intracellular gonococci bind pyruvate kinase via their Opa proteins and require host pyruvate for growth.
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PMID 10470201
 
Expression of pyruvate kinase M2 in preneoplastic hepatic foci of N-nitrososmorpholine-treated rats.
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Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein.
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PMID 9990017
 
Tumor type M2-pyruvate kinase expression in advanced breast cancer.
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PMID 11326672
 
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PMID 11687968
 
Regulation of glycolysis by A-Raf protein serine/threonine kinase.
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Insulin stimulates expression of the pyruvate kinase M gene in 3T3-L1 adipocytes.
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PMID 12843653
 
Interaction between HERC1 and M2-type pyruvate kinase.
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PMID 12650930
 
The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer.
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PMID 12890838
 
The dual activity of pyruvate kinase type M2 chromatin extracts of neoplastic cells.
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Contributor(s)

Written05-2008Sybille Mazurek, Ferdinand Hugo, Werner Zwerschke
Institute for Biochemistry & Endocrinology, Veterinary Medicine, University of Giessen, Frankfurter Strasse 100, 35392 Giessen, Germany (SM) ; ScheBo Biotech AG, Netanyastrasse 3, 35394 Giessen, Germany (SM) ; Institute of Medical Microbiology, Medical Faculty, University of Giessen, Frankfurter Strasse 107, 35392 Giessen, Germany (FH) ; Institute of Medical Diagnostics, Nicolaistrasse 22, 12247 Berlin, Germany (FH) ; Cell Metabolism and Differentiation Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, 6020 Innsbruck, Austria (WZ)

Citation

This paper should be referenced as such :
Mazurek, S ; Hugo, F ; Zwerschke, W
PKM2 (pyruvate kinase isoenzyme type M2)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(4):276-281.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/PKM2ID41728ch15q22.html

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