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FLASH GENE
Symbol PKM contributors: mct/npt/pgu - updated : 03-09-2015
HGNC name pyruvate kinase, muscle
HGNC id 9021
Location 15q23      Physical location : -
Synonym name
  • OPA-interacting protein 3
  • pyruvate kinase M2
  • thyroid hormone-binding protein, cytosolic pyruvate kinase M2
    • Synonym symbol(s) PK3, TCB, OIP3, CTHBP, THBP2, THBP1, MGC3932, PKM2
    EC.number 2.7.1.40
    DNA
    TYPE functioning gene
    STRUCTURE 32.53 kb     11 Exon(s)
    text structure putative Sp1-binding sites
    MAPPING cloned Y linked N status confirmed
    RNA
    TRANSCRIPTS type messenger
    text
  • two alternatively spliced isoforms, M1 and M2
  • alternative splicing has an important role in determining the metabolic phenotype of mammalian cells (PMID: 20010808)
  • exons 9 and 10 are alternatively spliced in a mutually exclusive fashion to give rise to the PK-M1 and PK-M2 isoforms, respectively (PMID: 20133837)
    • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    11 splicing 2516 58 531 . upregulated in cancer cells . expressed during development and in many adult tissues, including the spleen, lung, and all cancers 2013 24120138
  • lacking a segment within the 5' UTR compared to variant 2
  • variant PKM2, embryonic pyruvate kinase isoform, almost universally re-expressed in cancer, and promoting aerobic glycolysis
  • inclusion of exon 10
  • PKM2, but not PKM1, is regulated by the binding of tyrosine phosphorylated peptides, which results in release of the allosteric activator fructose-1-6-bisphosphate and inhibition of pyruvate kinase activity
  • activity of PK-M2 is allosterically regulated by fructose-1,6-bisphosphate levels and interaction with tyrosine-phosphorylated proteins
    • 11 splicing 2732 58 531 predominantly in differentiated adult tissues with high ATP requirements, such as the heart, brain, and muscle 2013 24120138
  • representing the longest transcript
  • encoding an isoform (2) that is the same length as isoform 1, but containing a different internal segment
  • variant PKM1, adult isoform, promoting oxidative phosphorylation
  • inclusion of exon 9
  • constitutively active
    • 12 splicing 2516 57 531 - 2012 23155487
  • lacking a segment in the 5' UTR
  • having an alternate in-frame coding exon compared to variant 2
  • resulting in an isoform (1) with a different internal segment than isoform 2, but being the same length
    • 10 - 2294 - 457 - 2012 23155487
    11 - 2541 - 516 - 2012 23155487
    12 - 2853 - 605 - 2012 23155487
    11 - 2421 - 536 - 2012 23155487
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestivepancreas exocrine   moderately
    Reproductivefemale systemovary  highly
     female systemuteruscervix highly
    Skin/Tegumentskin   predominantly
    Urinarykidney   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervousperipherous   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
    mono polymer homomer , tetramer
    HOMOLOGY
    interspecies ortholog to rattus Pkm2
    ortholog to murine Pkm2
    ortholog to zebrafish pkm2
    ortholog to drosophila PyK
    ortholog to S. cerevisiae CDC19
    Homologene
    FAMILY
  • pyruvate kinase family
    • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytosolic
    basic FUNCTION
  • catalyzing the production of phosphoenolpyruvate from pyruvate and ATP
  • may mediate cellular metabolic effects induced by thyroid hormones
  • phosphotyrosine-binding form of pyruvate kinase which is critical for rapid growth in cancer cells
  • essential non-metabolic functions of PKM (isoform PKM2) in EGFR-promoted CTNNB1 transactivation, cell proliferation and tumorigenesis
  • role as a protein kinase in its nonmetabolic functions of histone modification, which is essential for its epigenetic regulation of gene expression and tumorigenesis
  • plays an important role in the growth and metabolic reprogramming of cancer cells in stress conditions
  • importance of nuclear functions of PKM2 in the Warburg effect and tumorigenesis
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism carbohydrate , energetic
    signaling
  • glycolysis, final step
  • energy pathway
    • a component
  • PKM dimer is an active protein kinase, while the tetramer is an active pyruvate kinase
  • PKM/TGM2 interplay plays an important role in the regulation of autophagy in particular under cellular stressful conditions such as those displayed by cancer cells
    • INTERACTION
    DNA
    RNA
    small molecule cofactor,
  • Mg2+
  • K+
    • protein
  • binds directly and selectively to tyrosine-phosphorylated peptides
  • OPA protein
  • interacting with HNRNPA2B1, PTBP1, and HNRNPA1 (have critical role in promoting PKM2 production in tumours, and overexpression of some combination of them is, like PKM2 expression, likely to be a general phenomenon in cancer
  • interaction with PKM2, and inhibition of PKM2 by PRL contributes potentially to the PRL-stimulated cell proliferation
  • SAICAR stimulates PKM and promotes cancer cell survival in glucose-limited conditions
  • KDM8/PKM interaction resides at the intersubunit interface region of PKM, which hinders PKM tetramerization and blocks pyruvate kinase activity
  • ZBTB7A directly binds to the promoter and represses the transcription of critical glycolytic genes, including SLC2A3, PFKP, and PKM
  • TRIM35 interacts with PKM and the coiled-coil domain is required for such an interaction
  • ECM1 plays an important role in promoting the Warburg effect mediated by PKM
  • TRIM35 inhibits phosphorylation of pyruvate kinase isoform M2 (PKM), which is involved in aerobic glycolysis of cancer cells
  • TGM2 interacts with PKM, a rate limiting enzyme of glycolysis which is responsible for maintaining a glycolytic phenotype in malignant cells and displays non metabolic functions, including transcriptional co-activation and protein kinase activity
    • cell & other
  • serine can bind to and activate PKM2, and PKM2 activity in cells is reduced in response to serine deprivation
    • REGULATION
    Other regulation of PKM activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in gastric cancer
    tumoral     --over  
    with MYC, PTBP1, HNRNPA1 and HNRNPA2B1 in gliomas, correlated with PKM2 expression
    tumoral     --over  
    in a grade-specific manner in human glioma
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
  • PKM/TRIM35 expression could be a biomarker for the prognosis of hepatocellular carcinoma (HCC)
    • Therapy target
    SystemTypeDisorderPubmed
    cancer  
    because most normal tissues express an isoform of pyruvate kinase other than PKM2, selective targeting of PKM2 provides an opportunity to target cell metabolism for cancer therapy
    ANIMAL & CELL MODELS