Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Pyruvate Kinase M2

  • Gopinath Prakasam
  • Mohammad Askandar Iqbal
  • Vibhor Gupta
  • Bhupender Kumar
  • Rameshwar N. K. Bamezai
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101893


Historical Background

PKM2 (pyruvate kinase muscle isoform 2) is an isoform of pyruvate kinase (PK; ATP, pyruvate 2-O-phosphotranferase; EC, a terminal glycolytic enzyme that catalyzes an irreversible, rate-limiting transphosphorylation reaction between phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP) to generate pyruvate and ATP, accounting for net glycolytic energy (ATP) generation (Mazurek 2011). Consumption of pyruvate in a number of pathways places this enzyme at a crucial metabolic intersection. PK is ubiquitously present in simple to complex organisms. In organisms where PK is absent, its function is fulfilled by another homologue, pyruvate phosphate dikinase (PPDK) (Saavedra-Lira et al. 1998). In most bacteria and lower eukaryotes, only one form of PK is found, although many bacteria have two isozymes. In plants, PK exists in the form of cytoplasmic and plastid isoforms, and in vertebrate tissues, four different isozymes are distinguished. In the hierarchy of evolution, PKM1 and PKM2 are recognized as discrete isoforms, subsequent to the evolution of fish (Mazurek 2011).

PK Gene Isoforms, Their Expression Regulation, and Subcellular Localization

Mammals have four isoforms of pyruvate kinase, namely, PKR, PKL, PKM1, and PKM2 (Harada et al. 1978), encoded by two distinct pyruvate kinase genes (PKLR and PKM). The expression of PK isoforms is tightly regulated to exhibit tissue specificity and to meet the metabolic demands of tissues in which they are preferentially expressed. PKLR gene of Homo sapiens, positioned in chromosome 1q21, encodes for PKR and PKL isoforms in erythrocytes and liver by transactivating alternate promoters (Noguchi et al. 1987). PKM gene, located in chromosome 15q23, encodes alternative splice variants PKM1 and PKM2 with 12 exons, of which the PKM1 retains exon 9 and skips exon 10, whereas PKM2 retains exon 10 (Noguchi et al. 1986). The proteins encoded by the mutually exclusive exons represented in PKM1 and PKM2 thus differ by 23 of the 56-amino acid stretch at their C-terminal end. PKM2 expression dominates in cells with high proliferative capacity, such as embryonic cells, stem cells, and transformed cancer cells. Embryonic cells that show PKM2 expression gradually replace it with the tissue-specific isoforms during their differentiation. Thus, the expression of PKM1 is demonstrated to be ideal for the cell types (tissues of the muscle, brain, and heart) that are highly differentiated and require a large quantity of energy (ATP) supply (Fig. 1).
Pyruvate Kinase M2, Fig. 1

Schematic representation of human PKM gene, its isoforms, and expression regulation. PKM gene occupies q23 band position in chromosome 15, encoding 2 mutually exclusive alternative splice variants, PKM1 and PKM2. The expression of PKM is tightly regulated by various extracellular stimuli, such as nutrients, hypoxia, growth factors, hormones, cytokines and lipopolysaccharides (LPS) that largely influence glycolytic pathway. PKM promoter region harbors consensus binding sites for numerous transcription factors, including Sp1, Sp2, HIF-1α; and an extra level of c-Myc controlled expression of hnRNPs’ (heterogeneous nuclear ribonucleoproteins) regulates the alternative splicing of PKM transcripts. Higher expression of hnRNPs represses the inclusion of exon 9, enabling the proliferating cells to preferentially express PKM2; whereas a low expression of hnRNPs includes exon 9 to express PKM1

The exprssion of PKM gene is regulated by hormones (insulin, triiodothyronine-T3), cytokines (interleukin-2), mitogens, nutrient status, and hypoxia. PKM gene possesses the putative consensus DNA-binding sites of numerous transcription factors including Sp1, Sp2, HIF-1alpha, and Myc. Sp1/Sp2 and HIF1-alpha transcription factors are experimentally validated to regulate PKM2 expression (Iqbal et al. 2014a). c-Myc controlled expression of hnRNPs (heterogeneous nuclear ribonucleoproteins) has been shown to regulate the alternative splicing of PKM transcripts by repressing the presence of exon 9 and supporting the inclusion of exon 10 in PKM primary transcript to yield the PKM2 spliced isoform (Fig. 1) (David et al. 2010). Nuclear localization of PKM2 has been associated with various non-glycolytic functions, and the nuclear presence of PKM2 is regulated by epidermal growth factor (EGF), interleukin-3 (IL-3), lipopolysaccharide, and hypoxia (non-glycolytic features are discussed below).

Structure and Function of PKM2

PKM2 consists of 531 amino acids and its sequence partitioned into A-, B-, and C-domains possesses characteristic functional features. The interface between A- and B-domain together forms the catalytic active site, whereas C-domain involves allosteric activator – fructose 1,6-bisphosphate (FBP) – binding site and nuclear localization signal sequence (NLS) and inter-subunit contact domain (ISCD). The protein sequence of PKM2 that stretches across the ISCD domain markedly differs from its alternate splice variant PKM1 by 23 amino acids, offering characteristic kinetic features (i.e., allosteric regulation by FBP) to PKM2, and its ability to associate with unique protein partners including phosphotyrosine proteins. PKM2 exists both in tetrameric and dimeric forms; however, all other PK isoforms (i.e., PKL, PKR, and PKM1) occur as tetramers. The A-domain of PKM2 monomers associates to give rise to a dimer and two dimers interact at the interface of ISCD (C-domain) to form the PKM2 tetramer. Tetrameric form of PKM2 has a higher affinity toward PEP, demonstrating more pyruvate kinase activity, whereas dimeric PKM2 shows lower affinity toward PEP and remains nearly inactive at physiological conditions. PKM2, one of the rate-limiting glycolytic enzymes, is known to be allosterically regulated, besides FBP, by other metabolic intermediates, like serine, phosphatidylserine, and succinylaminoimidazolecarboxamide ribose-5′-phosphate (SAICAR). Amino acids, such as alanine, phenylalanine, and tryptophan, are known to allosterically inhibit the activity of PKM2 (Table 1 (Chaneton et al. 2012; Keller et al. 2012; Iqbal et al. 2014a)).
Pyruvate Kinase M2, Table 1

Molecular and biochemical properties of human pyruvate kinase enzyme

Molecular features

Pyruvate kinase muscle isoforms






Name of gene





Chromosome no.





Size of gene

19.43 kb

19.43 kb

32.79 kb

32.79 kb

No. of amino acids





Molecular mass of subunit (Da)





Cellular localization



Cytoplasmic and nuclear

Tissue specificity



Brain, heart, skeletal muscle, etc.

Embryonic cells, cancer cells, and proliferating cells

Biochemical properties

Subunit structure

Monomer and tetramers

Monomer dimer and tetramer

Enzyme commission no. (EC)

EC =






Allosteric activator



FBP, serine, SAICAR

Role of PKM2 in Cancer

PKM2 in Cancer Metabolism

In recent years, PKM2 biology has generated enormous interest, especially with regard to its role in cancer. Numerous studies have revealed that the embryonic PKM2 reappears during tumor development, in order to help cancer cells achieve metabolic transformation required for cell division and other important cancer traits, like invasion and migration. Intriguingly, PKM2 has been shown to be vital in producing a unique metabolic phenotype of “aerobic glycolysis” or “Warburg effect” in cancer cells. Unlike normal cells, cancer cells take up large amounts of glucose and break it primarily into lactate, regardless of the presence of molecular oxygen (O2), a tendency exploited in clinical detection of cancer by fluorodeoxyglucose positron emission tomography (FDG-PET) scan. Despite an elevated PKM2 expression, cancer cells choose to accumulate enzymatically inactive dimeric form of PKM2 by promoting subunit dissociation. Low-activity-dimeric PKM2 retards the final step of glycolysis, thus resulting in the pileup of glycolytic intermediates, which are precursor of pentose phosphate pathway (PPP) for biomass production, in addition to a balanced supply of ATP via glycolysis. The dimer/tetramer ratio of PKM2 in cancer cells is influenced by numerous factors like drop in concentration of allosteric activator FBP, competitive binding of tyrosine-phosphorylated proteins at the FBP-binding pocket (Christofk et al. 2008), dominant-negative mutation at ISCD region (Anitha et al. 2004), interaction with oncoproteins (e.g., HPV16 E7 oncoprotein), and remarkably by posttranslational modifications (PTMs) (reviewed in Gupta and Bamezai 2010; Iqbal et al. 2010a). Among the PTMs of PKM2, phosphorylation of Tyr105 residue is carried out by oncogenic tyrosine kinases (e.g., FGFR1, BCR-ABL, JAK2). In addition, acetylation of lysine-305 and oxidation of cysteine-358 have been shown to facilitate the formation of dimeric PKM2, eventually contributing to aerobic glycolysis in tumor (reviewed in Gupta et al. 2014; Iqbal et al. 2014a). In a study carried out by Iqbal et al., insulin was shown to regulate cancer metabolism by induction of high expression of PKM2, regulated by PI3K-mTOR-HIF1-α pathway, along with simultaneous inactivation of the same through ROS up-regulation, depicting a dual regulatory control within a cell to favor aerobic glycolysis and anabolism (Fig. 2) (Iqbal et al. 2013). Further, it was shown that cancer cell treated with DNA-damaging agent could stimulate PKM2 Tyr105 phosphorylation and redirect the glycolytic flux toward pentose phosphate pathway (PPP) for anabolism (Kumar and Bamezai 2015). Recently, PARP-14 has been shown to contribute to aerobic glycolysis by negatively regulating JNK-1 (pro-apoptotic factor) and preventing Thr365 phosphorylation of PKM2 and its activation.
Pyruvate Kinase M2, Fig. 2

Schematic diagram portraying the features that coordinate the dimeric and tetrameric state of PKM2 isoform and its resultant impact on metabolic phenotypes. Oncogenes, ROS, nutrient status and post translational modifications of PKM2 facilitate enzymatically inactive dimeric state (Red), which in turn reprograms the glycolytic pathway to exhibit aerobic glycolysis, essential for the biosynthesis of macromolecules to support cell growth and rapid proliferation. Conversely, FBP, SAICAR and serine, promote active tetrameric state of PKM2 (Green), which couples glycolysis with mitochondrial oxidative phosphorylation (OXPHOS) to yield ample amount of energy to meet the demands of differentiated cells. Red arrows in the illustration indicate the flux of the glycolysis and fate the glycolytic intermediates, as a result of the dimeric state of PKM2. Green arrows signify the path of glycolytic intermediates and flux governed by the tetrameric PKM2. Abbreviations: PPP pentose phosphate pathway, SAICAR succinylaminoimidazolecarboxamide ribose-5′-phosphate, G-6-P Glucose-6-phosphate, FBP fructose-1, 6-bisphosphate, 3-PG - 3-phosphoglyceric acid, PEP phophoenol pyruvate, RTKs receptor tyrosine kinase, TCA tricarboxylic cycle, ROS reactive oxygen species

Non-metabolic Attributes of PKM2 in Cancer

Besides regulating cancer metabolism, PKM2 plays an important role in tumor progression via non-metabolic attributes, e.g., gene regulation. A study carried out by Lee et al. was first of its kind to demonstrate PKM2 as a transcription coactivator that interacted with Oct-4 (transcription factor) to enhance transactivation of its target genes that retain pluripotency in embryonic stem cells (Lee et al. 2008). Several other studies have shown that PKM2 could act as a transcriptional coactivator of, HIF1α, signal transducer and activator of transcription (Stat-3), β-catenin, and aryl hydrocarbon receptor (AhR). This transcriptional co-activation results in expression of target genes involved in regulation of cell proliferation, survival, and metabolic reprogramming (Fig. 3). On the other hand, emerging studies propose that physical binding of PKM2 with a group of transcription factors could regress their transactivation in a context-dependent manner. As a proof of concept, Atsushi Hamabe et al. revealed that cancer cells undergoing epithelial–mesenchymal transition (EMT) direct PKM2 inside the nucleus where it binds to TGF-beta-induced factor homeobox 2 (TGIF2) (Hamabe et al. 2014). PKM2 bound to TGIF2 results in repression of E-cadherin (CDH1) expression, thus allowing epithelial to mesenchymal transition. A recent study by Li Xia et al. unraveled yet another co-repressor feature, where PKM2 interacts with p53 and represses it to transactivate cell cycle inhibitors (p21 and p27) upon exposure of cancer cells to DNA-damaging agents (Xia et al. 2016). This study provides a plausible explanation for the resistance shown by cancer cells against DNA-damaging drugs.
Pyruvate Kinase M2, Fig. 3

Schematic representation of the non-glycolytic nuclear function of PKM2. α- importin mobilizes post transnationally modified PKM2 dimer inside the nucleus in response to the distinct extrinsic stimuli. In brief, nuclear PKM2 exhibits the characteristic features of a transcriptional co-activator and a protein kinase to enhance the transactivation of HIF 1 alpha, β-catenin, STAT3 and AhR, transcription factors. The transactivation of mentioned transcription factors together code for the factors that control, cell proliferation, metabolism and survival. Abbreviations: OH hydroxylation, Ac acetylation, P phosphorylation, JMJD5 Jumonji C domain-containing dioxygenase, HIF1 hypoxic inducible factor 1, PHD3 HIF prolyl-hydroxylase 3, HRE hypoxic response elements, LCF/TCF lymphoid enhancing factor/T-cell factor, LDHA lactate dehydrogenase A, GLUT1 glucose transporter 1, PDK1 pyruvate dehydrogenase kinase, STAT 3 signal transducer and activator of transcription 3, MEK5 Mitogen-Activated Protein Kinase Kinase 5, CYP1A1 cytochrome P450 family 1 subfamily A member 1, Ahr aryl hydrocarbon receptor, Arnt aryl hydrocarbon receptor nuclear translocator

Another important non-metabolic attribute of PKM2 associated with tumor progression is by virtue of its protein kinase activity. Inactive dimeric PKM2 acts as a protein kinase, whereas the tetramer behaves as pyruvate kinase. Gao et al. found that the dimeric PKM2 with PEP as phosphate donor phosphorylates Stat3 at Tyr705 residue to transactivate factors that promote cell proliferation (Gao et al. 2012). Another study by Yang et al. showed that EGF stimulation mobilized dimeric PKM2 into the nucleus to interact and phosphorylate Thr11 of H3 to control the expression of c-Myc and cyclin D1 in cancer cells (Yang et al. 2012). Further, studies by Lv et al. describe that acetylation of PKM2 at lysine-433 residue, mediated by 300 acetyltransferase in response to diverse mitogenic and oncogenic signals, enables PKM2 to localize inside the nucleus and carry out Stat3 and H3 phosphorylation and transactivation, leading to expression of proteins that promote cell proliferation (Fig. 3) (Lv et al. 2013). Apart from its role in cell cycle initiation, PKM2 supports cell cycle progression by governing the precise chromosomal segregation by phosphorylating Tyr207 residue of spindle checkpoint protein Bub3. Recently, binding of SAICAR with PKM2 has been shown to enhance its protein kinase activity, where several novel putative protein substrates were reported to be phosphorylated by SAICAR–PKM2 complex. Earlier studies by Mazurek et al. have reported that the individuals with gastrointestinal and colorectal tumors secreted dimeric PKM2 in blood plasma and in stool, resulting in the use of dimeric PKM2 as a diagnostic and prognostic marker. However, the mechanism by which cancer cells secrete dimeric PKM2 in circulation and its precise function in cancer progression has remained obscure (Mazurek 2011). A recent study in this direction has shown the involvement of secreted dimeric PKM2 in tumor angiogenesis by stimulating angiogenic endothelial cell proliferation, migration, and cell–ECM adhesion. In addition, the non-secreted intracellular dimeric PKM2 of cancer cells promotes angiogenesis by transactivating HIF1α to enable the expression of vascular endothelial growth factor (VEGF), a proangiogenic factor.
Pyruvate Kinase M2, Fig. 4

Schematic illustration portraying the expression regulation of enzyme PKM2 by the extrinsic and intrinsic cues and an intricate balance of coordinated regulation and deregulation of PKM2 with resultant physiological and pathological outcomes

PKM2 as a Therapeutic Target in Cancer

Considering the variety of benefits that PKM2 confers to cancer, it could be a promising therapeutic target. Several reports have suggested strategies to target PKM2 and retard cancer progression. Natural compounds like resveratrol, gemcitabine, and shikonin have been shown to inhibit PKM2 (Chen et al. 2011; Iqbal and Bamezai 2012; Pandita et al. 2014). Small interfering RNA (siRNA) against PKM2 has been shown to significantly abrogate the tumor growth and induce caspase-dependent apoptosis in cancer cells, both in vitro and in vivo. It is also reported that silencing of PKM2 may have synergistic effect with anticancer drugs (Kumar and Bamezai 2015). Synthetic small molecule inhibitors ((N-(3-carboxy-4-hydroxy)phenyl 1–2, 5-dimethylpyrole) and Arava), identified through high-throughput screen, have been shown to selectively target PKM2 activity. In addition, cell permeable structural analogs of FBP, TEPP-46 (ML265; thieno-[3,2-b]pyrrole[3,2-d]pyridazinone), and DASA-58 (ML203; substituted N,N′-diarylsulfonamide) that drive PKM2 tetramer formation in cancer cells have been shown to inhibit human lung carcinoma progression in xenograft mouse models (reviewed in Gupta et al. 2014; Iqbal et al. 2014a).

Role of PKM2 Beyond Cancer

Multifunctional Role of PKM2 and Cellular Physiology

The understanding of PKM2, in the recent past, has been overemphasized in the context of cancer pathophysiology, neglecting its significance in governing physiology at cellular and whole-body level. In the past decades, a few studies proposing the involvement of PKM2 in diverse aspects of organismal physiology, such as regulating immune metabolism and supporting immune inflammatory response against harmful stimuli and maintaining homeostasis, should have earned a principal position for PKM2 in the several cellular signaling networks. Such multifunctional roles (Gupta and Bamezai 2010) in cellular physiology are now getting unraveled for PKM2. A study by Palsson et al. has demonstrated that lipopolysaccharide (LPS)-activated macrophages tend to accumulate less active dimeric PKM2 which translocate to the nucleus and form complex with HIF1α to enhance the transactivation of a pro-inflammatory cytokine IL-1β. Further, in their in vivo studies, they demonstrated that abolishment of PKM2 or induction of PKM2 tetramer formation in LPS- or S. typhimurium-induced macrophage abrogated PKM2 nuclear translocation and HIF1α-dependent transactivation of IL-1 β expression. Thus, the study established an important role for the glycolytic enzyme PKM2 in inflammatory responses (Palsson-McDermott et al. 2015). PKM2-HIF1α axis, in addition, has been involved in the release of a potent pro-inflammatory cytokine high-mobility group box-1 (HMGB1) in activated macrophages (Yang et al. 2014). Further, PKM2-dependent transactivation of STAT3 transcription factor has been shown in colorectal carcinoma cells stimulated with LPS with an increased production of IL-1β and TNF-α. Also, PKM2 secreted by the activated neutrophils at the site of wound has recently been proposed to be a key step in early inflammatory response in wound repair. PKM2 released by infiltrated neutrophils facilitates the early wound healing processes by promoting angiogenesis at the wound site (Zhang et al. 2016).

A recent work by Zhang et al. has shown an overexpression and nuclear translocation of PKM2 in astrocytes following spinal cord injury (SCI), which was further correlated with expression of β-catenin, cyclin D1, and PCNA. Authors suggested that PKM2 overexpression and its nuclear translocation may have a significant role in inducing astrocyte proliferation following SCI, thus uncovering the relevance of PKM2 in CNS injury and repair (Zhang et al. 2015). Further, Parkin (an E3 ubiquitin ligase, mutated in most cases of autosomal recessive early onset of Parkinson’s disease) has also been shown to regulate the energy metabolism by the ubiquitination and reduction in activity of PKM1 and PKM2 in vitro and in vivo, highlighting the novel importance of Parkin in energy metabolism and providing an insight in Parkinson’s disease and its possible therapeutic intervention (Liu et al. 2016).

PKM2 in Non-cancer Human Pathologies

Several studies have unraveled a potential link of PKM2 and associated metabolic phenotypes with various pathologies. For instance, studies carried out by Bamezai and associates have indicated that heterozygous mutations in PKM2 (observed in some Bloom syndrome, BS, patients) and/or downregulation of PKM2 activity could be responsible for the inherent susceptibility of BS patients to cancer (Anitha et al. 2004; Akhtar et al. 2009; Gupta and Bamezai 2010; Gupta et al. 2010; Iqbal et al. 2014b). Although aberrations in BLM gene are the prime cause for BS, yet these fail to explain all the clinical symptoms of BS (Bamezai 1996). In addition, about 7% BS patients do not show any mutation in BLM gene (German et al. 2007), thus leaving a scope to search for other genes, like PKM2, which could play a role in explaining the clinical features of BS, such as type 2 diabetes, compromised immune response and inflammation, premature aging, male infertility, and growth retardation, besides cancer occurrence, evaluated by in vitro and in vivo mouse xenograft studies (Akhtar et al. 2009; Gupta et al. 2010; Iqbal et al. 2014b).

The deregulated expression of PKM2 and resultant aerobic glycolysis has been shown to confer defects in energy metabolism of type I myofibers with a possibility of causing myotonic dystrophy (Gao and Cooper 2013). Similar studies conducted by Shirai T et al. have attempted to connect PKM2-driven aerobic glycolysis with atherosclerotic coronary artery disease (CAD). The study shows that the overexpression and nuclear translocation of PKM2 in monocytes and macrophages of CAD patients phosphorylate and activate STAT3 transcription factor for the excessive synthesis of interleukins (IL-6 and IL-1β), which in turn drives systemic and tissue inflammation (Shirai et al. 2016). In yet another study, deregulated expression of PKM2 in activated myeloid dendritic cells (mDCs) was linked with the hematological condition known as severe aplastic anemia (SAA). Notably, work from Bearss, J. Arroyo team highlighted the association of PKM2 with placental pathological condition named preeclampsia (PE) that accounts for premature deliveries and complications for the mother and neonate (Bahr et al. 2014). Further, high level of PKM2 expression has been reported in the intestine of patients with Crohn’s disease and in the synovial tissue of patients with rheumatoid arthritis (Alves-Filho and Palsson-McDermott 2016). Altogether, these reports have strongly suggested the role of deregulated PKM2 expression in a variety of inflammatory disorders.


PKM2 is an evolutionarily conserved, prototype enzyme of glycolytic pathway. Apart from glycolysis, fine-tuning of this dynamic macromolecule, in accordance with the complex intrinsic and extrinsic cues, enables the cells to accomplish key physiological tasks that preserve cellular and whole-body homeostasis. On the other hand, deregulation of PKM2 expression and its resultant awry metabolic pathways have been shown to associate with several pathologies (Fig. 4). The recent burst of studies in the field of cancer metabolism affirms the pivotal role of PKM2 in tumor. During the process of differentiation, PKM2 is replaced by PKM1 or other PK isoform depending upon the differentiated cell type. Remarkably, however, cancer cells revert to PKM2 expression owing to their reliance on this multifaceted enzyme which benefits cancer. The metabolic and non-metabolic support that PKM2 status provides to cancer reiterates the therapeutic value of this enzyme. In addition, the deregulation of PKM2 has also been reported in association with several pathologies, e.g., coronary artery disease, inflammatory bowel disease, myotonic dystrophy, etc., providing a wide scope in designing the therapeutic strategies based on targeting of PKM2 in cancer and treating individuals with the discussed pathologies.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Gopinath Prakasam
    • 1
  • Mohammad Askandar Iqbal
    • 1
    • 2
  • Vibhor Gupta
    • 1
  • Bhupender Kumar
    • 1
  • Rameshwar N. K. Bamezai
    • 1
  1. 1.National Center for Applied Human Genetics, School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
  2. 2.Department of Biotechnology, Faculty of Natural SciencesJamia Millia IslamiaNew DelhiIndia