Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 5032 word(s) 5032 2021-02-10 07:07:56 |
2 format correct -2266 word(s) 2766 2021-02-23 06:44:31 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Bettaieb, A.; Puckett, D. PKM2. Encyclopedia. Available online: https://encyclopedia.pub/entry/7486 (accessed on 29 March 2024).
Bettaieb A, Puckett D. PKM2. Encyclopedia. Available at: https://encyclopedia.pub/entry/7486. Accessed March 29, 2024.
Bettaieb, Ahmed, Dexter Puckett. "PKM2" Encyclopedia, https://encyclopedia.pub/entry/7486 (accessed March 29, 2024).
Bettaieb, A., & Puckett, D. (2021, February 22). PKM2. In Encyclopedia. https://encyclopedia.pub/entry/7486
Bettaieb, Ahmed and Dexter Puckett. "PKM2." Encyclopedia. Web. 22 February, 2021.
PKM2
Edit

The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. 

pyruvate kinases cancer metabolism metabolic reprogramming long non-coding RNAs

1. PKM2 Transcription and Dynamic Regulation

Mammalian pyruvate kinase is expressed as one of four different isoforms (M1, M2, L, and R) encoded by two distinct genes (PKM and PKLR)[1]. These isoforms share similar features, where they catalyze the final step in glycolysis and exhibit the same primary structure containing four major domains: A, B, C, and N[2][3][4][5]. However, the PK isoforms differ in their enzymatic potential, allosteric regulation[6], amino acid sequence, tissue distribution[7][8],  and contribution to health and disease[9][10]. PKM1 and PKM2 are both expressed from the PKM gene and conserved across vertebrates[11]. The amino acid sequence for PKM2 is highly similar between humans and mice at 82% similarity[12]. The PKM gene is located on chromosome 15 in humans and chromosome 9 in mice[13]. The human PKM PKM gene has 12 exons and 11 introns[14]. The two PK transcript isoforms M1 and M2 result from alternative splicing regulated by several spliceosomes including the heterogeneous nuclear ribonucleoprotein A1 and A2 (hnRNPA1 and hnRNPA2) and polypyrimidine tract binding protein (PTB)[15][16]. The inclusion of exon 9 and exclusion of exon 10 produces PKM1, whereas PKM2 includes exon 10 but not exon 9 [14]. Moreover, recent studies have shown that the insertion of exon 10 into the final PKM2 RNA is promoted through the action of the serine/arginine-rich splicing factor 3 (SRSF3)[17]. Both exon 9 and exon 10 are 167 base pairs and 56 amino acids in length[18],and the human PKM1 and PKM2 isoforms are both 531 amino acids long[3]. Consequently, the resulting M1 and the M2 isoforms differ by 22 amino acids located between amino acids 389 and 433 of the C-terminus domain[3]. The other two PK isozymes, PKL and PKR, are encoded by the PKLR gene, which is on chromosome 1 in humans and distinct from the PKM gene[19]. The human PKL and PKR isozymes still share approximately 71–72% amino acid similarity with PKM1 and PKM2, despite being transcribed from different genes[19]. Alternative splicing produces the R isoform, a 574 amino acid long protein that is strictly expressed in erythrocytes, and the L isoform, a 543 amino acid long protein that is highly expressed in the liver[1] and other tissues[20][21].

Even though all PK isoforms perform a similar enzymatic function, these isoforms differ in their kinetic properties and affinity towards phosphoenolpyruvate (PEP), while their affinity potential toward ADP remains comparable[4]. PKM2 exhibits lower enzymatic activity[22] and is the only isoform, to our knowledge, capable of existing in the enzymatically active “R-State” or inactive tetramer “T-State”, dimer, and monomer configurations[23]. This enables PKM2 to substantially alter its dynamics by existing in either the dimeric (high Km for PEP) and tetrameric forms (low Km for PEP)[24] to meet differential metabolic demands. The equilibrium of PKM2 configurations is tightly regulated by allosteric effectors, altering PKM2 kinetics and Km values for PEP[25]. In contrast, PKM1 predominantly exists in an active tetrameric form[26]. Similarly, the unphosphorylated PKL is considered active with higher affinity for PEP (K0.5 = 0.3 mM) in comparison to the phosphorylated form (K0.5 = 0.8 mM)[27]. However, under abnormal conditions, PKR was reported to exist in a mutated form with a tendency to dissociate into dimeric or monomeric configurations with altered Km value compared to unmutated enzyme[28]. Furthermore, PKM2 exhibits lower Vmax compared to to PKM1[23], even though the fructose-1,6-bisphosphate (FBP) binding pockets of M1 and M2 are almost identical. The only reported difference is the presence of a glutamate residue in the M1 isoform instead of lysine in the M2 isoform[29]. Although minor, this difference was demonstrated to play a significant role in blocking the allosteric regulation of FBP in PKM1; however, it does not fully explain the kinetic variation between PKM isoforms.

Notably, the different PK isoforms are expressed in a tissue-specific manner that seems to be dependent upon energy requirements and the availability of nutrients[30]. For instance, PKL plays a role in gluconeogenic organs such as the kidney, liver, and small intestine[31], and can be phosphorylated and inhibited in response to high cellular levels of glucagon and ATP[30]. On the other hand, PKM1 is highly abundant amongst differentiated tissues (heart, brain, muscle, stomach, bone, skin, among others), where energy is produced and used rapidly[30]. PKM2, however, is expressed in the embryonic stages initially and, in most cases, is gradually replaced by other PK isoforms[8]. Notably, it has been revealed that various differentiated tissues continue to express PKM2 across the lifespan[1][32]. PKM2 also differs from other PK isoforms through its ability to translocate to the nucleus and regulate the transcription of numerous genes with key functions in a plethora of cellular processes[33]. Additionally, while other PK isoforms exist in a stable tetrameric configuration, PKM2 may switch between the dimer or tetramer form in response to biological circumstances and metabolic needs[34]. This unique property of PKM2 allows for dynamic metabolic regulation, due in part to the variation in the affinity of the dimer and tetramer configurations of PKM2 to PEP.

2. Impact of PKM2 Mutations on Gene Expression

PKM2 expression, subcellular localization, and activity are regulated by several mechanisms. At the gene level, earlier studies have identified two missense mutations of PKM2 (H391Y and K422R) that could support the aggressive nature of cancer metabolism [35]. The two mutations are both specific to PKM2 but not PKM1 since they are encoded by exon 10 and were discovered in Bloom syndrome cells (H391Y) and a Bloom syndrome patient (K422R)[36].  Iqbal et al. transfected H1299 cells with either mutant or wild-type PKM2 mimicking the missense mutations, H391Y and K422R, and demonstrated that these missense mutations promote cancer proliferation through a variety of proposed metabolic alterations[35]. Cells transfected with the mutant PKM2 exhibited higher glucose uptake and lactate production, concomitant with a reduction in oxidative stress[35].  Moreover, in recent studies by Chen and colleagues, mutations in the exon 10 region of the PKM gene have been proposed to promote the translocation of PKM2 to the nucleus and have been associated with increased activity of the hypoxia-inducible factor 1-alpha (HIF-1α)[37]. HIF-1α is a well-established oxygen sensor in tumor cells and also a modulator of glycolysis and PKM2 expression through direct regulation of the c-Myc/hnRNP splicing axis to favor PKM2 expression[32]. In another study by M.V. Vander Heiden’s group, the authors argued that since PKM2 is not required for the growth of several cancers, as demonstrated by earlier studies, loss-of-function mutations observed in some human tumors are not oncogenic but rather help to create a metabolic state that favors the proliferation of tumor cells[4]. Further efforts towards a comprehensive understanding of the metabolic and physiological consequences of PKM2 mutations as well as their associated clinical outcomes are needed.

As noted above, PKM2 is highly expressed during neonatal stages and phases of proliferation, a fact that may explain the increase in PKM2 expression in tumors given their highly proliferative nature and the associated metabolic requirements. For instance, the oncogenic transcription factor c-Myc enhances the expression of PKM2 through upregulating the expression of  PKM spliceosomes [38]. Similarly, the activation of the rapamycin (RTK/PI3K/AKT/mTOR) signaling pathway in tumor suppressor (Tsc1/2) deficient mouse embryonic fibroblasts (MEF) leads to a cascade of events that upregulates the levels of HIF-1α and, subsequently, increased PKM2 levels. Comparable to c-Myc, mTOR activation can promote tumorigenesis and metabolic transformation[39] and was shown to be integral to oncogenesis, and the transition towards the Warburg effect[32].

A large number of factors have been shown to modulate the quaternary structure and physical configuration of PKM2, thus altering its enzymatic activity and subcellular localization[30][32].  For example, the cis-trans isomerization plays a critical role in mediating the non-enzymatic function of PKM2[40][41][42] through its conversion from a tetramer to a dimer or monomer. Although the tetrameric form is considered the active form and a higher tetramer/dimer ratio results in a higher conversion rate of PEP to pyruvate[1], PKM2 in tumor cells exists predominantly in the dimeric form and has been directly correlated with increased levels of lactate. It is likely that the high levels of dimer PKM2 relate to the “damming up effect” or the accumulation of glycolytic phospho-metabolites[1]. Meanwhile, the cis-trans isomerization of PKM2 and its transition between the tetramer and dimer forms can drastically alter its localization and functions. In tumors, the altered configuration of PKM2 provides cancer cells with the excess amino acids, nucleotides, and phospholipids needed for biosynthetic pathways during proliferation[1]. Notably, post-translational modifications play a key role in regulating the cis-trans isomerization of PKM2 and the associated metabolic consequences. For example, serine phosphorylation of PKM2 at position 37 (Ser-37) by ERK1/2 facilitates the recruitment of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), which mediates PKM2 cis‐trans isomerization[40][42]. This conformational change exposes the nuclear localization signal (NLS) and results in the translocation of PKM2 to the nucleus, a process that requires the binding of PKM2 to importin α5 [40].

In addition to the cis-trans regulation of PKM2, several other factors were demonstrated to alter the quaternary structure and physical configuration of PKM2[1][3], PKM2 subcellular localization, and, subsequently, its functions. For instance, it is well established that phenylalanine acts as an allosteric inhibitor for both PKM1[43] and PKM2[23], thus reducing their affinity to PEP. FBP, on the other hand, is an allosteric regulator that promotes PKM2 tetramerization[44] resulting in PKM2 activation and the subsequent increase in glucose utilization[45]. Unlike PKM2, PKM1 lacks the regulatory effect of FBP due to differences in the orientation of the FBP-activating loop[3], which results in a significant reduction in PKM1’s ability to sense glucose. Accordingly, PKM2 missense mutations could potentially alter glucose uptake in cancer cells[35]. Moreover, SAICAR (succinyl-5′-phosphoribosyl-5-amino-4-imidazole carboxamide) and serine have also been identified as independent stimulants of PKM2 activity[46][47]. SAICAR allosterically stimulates PKM2 in a nutrient-dependent manner[47], while serine acts as an allosteric activator and ligand of PKM2 and both may play a critical role in the metabolic transformation required in oncogenesis[46]. These allosteric regulators could aid cancer cells in the metabolic transformation, allowing them to thrive in an environment limited in nutrients[22].

Moreover, post-translational modifications of PKM2 through oxidation, phosphorylation, and acetylation can also modify its activity, conformation, and localization[22]. Phosphorylation of PKM2 at tyrosine 105 residue (Tyr-105) stabilizes the dimer configuration, leading to inactivation of PKM2’s glycolytic activity[48]. A similar reduction in glycolytic function was also seen in response to PKM2 oxidation at cysteine (Cys)-358, which results in the entrance of glucose into the pentose phosphate pathway[49]. PKM2 is sensitive to oxidation by several oxidants including nitric oxide (NO), endothelial NO synthase (eNOS), and hydrogen peroxide (H2O2), all of which were demonstrated to be capable of regulating PKM2’s activity and its subcellular localization[8]. Notably, the redox regulation of PKM2 was shown to have substantial effects on both cancerous and non-cancerous metabolic outcomes. Therefore, it is imperative to consider redox homeostasis when investigating PKM2, although more research is still needed for a better understanding of the clinical impact of the full scope of oxidants and their regulation of PKM2 in metabolic transformation. It is worth noting, however, that alterations in PKM2 activity through oxidation in tumors facilitate cancer cells’ adaptation to oxidative stress through multiple distinct pathways. Post-translational modifications that reduce PKM2 activity, such as the oxidation of Cys-358[49] and the dessuccinylation of Lys-498[50] residues, increase the accumulation of glycolytic metabolites that promote glucose entrance into the pentose phosphate pathway, which generates reduced equivalents in the form of NADPH to clear excessive oxidant accumulation and maintain cancer cell survival. In addition, recent studies have shown that the PKM2-specific Cys-424 plays a crucial role in its conformational change and the transition between the tetrameric and dimeric forms. Mutation of this residue to leucine resulted in a higher tetramer to dimer ratio and resistance to oxidative stress-induced oxidation and inhibition of PKM2[51].

3. Regulation of PKM2 Subcellular Distribution

The functions of PKM2 and its location within the cells are heavily dependent on its final assembled structure[1]. In the cytosol, PKM2 exhibits both tetrameric and dimeric isoforms and mainly converts PEP to pyruvate and controls a key regulatory step in glycolysis[52]. However, within the nucleus, PKM2 exists in the dimeric form and is involved in the regulation of gene expression [33]. The nuclear translocation of PKM2 is shown to be dependent upon a variety of complex protein–protein interactions. Recently, it has been demonstrated that the phosphorylation of PKM2 at Ser-37 by extracellular signal-regulated kinase 2 (ERK2) could ultimately allow the proper conformational change required for PKM2 translocation into the nucleus[40], a process that requires the binding of PKM2 to importin α5[40].  The nuclear accumulation of PKM2 promotes the phosphorylation of histone H3, which can promote mitotic chromatin condensation[53], and upregulates the transcription of cell-cycle-regulating genes including MYC and CCND1[40].  Additionally, nuclear PKM2 was shown to play a key role in breast cancer cell proliferation and angiogenesis through modulation of epidermal growth factor receptor (EGFR) signaling and its downstream miR-148a and miR-152 genes. Furthermore, evidence suggests a direct interaction between PKM2 and the p65 subunit of nuclear factor kappa light chain enhancer of activated B cells (NF-κB), a well-established factor involved in cancer development and progression[54]. Furthermore, the nuclear translocation of the dimeric form of PKM2 was shown to be responsible for mediating HIF-1α function in the transition towards aerobic glycolysis[55]. According to recent studies, the interaction between PKM2 and HIF-1α leading to the activation of the latter’s transcriptional activity is dependent upon PKM2 hydroxylation at proline residues 403 and 408 by prolyl hydroxylase 3 (PHD3)[56]. Importantly, this interaction between the two proteins underscores the role of PKM2 in several aspects of cancer biology, given the role of HIF-1α in tumor progression, angiogenesis, invasion, metastasis, as well as adaptation to oxidative stress caused by exposure to chemicals and radiation[57][58][59].

In the nucleus, PKM2 was also shown to play a critical role in regulating β-catenin expression and downstream signaling with profound effects on the cell cycle, survival, and proliferation of tumor cells. Increased β-catenin levels have been implemented as a potential contributor to cancer development and proliferation[33][60]. The precise mechanisms by which PKM2 interacts and regulates β-catenin have been described previously[33][61][62] and were suggested to be essential to cancer cell proliferation[33][62]. Yang et al. identified that EGFR-activated ERK phosphorylates PKM2 but not PKM1, promoting PKM2 binding to importin α5 and its subsequent nuclear translocation[40]. Within the nucleus, PKM2-mediated phosphorylation of β-catenin at Y333 results in the subsequent induction of c-Myc[40]. Supportively, in another study, the activation of EGFR signaling resulted in PKM2-dependent β-catenin phosphorylation at Y333 and subsequent upregulation of c-Myc expression[63]. Consistent with these findings, in a more recent study; PKM2 silencing reduced the nuclear accumulation of β-catenin[64]. Likewise, the downregulation of PKM2 expression in Hep3B cells suppressed β-catenin activity and promoted its proteolytic degradation[65]. Conversely, the overexpression of PKM2 negatively modulated β-catenin signaling through a mechanism that was proposed to be dependent on the upregulation of miR-200a[61]. Interestingly, in thyroid cancer (TC) cells, the interaction between PKM2 and β-catenin was recently demonstrated to be dependent upon AMPK activation [66]. In this study, the binding of AMPK to PKM2 promoted β-catenin nuclear translocation and was deemed necessary for the migration of TC cells. Notably, findings from this study suggest that PKM2/β-catenin interaction and perhaps phosphorylation occur in the nucleus as PKM2 deficiency suppressed the nuclear accumulation of β-catenin, but not AMPK. Regardless, when combined, these studies emphasize the importance of the regulatory actions that PKM2 can exert on the β-catenin pathway. Moreover, the evidence shows that the induced nuclear activity and translocation of PKM2 can result in diverse cellular and metabolic outcomes, warranting continued exploration beyond its known cytosolic functions.

Outside the nucleus, PKM2 has been detected within other subcellular fractions including the mitochondria[67][68] and exosomes [69][70]. Under increasing oxidative stress, PKM2 can translocate to the mitochondria, where it can inhibit apoptosis through the phosphorylation and stabilization of BCL2[67]. Likewise, glucose deprivation can lead to PKM2 succinylation and its mitochondrial translocation in HCT116 cells. Subsequently, this translocation resulted in an increase in ATP generation and mitochondrial permeability through inhibiting voltage-dependent anion channel 3 (VDAC3) ubiquitination, promoting cancer cell survival[68]. Recent studies have also identified a novel mechanism through which PKM2 regulates cancer cells’ interaction with their microenvironment through exosome release. Indeed, Wei and colleagues demonstrated that PKM2 could enable the release of exosomes through the phosphorylation of synaptosome-associated protein 23 (SNAP-23) and subsequent formation of the SNARE complex[69]. Exosomes have been shown to play critical roles in tumorigenesis through their role in promoting growth and expansion[71]. Taken together, these findings emphasize the crucial role that PKM2 may exhibit as a key regulator of various aspects of tumorigenesis through its ability to modulate multiple signaling pathways at different subcellular locations.

References

  1. Mazurek, S., Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells. The international journal of biochemistry & cell biology 2011, 43, (7), 969-980.
  2. Valentini, G.; Chiarelli, L. R.; Fortin, R.; Dolzan, M.; Galizzi, A.; Abraham, D. J.; Wang, C.; Bianchi, P.; Zanella, A.; Mattevi, A., Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia. The Journal of biological chemistry 2002, 277, (26), 23807-14.
  3. Dombrauckas, J. D.; Santarsiero, B. D.; Mesecar, A. D., Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry 2005, 44, (27), 9417-29.
  4. Israelsen, W. J.; Vander Heiden, M. G., Pyruvate kinase: Function, regulation and role in cancer. Seminars in cell & developmental biology 2015, 43, 43-51.
  5. Lang, N.; Wang, C.; Zhao, J.; Shi, F.; Wu, T.; Cao, H., Long non‑coding RNA BCYRN1 promotes glycolysis and tumor progression by regulating the miR‑149/PKM2 axis in non‑small‑cell lung cancer. Molecular medicine reports 2020, 21, (3), 1509-1516.
  6. Mattevi, A.; Bolognesi, M.; Valentini, G., The allosteric regulation of pyruvate kinase. FEBS letters 1996, 389, (1), 15-9.
  7. Cardenas, J. M.; Dyson, R. D., Mammalian pyruvate kinase hybrid isozymes: tissue distribution and physiological significance. The Journal of experimental zoology 1978, 204, (3), 361-7.
  8. Alquraishi, M.; Puckett, D. L.; Alani, D. S.; Humidat, A. S.; Frankel, V. D.; Donohoe, D. R.; Whelan, J.; Bettaieb, A., Pyruvate kinase M2: A simple molecule with complex functions. Free radical biology & medicine 2019, 143, 176-192.
  9. Zahra, K.; Dey, T.; Ashish; Mishra, S. P.; Pandey, U., Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis. Front Oncol 2020, 10, 159.
  10. Secrest, M. H.; Storm, M.; Carrington, C.; Casso, D.; Gilroy, K.; Pladson, L.; Boscoe, A. N., Prevalence of Pyruvate Kinase Deficiency: A Systematic Literature Review. European journal of haematology 2020.
  11. Noguchi, T.; Inoue, H.; Tanaka, T., The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. The Journal of biological chemistry 1986, 261, (29), 13807-12.
  12. Izumi, S.; Manabe, A.; Tomoyasu, A.; Kihara-Negishi, F.; Ariga, H., Molecular cloning of the complementary DNA for the mouse pyruvate kinase M-2 gene whose expression is dependent upon cell differentiation. Biochimica et biophysica acta 1995, 1267, (2-3), 135-8.
  13. van Heyningen, V.; Bobrow, M.; Bodmer, W. F.; Gardiner, S. E.; Povey, S.; Hopkinson, D. A., Chromosome assignment of some human enzyme loci: mitochondrial malate dehydrogenase to 7, mannosephosphate isomerase and pyruvate kinase to 15 and probably, esterase D to 13. Ann Hum Genet 1975, 38, (3), 295-303.
  14. Takenaka, M.; Noguchi, T.; Sadahiro, S.; Hirai, H.; Yamada, K.; Matsuda, T.; Imai, E.; Tanaka, T., Isolation and characterization of the human pyruvate kinase M gene. European Journal of Biochemistry 1991, 198, (1), 101-106.
  15. Clower, C. V.; Chatterjee, D.; Wang, Z.; Cantley, L. C.; Vander Heiden, M. G.; Krainer, A. R., The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proceedings of the National Academy of Sciences of the United States of America 2010, 107, (5), 1894-9.
  16. David, C. J.; Chen, M.; Assanah, M.; Canoll, P.; Manley, J. L., HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 2010, 463, (7279), 364-8.
  17. Wang, Z.; Chatterjee, D.; Jeon, H. Y.; Akerman, M.; Vander Heiden, M. G.; Cantley, L. C.; Krainer, A. R., Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons. Journal of Molecular Cell Biology 2012, 4, (2), 79-87.
  18. Zhang, Z.; Deng, X.; Liu, Y.; Liu, Y.; Sun, L.; Chen, F., PKM2, function and expression and regulation. Cell Biosci 2019, 9, 52.
  19. Tani, K.; Fujii, H.; Tsutsumi, H.; Sukegawa, J.; Toyoshima, K.; Yoshida, M. C.; Noguchi, T.; Tanaka, T.; Miwa, S., Human liver type pyruvate kinase: cDNA cloning and chromosomal assignment. Biochemical and biophysical research communications 1987, 143, (2), 431-8.
  20. Imamura, K.; Tanaka, T., Multimolecular forms of pyruvate kinase from rat and other mammalian tissues. I. Electrophoretic studies. Journal of biochemistry 1972, 71, (6), 1043-51.
  21. Consortium, T. U., UniProt: a worldwide hub of protein knowledge. Nucleic acids research 2018, 47, (D1), D506-D515.
  22. Dong, G.; Mao, Q.; Xia, W.; Xu, Y.; Wang, J.; Xu, L.; Jiang, F., PKM2 and cancer: The function of PKM2 beyond glycolysis. Oncology letters 2016, 11, (3), 1980-1986.
  23. Morgan, H. P.; O'Reilly, F. J.; Wear, M. A.; O'Neill, J. R.; Fothergill-Gilmore, L. A.; Hupp, T.; Walkinshaw, M. D., M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 2013, 110, (15), 5881-6.
  24. Wu, S.; Le, H., Dual roles of PKM2 in cancer metabolism. Acta biochimica et biophysica Sinica 2013, 45, (1), 27-35.
  25. Macpherson, J. A.; Theisen, A.; Masino, L.; Fets, L.; Driscoll, P. C.; Encheva, V.; Snijders, A. P.; Martin, S. R.; Kleinjung, J.; Barran, P. E.; Fraternali, F.; Anastasiou, D., Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation. eLife 2019, 8.
  26. Morita, M.; Sato, T.; Nomura, M.; Sakamoto, Y.; Inoue, Y.; Tanaka, R.; Ito, S.; Kurosawa, K.; Yamaguchi, K.; Sugiura, Y.; Takizaki, H.; Yamashita, Y.; Katakura, R.; Sato, I.; Kawai, M.; Okada, Y.; Watanabe, H.; Kondoh, G.; Matsumoto, S.; Kishimoto, A.; Obata, M.; Matsumoto, M.; Fukuhara, T.; Motohashi, H.; Suematsu, M.; Komatsu, M.; Nakayama, K. I.; Watanabe, T.; Soga, T.; Shima, H.; Maemondo, M.; Tanuma, N., PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth. Cancer cell 2018, 33, (3), 355-367.e7.
  27. Ekman, P.; Dahlqvist, U.; Humble, E.; Engström, L., Comparative kinetic studies on the L-type pyruvate kinase from rat liver and the enzyme phosphorylated by cyclic 3', 5'-AMP-stimulated protein kinase. Biochimica et biophysica acta 1976, 429, (2), 374-82.
  28. Adachi, K.; Ghory, P. K.; Asakura, T.; Schwartz, E., A monomeric form of pyruvate kinase in human pyruvate kinase deficiency. Proceedings of the National Academy of Sciences of the United States of America 1977, 74, (2), 501-4.
  29. Ikeda, Y.; Taniguchi, N.; Noguchi, T., Dominant negative role of the glutamic acid residue conserved in the pyruvate kinase M(1) isozyme in the heterotropic allosteric effect involving fructose-1,6-bisphosphate. The Journal of biological chemistry 2000, 275, (13), 9150-6.
  30. Yamada, K.; Noguchi, T., Nutrient and hormonal regulation of pyruvate kinase gene expression. Biochemical Journal 1999, 337, (Pt 1), 1-11.
  31. Brinck, U.; Fischer, G.; Eigenbrodt, E.; Oehmke, M.; Mazurek, S., L- and M2- pyruvate kinase expression in renal cell carcinomas and their metastases. Virchows Archiv 1994, 424, (2), 177-185.
  32. Sun, Q.; Chen, X.; Ma, J.; Peng, H.; Wang, F.; Zha, X.; Wang, Y.; Jing, Y.; Yang, H.; Chen, R.; Chang, L.; Zhang, Y.; Goto, J.; Onda, H.; Chen, T.; Wang, M.-R.; Lu, Y.; You, H.; Kwiatkowski, D.; Zhang, H., Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proceedings of the National Academy of Sciences of the United States of America 2011, 108, (10), 4129-4134.
  33. Gao, X.; Wang, H.; Yang, Jenny J.; Liu, X.; Liu, Z.-R., Pyruvate Kinase M2 Regulates Gene Transcription by Acting as a Protein Kinase. Molecular cell 2012, 45, (5), 598-609.
  34. Mazurek, S.; Boschek, C. B.; Hugo, F.; Eigenbrodt, E., Pyruvate kinase type M2 and its role in tumor growth and spreading. Seminars in cancer biology 2005, 15, (4), 300-8.
  35. Iqbal, M. A.; Siddiqui, F. A.; Chaman, N.; Gupta, V.; Kumar, B.; Gopinath, P.; Bamezai, R. N., Missense mutations in pyruvate kinase M2 promote cancer metabolism, oxidative endurance, anchorage independence, and tumor growth in a dominant negative manner. The Journal of biological chemistry 2014, 289, (12), 8098-105.
  36. Anitha, M.; Kaur, G.; Baquer, N. Z.; Bamezai, R., Dominant negative effect of novel mutations in pyruvate kinase-M2. DNA and cell biology 2004, 23, (7), 442-9.
  37. Chen, T. J.; Wang, H. J.; Liu, J. S.; Cheng, H. H.; Hsu, S. C.; Wu, M. C.; Lu, C. H.; Wu, Y. F.; Wu, J. W.; Liu, Y. Y.; Kung, H. J.; Wang, W. C., Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation. Commun Biol 2019, 2, 105.
  38. Charles, J. D.; Mo, C.; Marcela, A.; Peter, C.; James, L. M., HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 2009, 463, (7279), 364.
  39. Magaway, C.; Kim, E.; Jacinto, E., Targeting mTOR and Metabolism in Cancer: Lessons and Innovations. Cells 2019, 8, (12).
  40. Yang, W.; Zheng, Y.; Xia, Y.; Ji, H.; Chen, X.; Guo, F.; Lyssiotis, C. A.; Aldape, K.; Cantley, L. C.; Lu, Z., ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nature cell biology 2012, 14, (12), 1295-304.
  41. Yang, W.; Lu, Z., Regulation and function of pyruvate kinase M2 in cancer. Cancer letters 2013, 339, (2), 153-8.
  42. Lu, Z.; Hunter, T., Prolyl isomerase Pin1 in cancer. Cell research 2014, 24, (9), 1033-49.
  43. Williams, R.; Holyoak, T.; McDonald, G.; Gui, C.; Fenton, A. W., Differentiating a ligand's chemical requirements for allosteric interactions from those for protein binding. Phenylalanine inhibition of pyruvate kinase. Biochemistry 2006, 45, (17), 5421-9.
  44. Christofk, H. R.; Vander Heiden, M. G.; Harris, M. H.; Ramanathan, A.; Gerszten, R. E.; Wei, R.; Fleming, M. D.; Schreiber, S. L.; Cantley, L. C., The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 2008, 452, (7184), 230-3.
  45. Allen, A. E.; Locasale, J. W., Glucose Metabolism in Cancer: The Saga of Pyruvate Kinase Continues. Cancer cell 2018, 33, (3), 337-339.
  46. Chaneton, B.; Hillmann, P.; Zheng, L.; Martin, A. C. L.; Maddocks, O. D. K.; Chokkathukalam, A.; Coyle, J. E.; Jankevics, A.; Holding, F. P.; Vousden, K. H.; Frezza, C.; O'Reilly, M.; Gottlieb, E., Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 2012, 491, (7424), 458-462.
  47. Keller, K. E.; Tan, I. S.; Lee, Y. S., SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions. Science (New York, N.Y 2012, 338, (6110), 1069-72.
  48. Luo, W.; Semenza, G. L., Emerging roles of PKM2 in cell metabolism and cancer progression. Trends in Endocrinology & Metabolism 2012, 23, (11), 560-566.
  49. Anastasiou, D.; Poulogiannis, G.; Asara, J. M.; Boxer, M. B.; Jiang, J. K.; Shen, M.; Bellinger, G.; Sasaki, A. T.; Locasale, J. W.; Auld, D. S.; Thomas, C. J.; Vander Heiden, M. G.; Cantley, L. C., Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science (New York, N.Y 2011, 334, (6060), 1278-83.
  50. Xiangyun, Y.; Xiaomin, N.; Linping, G.; Yunhua, X.; Ziming, L.; Yongfeng, Y.; Zhiwei, C.; Shun, L., Desuccinylation of pyruvate kinase M2 by SIRT5 contributes to antioxidant response and tumor growth. Oncotarget 2017, 8, (4), 6984-6993.
  51. Masaki, S.; Hashimoto, K.; Kihara, D.; Tsuzuki, C.; Kataoka, N.; Suzuki, K., The cysteine residue at 424th of pyruvate kinase M2 is crucial for tetramerization and responsiveness to oxidative stress. Biochemical and biophysical research communications 2020, 526, (4), 973-977.
  52. Wong, N.; De Melo, J.; Tang, D., PKM2, a Central Point of Regulation in Cancer Metabolism. International Journal of Cell Biology 2013, 2013, 242513.
  53. Sawicka, A.; Seiser, C., Histone H3 phosphorylation - a versatile chromatin modification for different occasions. Biochimie 2012, 94, (11), 2193-2201.
  54. Xu, Q.; Liu, L. Z.; Yin, Y.; He, J.; Li, Q.; Qian, X.; You, Y.; Lu, Z.; Peiper, S. C.; Shu, Y.; Jiang, B. H., Regulatory circuit of PKM2/NF-kappaB/miR-148a/152-modulated tumor angiogenesis and cancer progression. Oncogene 2015, 34, (43), 5482-93.
  55. Semenza, G. L., Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 2009, 29, (5), 625.
  56. Luo, W.; Hu, H.; Chang, R.; Zhong, J.; Knabel, M.; O'Meally, R.; Cole, R. N.; Pandey, A.; Semenza, G. L., Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 2011, 145, (5), 732-44.
  57. Masoud, G. N.; Li, W., HIF-1alpha pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 2015, 5, (5), 378-89.
  58. Speer, R. E.; Karuppagounder, S. S.; Basso, M.; Sleiman, S. F.; Kumar, A.; Brand, D.; Smirnova, N.; Gazaryan, I.; Khim, S. J.; Ratan, R. R., Hypoxia-inducible factor prolyl hydroxylases as targets for neuroprotection by "antioxidant" metal chelators: From ferroptosis to stroke. Free radical biology & medicine 2013, 62, 26-36.
  59. Ziello, J. E.; Jovin, I. S.; Huang, Y., Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med 2007, 80, (2), 51-60.
  60. Lu, Z.; Hunter, T., Wnt-independent beta-catenin transactivation in tumor development. Cell cycle (Georgetown, Tex.) 2004, 3, (5), 571.
  61. Wu, H.; Li, Z.; Yang, P.; Zhang, L.; Fan, Y.; Li, Z., PKM2 depletion induces the compensation of glutaminolysis through [beta]-catenin/c-Myc pathway in tumor cells. Cellular signalling 2014, 26, (11), 2397.
  62. Yang, W.; Xia, Y.; Ji, H.; Zheng, Y.; Liang, J.; Huang, W.; Gao, X.; Aldape, K.; Lu, Z., Nuclear PKM2 regulates [beta]-catenin transactivation upon EGFR activation.(RESEARCH: LETTER)(epidermal growth factor receptor)(Report). Nature 2011, 480, (7375), 118.
  63. Yang, W.; Xia, Y.; Ji, H.; Zheng, Y.; Liang, J.; Huang, W.; Gao, X.; Aldape, K.; Lu, Z., Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 2011, 480, (7375), 118-22.
  64. Liu, M.; Zhang, Z.; Wang, H.; Chen, X.; Jin, C., Activation of AMPK by metformin promotes renal cancer cell proliferation under glucose deprivation through its interaction with PKM2. International journal of biological sciences 2019, 15, (3), 617-627.
  65. Zheng, Q.; Lin, Z.; Xu, J.; Lu, Y.; Meng, Q.; Wang, C.; Yang, Y.; Xin, X.; Li, X.; Pu, H.; Gui, X.; Li, T.; Xiong, W.; Lu, D., Long noncoding RNA MEG3 suppresses liver cancer cells growth through inhibiting beta-catenin by activating PKM2 and inactivating PTEN. Cell death & disease 2018, 9, (3), 253.
  66. Chen, J.; Zhou, Q.; Feng, J.; Zheng, W.; Du, J.; Meng, X.; Wang, Y.; Wang, J., Activation of AMPK promotes thyroid cancer cell migration through its interaction with PKM2 and beta-catenin. Life sciences 2019, 239, 116877.
  67. Ji, L.; Ruixiu, C.; Xiongjun, W.; Yajuan, Z.; Pan, W.; Hong, G.; Chen, L.; Fan, Y.; Rong, Z.; Ping, W.; Dawei, L.; Wenfeng, L.; Weiwei, Y., Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2. Cell research 2016, 27, (3).
  68. Qi, H.; Ning, X.; Yu, C.; Ji, X.; Jin, Y.; McNutt, M. A.; Yin, Y., Succinylation-dependent mitochondrial translocation of PKM2 promotes cell survival in response to nutritional stress. Cell death & disease 2019, 10, (3), 170-170.
  69. Wei, Y.; Wang, D.; Jin, F.; Bian, Z.; Li, L.; Liang, H.; Li, M.; Shi, L.; Pan, C.; Zhu, D.; Chen, X.; Hu, G.; Liu, Y.; Zhang, C.-Y.; Zen, K., Pyruvate kinase type M2 promotes tumour cell exosome release via phosphorylating synaptosome-associated protein 23. Nature communications 2017, 8, (1), 14041.
  70. Hsu, M.-C.; Hung, W.-C., Pyruvate kinase M2 fuels multiple aspects of cancer cells: from cellular metabolism, transcriptional regulation to extracellular signaling. Molecular Cancer 2018, 17, (1), 35.
  71. Martins, V. R.; Dias, M. S.; Hainaut, P., Tumor-cell-derived microvesicles as carriers of molecular information in cancer. Current opinion in oncology 2013, 25, (1), 66-75.
More
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : ,
View Times: 757
Revisions: 2 times (View History)
Update Date: 23 Feb 2021
1000/1000