Pyruvate Kinase M2 Regulates Gene Transcription by Acting as a Protein Kinase
Open accessAbstract
Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme catalyzing conversion of phosphoenolpyruvate (PEP) to pyruvate by transferring a phosphate from PEP to ADP. We report here that PKM2 localizes to the cell nucleus. The levels of nuclear PKM2 correlate with cell proliferation. PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor. ADP competes with the protein substrate binding, indicating that the substrate may bind to the ADP site of PKM2. Our experiments suggest that PKM2 dimer is an active protein kinase, while the tetramer is an active pyruvate kinase. Expression of a PKM2 mutant that exists as a dimer promotes cell proliferation, indicating that protein kinase activity of PKM2 plays a role in promoting cell proliferation. Our study reveals an important link between metabolism alteration and gene expression during tumor transformation and progression.
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PKM2 can phosphorylate STAT3 at Tyr705, promoting increased STAT3-dependent transcription.
“Of particular interest to immunologists is that PKM2 can phosphorylate signal transducer and activator of transcription 3 (STAT3) at Tyr705, promoting increased STAT3-dependent transcription (63).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [63]
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Cites
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
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. (2008) · Nature · doi:10.1038/nature06734 · Cited by 2,820 · see citing works
Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1
Luo, W., Hu, H., Chang, R., Zhong, J., Knabel, M., O'Meally, R., Cole, R. N., Pandey, A., & Semenza, G. L. (2011) · Cell · doi:10.1016/j.cell.2011.03.054 · Cited by 1,463 · see citing works
Jeffery, C. J. (1999) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(98)01335-8 · Cited by 1,084 · see citing works
Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation
Yang, W., Xia, Y., Ji, H., Zheng, Y., Liang, J., Huang, W., Gao, X., Aldape, K., & Lu, Z. (2011) · Nature · doi:10.1038/nature10598 · Cited by 1,033 · see citing works
Self-citationBrick by brick: metabolism and tumor cell growth
DeBerardinis, R. J., Sayed, N., Ditsworth, D., & Thompson, C. B. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2008.02.003 · Cited by 1,018 · see citing works
Pyruvate kinase M2 is a phosphotyrosine-binding protein
Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M., & Cantley, L. C. (2008) · Nature · doi:10.1038/nature06667 · Cited by 995 · see citing works
Pyruvate kinase type M2 and its role in tumor growth and spreading
Mazurek, S., Boschek, C. B., Hugo, F., & Eigenbrodt, E. (2005) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2005.04.009 · Cited by 812 · see citing works
Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth
Hitosugi, T., Kang, S., Vander Heiden, M. G., Chung, T.-W., Elf, S., Lythgoe, K., Dong, S., Lonial, S., Wang, X., Chen, G. Z., et al. (2009) · Science Signaling · doi:10.1126/scisignal.2000431 · Cited by 784 · see citing works
Gao, S. P., Mark, K. G., Leslie, K., Pao, W., Motoi, N., Gerald, W. L., Travis, W. D., Bornmann, W., Veach, D., Clarkson, B., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31871 · Cited by 666 · see citing works
Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes
Altenberg, B., & Greulich, K. O. (2004) · Genomics · doi:10.1016/j.ygeno.2004.08.010 · Cited by 662 · see citing works
Structural Basis for Tumor Pyruvate Kinase M2 Allosteric Regulation and Catalysis ,
Dombrauckas, J. D., Santarsiero, B. D., & Mesecar, A. D. (2005) · Biochemistry · doi:10.1021/bi0474923 · Cited by 414 · see citing works
Activation of Stat3 in Human Melanoma Promotes Brain Metastasis
Xie, T.-X., Huang, F.-J., Aldape, K. D., Kang, S.-H., Liu, M., Gershenwald, J. E., Xie, K., Sawaya, R., & Huang, S. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2674 · Cited by 393 · see citing works
STAT3 as a central mediator of neoplastic cellular transformation
Frank, D. A. (2006) · Cancer Letters · doi:10.1016/j.canlet.2006.10.017 · Cited by 364 · see citing works
Energy Deregulation: Licensing Tumors to Grow
Garber, K. (2006) · Science · doi:10.1126/science.312.5777.1158 · Cited by 275 · see citing works
Modulation of type M 2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein
Zwerschke, W., Mazurek, S., Massimi, P., Banks, L., EIGENBRODT, E., & Jansen‐Dürr, P. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.4.1291 · Cited by 257 · see citing works
Huang, S. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-2313 · Cited by 249 · see citing works
The structure of cat muscle pyruvate kinase.
Muirhead, H., Clayden, D. A., Barford, D., et al. (1986) · The EMBO Journal · doi:10.1002/j.1460-2075.1986.tb04236.x · Cited by 247 · see citing works
Lee, J., Kim, H., Han, Y., & Kim, J. (2007) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2007.11.009 · Cited by 214 · see citing works
Single-Gene Disorders: What Role Could Moonlighting Enzymes Play?
Sriram, G., Martínez-Agosto, J. A., McCabe, E. R. B., Liao, J. C., & Dipple, K. M. (2005) · The American Journal of Human Genetics · doi:10.1086/430799 · Cited by 213 · see citing works
Bradbury, D. A., Simmons, T. D., Slater, K. J., et al. (2000) · Journal of Immunological Methods · doi:10.1016/s0022-1759(00)00178-2 · Cited by 183 · see citing works
Nuclear Translocation of the Tumor Marker Pyruvate Kinase M2 Induces Programmed Cell Death
Steták, A., Veress, R., Ovádi, J., Csermely, P., Kéri, G., & Ullrich, A. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2870 · Cited by 183 · see citing works
Ashizawa, K., Willingham, M. C., Liang, C. M., & Cheng, S. Y. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)55378-3 · Cited by 172 · see citing works
The function of Stat3 in tumor cells and their microenvironment.
Groner, B., Lucks, P., & Borghouts, C. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.06.005 · Cited by 165 · see citing works
SOX4 Expression in Bladder Carcinoma: Clinical Aspects and In vitro Functional Characterization
Aaboe, M., Birkenkamp‐Demtröder, K., Wiuf, C., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3456 · Cited by 157 · see citing works
Mazurek, S., & EIGENBRODT, E. (2003) · PubMed · Cited by 136 · see citing works
Paradigm shifts in the cell biology of STAT signaling
Sehgal, P. B. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.07.003 · Cited by 130 · see citing works
Signal transducer and activator of transcription 3 (Stat3) in epithelial carcinogenesis
Kim, D. J., Chan, K. S., Sano, S., & DiGiovanni, J. (2007) · Molecular Carcinogenesis · doi:10.1002/mc.20342 · Cited by 113 · see citing works
Regulation of Cell Proliferation by Interleukin-3-induced Nuclear Translocation of Pyruvate Kinase
Hoshino, A., Hirst, J. A., & Fujii, H. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700094200 · Cited by 94 · see citing works
Hacker, H. J. (1998) · Carcinogenesis · doi:10.1093/carcin/19.1.99 · Cited by 81 · see citing works
Schneider, J., Neu, K., Grimm, H., Velcovsky, H. G., Weisse, G., & EIGENBRODT, E. (2002) · PubMed · Cited by 79 · see citing works
The SUMO‐E3 ligase PIAS3 targets pyruvate kinase M2
Spoden, G. A., Morandell, D., Ehehalt, D., Fiedler, M., Jansen‐Dürr, P., Hermann, M., & Zwerschke, W. (2009) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22125 · Cited by 77 · see citing works
Roossien, F. F., Brink, J., & Robillard, G. T. (1983) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(83)90141-1 · Cited by 65 · see citing works
The Stat family of transcription factors have diverse roles in mammary gland development
Watson, C. J. E., & Neoh, K. (2008) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2008.07.021 · Cited by 60 · see citing works
Stat3 upregulates MEK5 expression in human breast cancer cells
Song, H., Jin, X., & Lin, J. (2004) · Oncogene · doi:10.1038/sj.onc.1208026 · Cited by 59 · see citing works
Regulation of pyruvate kinase type M2 by A-Raf: a possible glycolytic stop or go mechanism.
Mazurek, S., Drexler, H. C. A., Troppmair, J., EIGENBRODT, E., & Rapp, U. R. (2007) · PubMed · Cited by 53 · see citing works
Brosnan, M. J., Chen, L., Dyke, T. A. V., et al. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)45293-8 · Cited by 52 · see citing works
Isozymes of pyruvate kinase from human brain, meningiomas, and malignant gliomas.
Veelen, C. W. M. V., Verbiest, H., Vlug, A. M. C., et al. (1978) · PubMed · Cited by 45 · see citing works
Xu, J., Cole, D. C., Chang, C.-P. B., Ayyad, R., Asselin, M., Hao, W., Gibbons, J. J., Jelinsky, S. A., Saraf, K. A., & Park, K. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm701271y · Cited by 43 · see citing works
Interaction between HERC1 and M2‐type pyruvate kinase
García-Gonzalo, F. R., Cruz, C., Muñoz, P., Mazurek, S., EIGENBRODT, E., Ventura, F., Bartrons, R., & Rosa, J. L. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00205-9 · Cited by 42 · see citing works
The dual activity of pyruvate kinase type M2 from chromatin extracts of neoplastic cells
Ignacak, J., & Stachurska, M. (2003) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/s1096-4959(02)00283-x · Cited by 34 · see citing works
Effects of Glucose and Amino Acids on Free ADP in βHC9 Insulin-Secreting Cells
Ronner, P., Naumann, C. M., & Friel, E. (2001) · Diabetes · doi:10.2337/diabetes.50.2.291 · Cited by 32 · see citing works
Estimate of breast cancer risk reduction with weight loss
Schapira, D. V., Kumar, N. B., & Lyman, G. H. (1991) · Cancer · doi:10.1002/1097-0142(19910515)67:10 · Cited by 23 · see citing works
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Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363 · see citing works
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Israelsen, W. J., Dayton, T. L., Davidson, S. M., Fiske, B. P., Hosios, A. M., Bellinger, G., Li, J., Yu, Y., Sasaki, M., Horner, J. W., et al. (2013) · Cell · doi:10.1016/j.cell.2013.09.025 · Cited by 549 · see citing works
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- Authors
- Gao, X., Wang, H., Yang, J. J., Liu, X., & Liu, Z.-R.
- Affiliations
- Georgia State University (US)
- Corresponding author
- Liu, Zhi-Ren
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 45
- Issue
- 5
- Pages
- 598-609
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3299833
- OpenAlex
- W1980121152
- Cited by
- 772
- References
- 42
- Citations by year
- 2026: 37 · 2025: 59 · 2024: 50 · 2023: 50 · 2022: 48 · 2021: 67 · 2020: 66 · 2019: 61 · 2018: 56 · 2017: 38 · 2016: 57 · 2015: 60 · 2014: 57 · 2013: 44 · 2012: 22
- FWCI
- 19.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 539 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Georgia Cancer Coalition
- Georgia State University
- National Cancer Institute (CA118113)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Keywords
- PKM2, protein kinase activity, nuclear localization, MEK5, STAT3 phosphorylation, cell proliferation, glycolysis, protein dimerization, tumor progression, metabolic regulation of gene expression
- MeSH terms
- Binding Sites, Gene Expression Regulation, Humans, Phosphorylation, Pyruvate Kinase, Transcription, Genetic, Cell Line, Tumor, MAP Kinase Kinase 5, Cell Proliferation, STAT3 Transcription Factor
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