PKM2, Function and Expression and Regulation Ze Zhang1, Xinyue Deng2, Yuanda Liu3, Yahui Liu1* , Liankun Sun2* and Fangfang Chen4*

Zhang et al. Cell Biosci (2019) 9:52 https://doi.org/10.1186/s13578-019-0317-8 Cell & Bioscience REVIEW Open Access PKM2, function and expression and regulation Ze Zhang1, Xinyue Deng2, Yuanda Liu3, Yahui Liu1* , Liankun Sun2* and Fangfang Chen4* Abstract Pyruvate kinase (PK), as one of the key enzymes for glycolysis, can encode four diferent subtypes from two groups of genes, although the M2 subtype PKM2 is expressed mainly during embryonic development in normal humans, and is closely related to tissue repair and regeneration, with the deepening of research, the role of PKM2 in tumor tissue has received increasing attention. PKM2 can be aggregated into tetrameric and dimeric forms, PKM2 in the dimer state can enter the nuclear to regulate gene expression, the transformation between them can play an important role in tumor cell energy supply, epithelial–mesenchymal transition (EMT), invasion and metastasis and cell proliferation. We will use the switching efect of PKM2 in glucose metabolism as the entry point to expand and enrich the Warburg efect. In addition, PKM2 can also regulate each other with various proteins by phosphorylation, acetylation and other modifcations, mediate the diferent intracellular localization of PKM2 and then exert specifc biological functions. In this paper, we will illustrate each of these points. Keywords: Cancer metabolism, Glycolysis, Pyruvate kinase, Warburg efect Introduction tissues such as brain and liver [5]. Although the PKM2 At the beginning of the twentieth century, German sci- tetramer and dimer are composed of the same mono- entist Warburg discovered that in tumor tissues, even if mer [6], the biological efects between the tetramer and oxygen is sufcient, malignant tumor cells still undergo the dimer are signifcantly diferent [7]. Te tetramer active glucose glycolysis, the metabolic characteristic of mainly plays the role of pyruvate kinase and regulates this aerobic glycolysis is called Warburg efect [1]. And it the glycolysis and the dimer PKM2 in the context of is characterized by high glucose uptake rate, active gly- glucose metabolism can be used as a switch for energy colysis, and decrease of local microenvironment pH [2]. metabolism and material synthesis [8], routing glucose Pyruvate kinase (PK), as one of the key enzymes of gly- metabolism to pyruvate into the tricarboxylic acid cycle, colysis, acts on its substrate phosphoenolpyruvate (PEP) converting to the pentose phosphate pathway, the uronic to form pyruvate [3], and pyruvate kinase (PK) has four acid pathway, and the polyol pathway. In turn, a carbon diferent subtypes: L, R, M1, M2 [4]. PKL isoforms are source and a oxidation–reduction (REDOX) equivalent mainly found in liver, kidney and red blood cells; while are provided for quinochrome ribose anabolism and non- PKR is mainly expressed in red blood cells, biological essential amino acid anabolism [9, 10]. If in the context of activity is not clear; PKM1 is distributed in myocardium, non-glucose metabolism, after the tetramer is converted skeletal muscle and brain tissue; PKM2 is distributed in into a dimer, PKM2 can exist in a variety of diferent intracellular localizations, enter the nuclear to regulate *Correspondence: [email protected]; [email protected]; gene expression, and attaches to the mitochondrial outer [email protected] membrane to maintain mitochondrial function and 1 Department of General Surgery, The First Hospital of Jilin University, localizes to the endoplasmic reticulum to inhibit endo- Changchun 130021, China 2 Department of Pathophysiology, College of Basic Medical Sciences, plasmic reticulum stress [11]. Once again, PKM2 can Jilin University, Changchun 130021, China also be modifed with phosphorylation, acetylation and 4 Department of Gastrointestinal Colorectal and Anal Surgery, other proteins to regulate protein activity and intracellu- China-Japan Union Hospital of Jilin University, Changchun 130021, China Full list of author information is available at the end of the article lar localization. PKM2 can increase or even replace the © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhang et al. Cell Biosci (2019) 9:52 Page 2 of 25 original PK form regardless of the tissue-derived cells. entering the tricarboxylic acid cycle (TCA) is more Terefore, some researchers refer to PKM2 as tumor- likely to come from fatty acid oxidation (FAO), amino specifc PK [12]. acid replenishment and gluconeogenesis pathway etc. [20], and the main purpose of the tricarboxylic acid PKM2 dimer, tetramer and glucose metabolism cycle (TCA) is no longer supplies H + and REDOX Glucose is the main energy supply substance in nor- equivalents to the subsequent electron transport chain, mal tissues, under the condition of sufcient oxygen, but provides tumor cells such as Glutamine, Proline, glucose undergoes biological processes such as gly- Ornithine, Lysine, Methionine and other non-essential colysis, tricarboxylic acid cycle (TCA) and oxidative amino acids which tumor cells biosynthesis required phosphorylation (OXPHOS) to completely decompose for (Fig. 1 the section of amino acid complement) [21, glucose into carbon dioxide and water, and when con- 22]. In this knowledge framework, the tricarboxylic sumes oxygen, the cell itself is supplied with a large acid cycle (TCA) is more similar to the spinning gyro, amount of ATP at the same time [13]. Warburg found which automatically balances the unstable factors, that abnormal glucose metabolism is an important which also reveals why many experimenters simply feature of tumor cells, that is, tumor cells under the inhibit the activity of a key enzyme in the tricarboxylic conditions of oxygen enrichment, but with a less ef- acid cycle (TCA) or remove some important interme- cient aerobic glycolysis, and then proposed the famous diate metabolites, the tumor still survives [23, 24]. Te “Warburg efect”, the tumor supplies energy through a reason is that when this gyro is given an unstable fac- low-efciency ATP production process that uses glu- tor, the tumor cells can regulate other enzyme activi- cose uptake for aerobic glycolysis [14]. Although the ties upstream and downstream of this unstable factor Warburg efect has been practiced for nearly a century, in the tricarboxylic acid cycle (TCA), and through the with the deepening of research on glucose metabolism amino acid replenishment and balance the yield of each in tumor cells, it has been found that although there is intermediate metabolites to reach the next dynamic indeed high consumption of glucose in tumor tissues, equilibrium [25]. Terefore, it is suitable for tumor sur- there is a proportional diference between glucose con- vival. After the glucose metabolism pathway of tumor sumption and ATP supply, the production of ATP is cells turning to a pentose phosphate pathway, a uronic more than the corresponding amount of ATP produced acid pathway, a polyol pathway, etc., also provides a by glucose aerobic glycolysis [15], therefore, after years large amount of REDOX equivalents such as NADPH, of academic debate and continuous improvement of the NADH and FADH2. Many researchers have realized second stage of Warburg efect, the speculation that that glutamine plays a crucial role in REDOX equiva- most scholars can accept at this stage is that tumor cells lent replenishment, and certain researchers have found divide glucose metabolism into three separate parts of that this model can produce a considerable amount of glycolysis, tricarboxylic acid cycle (TCA), and oxida- REDOX equivalents, however, few people are aware tive phosphorylation (OXPHOS) [16], Dr. Warburg of the important role that essential and non-essential only explained the glycolysis part of glucose metabo- amino acids play in participating in REDOX equivalent lism in tumor cells, namely aerobic glycolysis, which replenishment. If only the REDOX equivalent produc- is produced by the efect is currently thought to be the tion is considered to be a simple chemical equation, interception of glucose metabolism rather than the this new REDOX equivalent generation mode can pro- shunt [17], the purpose of which is to switch glucose duce about 70% of the TCA mode, which also reveals metabolites pathway of entering the tricarboxylic acid why the mitochondrial function still exists in the con- cycle, oxidizing the respiratory chain for complete oxi- text of the traditional Warburg efect. Tese REDOX dative decomposition into the pentose phosphate path- equivalents can be combined with fatty acid metabo- way, aldose acid pathway, polyol pathway etc. (Fig. 1 lism, amino acid replenishment, and reducing equiva- the section of glucose metabolism) for the synthesis lents in the tricarboxylic acid cycle to form a REDOX of fve-carbon ribose and non-essential amino acids equivalent pool [26, 27], while providing a carbon [18], after that, provide the biomass needed for prolif- source for tumor cell proliferation, at the same time eration to the tumor cells, although a small amount of

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