Protein kinase function of pyruvate kinase M2 and cancer
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Cancer Cell International Open Access
REVIEW
Protein kinase function of pyruvate kinase M2 and cancer Xun Chen1, Shangwu Chen2* and Dongsheng Yu1*
Abstract Pyruvate kinase is a terminal enzyme in the glycolytic pathway, where it catalyzes the conversion of phosphoenolpyruvate to pyruvate and production of ATP via substrate level phosphorylation. PKM2 is one of four isoforms of pyruvate kinase and is widely expressed in many types of tumors and associated with tumorigenesis. In addition to pyruvate kinase activity involving the metabolic pathway, increasing evidence demonstrates that PKM2 exerts a nonmetabolic function in cancers. PKM2 has been shown to be translocated into nucleus, where it serves as a protein kinase to phosphorylate various protein targets and contribute to multiple physiopathological processes. We discuss the nuclear localization of PKM2, its protein kinase function and association with cancers, and regulation of PKM2 activity. Keywords: Pyruvate kinase M2, Protein kinase, Glycolytic pathway, Non-metabolic function, Tumorigenesis Background Glycolysis is an important process of glucose degradation in which a glucose is broken down into two pyruvates. The basic metabolic function of pyruvate kinase (PK) in the glycolytic pathway is to catalyze the final step, in which a phosphate group in phosphoenolpyruvate (PEP) is transferred to ADP, yielding pyruvate and ATP [1]. Pyruvate kinase has four different tissue-specific isozymes in animals, PKL, PKR, PKM1, and PKM2. The L and R isozymes are expressed in the liver (L) and red blood cells (R), whereas PKM2 is expressed in early embryonic cells and other proliferating cells, and PKM1 is expressed in the brain, skeletal muscle, and heart which need high energy [2]. Pyruvate kinase L and R are encoded by the PKLR gene, and PKM1 and PKM2 are *Correspondence: [email protected]; [email protected] 1 Department of Oral and Maxillofacial Surgery, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, 56 Lingyuan West Road, Guangzhou 510055, People’s Republic of China 2 Department of Biochemistry, Guangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, People’s Republic of China
transcribed from the PKM gene via alternative splicing. PKM2 possesses the PKM2-specific exon 10 and lacks the PKM1-specific exon 9. The splicing process is regulated by splicing factors of the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and A2 (hnRNPA2) and polypyrimidine tract binding protein (PTB) [3]. The expression of these splicing factors is induced by transcription factor c-Myc and correlated with PKM2 level in tumors [3]. Pyruvate kinase can be present as a tetrameric or a dimeric form. The tetrameric structure is an active form with high binding affinity to PEP, while the dimeric form is less active with low binding affinity to PEP. The sing
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