Proviral insertion in murine lymphomas 2 (PIM2) oncogene phosphorylates pyruvate kinase M2 (PKM2) and promotes glycolysis in cancer cells.

Abstract

Pyruvate kinase M2 (PKM2) is a key player in the Warburg effect of cancer cells. However, the mechanisms of regulating PKM2 are not fully elucidated. Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis, co-activating HIF-1α and β-catenin, and cell proliferation, while enhancing mitochondrial respiration of cancer cells. These findings demonstrate that PIM2-dependent phosphorylation of PKM2 is critical for regulating the Warburg effect in cancer, highlighting PIM2 as a potential therapeutic target.

• Authors: Zhenhai Yu, Xiaoping Zhao, Liangqian Huang, Teng Zhang, Fajun Yang, Lei Xie, Shaoli Song, Ping Miao, Li Zhao, Xiaoguang Sun, Jianjun Liu, Gang Huang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 49 Pg. 35406-16 (Dec 06 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 24142698 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• PIM2 protein, human
• Proto-Oncogene Proteins
• Recombinant Fusion Proteins
• Threonine
• Pyruvate Kinase
• Protein Serine-Threonine Kinases

Topics

• Cell Line, Tumor
• Glycolysis
• HEK293 Cells
• Hep G2 Cells
• Humans
• Neoplasms (genetics, metabolism)
• Oncogenes
• Phosphorylation
• Protein Binding
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Pyruvate Kinase (chemistry, genetics, metabolism)
• Recombinant Fusion Proteins (genetics, metabolism)
• Threonine (chemistry)
• Two-Hybrid System Techniques
• Virus Integration (genetics)