Proviral Insertion in Murine Lymphomas 2 (PIM2) Oncogene Phosphorylates Pyruvate Kinase M2 (PKM2) and Promotes Glycolysis in Cancer Cells
Proviral Insertion in Murine Lymphomas 2 (PIM2) Oncogene Phosphorylates Pyruvate Kinase M2 (PKM2) and Promotes Glycolysis in Cancer Cells
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前病毒插入小鼠淋巴瘤 2 (PIM2) 癌基因磷酸化丙酮酸激酶 M2 (PKM2) 并促进癌细胞中的糖酵解
DOI：
10.1074/jbc.m113.508226
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发表时间：
2013-12-06
影响因子：
4.8
通讯作者：
Huang, Gang
中科院分区：
文献类型：
--
作者：
Yu, Zhenhai;Zhao, Xiaoping;Huang, Gang
丙酮酸激酶M2 （PKM2）在癌细胞的Warburg效应中起关键作用。然而，调控PKM2的机制尚未完全阐明。在这里，我们确定了蛋白-丝氨酸/苏氨酸激酶PIM2，一个已知的致癌基因，作为PKM2的一个新的结合伙伴。在体外和培养细胞中，多种生化方法证实了PIM2和PKM2之间的相互作用。重要的是，我们发现PIM2可以直接磷酸化Thr-454残基上的PKM2，导致PKM2蛋白水平升高。与野生型相比，磷酸化缺陷突变的PKM2对糖酵解、共激活HIF-1和-catenin以及细胞增殖的影响降低，同时增强了癌细胞的线粒体呼吸。这些发现表明，PIM2依赖性的PKM2磷酸化对于调节癌症中的Warburg效应至关重要，强调了PIM2是一个潜在的治疗靶点。
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-1 and -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.