Mitogenic and Oncogenic Stimulation of K433 Acetylation Promotes PKM2 Protein Kinase Activity and Nuclear Localization
Mitogenic and Oncogenic Stimulation of K433 Acetylation Promotes PKM2 Protein Kinase Activity and Nuclear Localization
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K433 乙酰化的促有丝分裂和致癌刺激可促进 PKM2 蛋白激酶活性和核定位。
DOI：
10.1016/j.molcel.2013.09.004
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发表时间：
2013-11-07
期刊：
影响因子：
16
通讯作者：
Xiong, Yue
中科院分区：
文献类型：
--
作者：
Lv, Lei;Xu, Yan-Ping;Xiong, Yue
PKM2基因的选择性剪接产生两种亚型M1和M2，分别在成人和胚胎组织中优先表达。M2亚型在人类癌症中重新表达，在细胞核中作为蛋白激酶具有非代谢功能。在这里，我们报道了PKM2被K433上的p300乙酰转移酶乙酰化，K433是PKM2所特有的，直接与其变构激活剂1，6-二磷酸果糖(FBP)接触。乙酰化通过干扰FBP结合来阻止PKM2的激活，并促进PKM2的核积聚和蛋白激酶活性。拟乙酰化PKM2(K433)突变体促进细胞增殖和肿瘤发生。K433乙酰化水平因血清饥饿和细胞间接触而降低，因细胞周期刺激、表皮生长因子(EGF)和癌蛋白E7而增加，并在乳腺癌中丰富。因此，K433乙酰化将细胞增殖和转化与PKM2从细胞质代谢产物激酶转换为核蛋白激酶联系在一起。
Alternative splicing of the PKM2 gene produces two isoforms, M1 and M2, which are preferentially expressed in adult and embryonic tissues, respectively. The M2 isoform is reexpressed in human cancer and has nonmetabolic functions in the nucleus as a protein kinase. Here, we report that PKM2 is acetylated by p300 acetyltransferase at K433, which is unique to PKM2 and directly contacts its allosteric activator, fructose 1,6-bisphosphate (FBP). Acetylation prevents PKM2 activation by interfering with FBP binding and promotes the nuclear accumulation and protein kinase activity of PKM2. Acetylation-mimetic PKM2(K433) mutant promotes cell proliferation and tumorigenesis. K433 acetylation is decreased by serum starvation and cell-cell contact, increased by cell cycle stimulation, epidermal growth factor (EGF), and oncoprotein E7, and enriched in breast cancers. Hence, K433 acetylation links cell proliferation and transformation to the switch of PKM2 from a cytoplasmic metabolite kinase to a nuclear protein kinase.