Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma
Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma
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DOI：
10.1182/blood-2013-01-482026
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发表时间：
2013-08-08
期刊：
影响因子：
20.3
通讯作者：
Lim, Megan S.
中科院分区：
文献类型：
--
作者：
McDonnell, Scott R. P.;Hwang, Steven R.;Lim, Megan S.
表达间变性大细胞淋巴瘤的结构性活性酪氨酸激酶核蛋白间变性淋巴瘤(NPM-ALK)的发病机制尚不完全清楚。在这里，我们展示了使用整合的磷酸蛋白质组和代谢组学策略，NPM-ALK诱导代谢转向有氧糖酵解，增加乳酸产量和生物量生产。代谢转变是通过间变性淋巴瘤激酶(ALK)对肿瘤特异性丙酮酸激酶(PKM2)亚型(PKM2)在Y105处的磷酸化而介导的，导致酶活性降低。在体内异种移植模型中，小分子PKM2的激活或Y105F PKM2突变体的表达导致代谢开关逆转，氧化磷酸化增加，乳酸产生减少，同时细胞死亡增加，克隆形成减少，肿瘤生长减少。这项研究提供了NPM-ALK表达的磷酸化、蛋白质组学和代谢学结果的综合图谱，并揭示了ALK在调节细胞代谢的多种成分中的新作用。我们的研究表明，PKM2是一种新的碱性磷酸酶底物，在调节代谢向生物质生产和肿瘤发生的转变中发挥关键作用。
The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis.