An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling
An enzyme that regulates ether lipid signaling pathways in cancer annotated by multidimensional profiling
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DOI：
10.1016/j.chembiol.2006.08.008
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发表时间：
2006-10-01
影响因子：
--
通讯作者：
Cravatt, Benjamin F.
中科院分区：
文献类型：
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作者：
Chiang, Kyle P.;Niessen, Sherry;Cravatt, Benjamin F.
目前，人类蛋白质组中有数百种（如果不是数千种的话）未被表征的酶。将这些蛋白质组装到控制细胞生理学和病理学的代谢和信号通路中构成了一个巨大的实验挑战。在这里，我们解决这个问题，通过使用多维分析策略，结合基于活性的蛋白质组学和代谢组学。这种方法确定了KIAA 1363，一种在侵袭性癌细胞中高度升高的未表征的酶，作为桥接血小板活化因子和溶血磷脂酸的醚脂质信号网络中的中心节点。生物化学研究证实，KIAA 1363通过水解代谢中间体2-乙酰基单烷基甘油来调节该途径。KIAA 1363的失活破坏了癌细胞中的醚脂代谢，并损害了体内细胞迁移和肿瘤生长。本文所述的整合分子谱分析方法应有助于任何生命系统中代谢酶的功能注释。
Hundreds, if not thousands, of uncharacterized enzymes currently populate the human proteome. Assembly of these proteins into the metabolic and signaling pathways that govern cell physiology and pathology constitutes a grand experimental challenge. Here, we address this problem by using a multidimensional profiling strategy that combines activity-based proteomics and metabolomics. This approach determined that KIAA1363, an uncharacterized enzyme highly elevated in aggressive cancer cells, serves as a central node in an ether lipid signaling network that bridges platelet-activating factor and lysophosphatidic acid. Biochemical studies confirmed that KIAA1363 regulates this pathway by hydrolyzing the metabolic intermediate 2-acetyl monoalkylglycerol. Inactivation of KIAA1363 disrupted ether lipid metabolism in cancer cells and impaired cell migration and tumor growth in vivo. The integrated molecular profiling method described herein should facilitate the functional annotation of metabolic enzymes in any living system.