Quantitative proteomics reveals reduction of endocytic machinery components in gliomas
Quantitative proteomics reveals reduction of endocytic machinery components in gliomas
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DOI：
10.1016/j.ebiom.2019.07.039
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发表时间：
2019-08-01
期刊：
影响因子：
11.1
通讯作者：
Hutter, Gregor
中科院分区：
文献类型：
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作者：
Buser, Dominik P.;Ritz, Marie-Francoise;Hutter, Gregor
背景：脑胶质瘤是中枢神经系统最常见、最具侵袭性的恶性肿瘤。几十年的分子分析表明，神经胶质瘤积累的遗传变异，最终在受体酪氨酸激酶和下游介质的活性增强。虽然基因的改变，如基因扩增或丢失，已被很好地表征，存在的信息很少的变化，在不同级别的胶质瘤的蛋白质组。方法：我们进行了无偏见的定量蛋白质组学的人脑胶质瘤活检的质谱，然后由bioinformatic analysis.Findings：各种途径被发现是上调或下调。特别是，内吞作为途径受到大量的和伴随的减少参与启动，形成和切割的内吞载体的多个机械组件。网格蛋白依赖性和非依赖性的内吞作用都发生了变化，因为不仅网格蛋白、AP-2适配蛋白和内亲蛋白下调，而且两种途径共享的发动蛋白也下调。内吞机制组件的减少引起受体细胞表面水平的增加，这是内吞缺陷的突出表型。额外的活检分析表明，内吞机械组件的耗尽是一个共同的特点，各种胶质瘤等级和subclass.Interpretation：我们建议，受损的内吞作用产生一个选择性的优势，由于从细胞表面的受体酪氨酸激酶信号在胶质瘤肿瘤进展。
Background: Gliomas are the most frequent and aggressive malignancies of the central nervous system. Decades of molecular analyses have demonstrated that gliomas accumulate genetic alterations that culminate in enhanced activity of receptor tyrosine kinases and downstream mediators. While the genetic alterations, like gene amplification or loss, have been well characterized, little information exists about changes in the proteome of gliomas of different grades.Methods: We performed unbiased quantitative proteomics of human glioma biopsies by mass spectrometry followed by bioinformatic analysis.Findings: Various pathways were found to be up- or downregulated. In particular, endocytosis as pathway was affected by a vast and concomitant reduction of multiple machinery components involved in initiation, formation, and scission of endocytic carriers. Both clathrin-dependent and -independent endocytosis were changed, since not only clathrin, AP-2 adaptins, and endophilins were downregulated, but also dynamin that is shared by both pathways. The reduction of endocytic machinery components caused increased receptor cell surface levels, a prominent phenotype of defective endocytosis. Analysis of additional biopsies revealed that depletion of endocytic machinery components was a common trait of various glioma grades and subclasses.Interpretation: We propose that impaired endocytosis creates a selective advantage in glioma tumor progression due to prolonged receptor tyrosine kinase signaling from the cell surface.