文章：

功能蛋白质组学分析癌症中酪氨酸激酶信号通路

Functional proteomics to dissect tyrosine kinase signalling pathways in cancer

原文发布日期：2010-08-19

DOI: 10.1038/nrc2900

类型: Review Article

开放获取: 否

要点：

1. Signalling pathways are commonly deranged in cancer and quantitative proteomics offers powerful approaches to map these pathways and their aberrations in cancer.
2. Hubs in signalling pathways feature multiple protein interactions, which are involved in information processing and specification of the biological responses. These networks can be mapped by interaction proteomics to reveal molecular mechanisms of transformation and potential targets for therapeutic interventions.
3. The oncogenic actions of the epidermal growth factor receptor (EGFR) network and the breakpoint cluster region (BCR)–ABL1 oncogene rely on the dynamic assembly of multiprotein complexes, which activate multiple downstream pathways that cooperate in transformation. In EGFR networks, the oncogenic potential increases with the number of downstream pathways being activated.
4. The dynamic assembly of protein complexes is regulated by post-translational modifications (PTMs) such as phosphorylation. Advances in phosphoproteomics allow the targeted and global mapping of phosphorylation networks, confirming that kinase networks play major parts in cancer and offer numerous new targets for therapeutic intervention.
5. In addition to phosphorylation, a role for PTMs in the regulation of cancer cell biology is becoming increasingly recognized. For example, proteomic studies of ubiquitylation are beginning to unravel extensive alterations that contribute to cancer, such as growth factor receptor activation, transcription factor function, protein localization and degradation.
6. Dynamic changes in protein abundance and PTMs may also contribute to cancer cell heterogeneity, and new proteomics technologies based on optical, spectroscopic and microarray methods are being developed to analyse individual cells.

要点翻译：

1. 信号通路在癌症中通常发生紊乱，定量蛋白质组学为绘制这些通路及其在癌症中的异常提供了强大的方法。
2. 信号通路中的枢纽节点具有多重蛋白质相互作用，这些作用参与信息处理和生物应答的精确调控。通过相互作用蛋白质组学可以绘制这些网络，以揭示转化的分子机制及治疗干预的潜在靶点。
3. 表皮生长因子受体（EGFR）网络的致癌作用和断点簇区域（BCR）-ABL1癌基因依赖于多蛋白复合物的动态组装，这些复合物激活多个下游通路协同促进转化。在EGFR网络中，随着被激活的下游通路数量增加，其致癌潜力也随之增强。
4. 蛋白质复合物的动态组装受翻译后修饰（如磷酸化）的调控。磷酸化蛋白质组学的进展使得我们能够对磷酸化网络进行靶向和全局性绘制，证实了激酶网络在癌症中起主要作用，并为治疗干预提供了大量新靶点。
5. 除磷酸化外，翻译后修饰在调控癌细胞生物学功能中的作用日益受到重视。例如，泛素化的蛋白质组学研究开始揭示导致癌症的广泛改变，包括生长因子受体激活、转录因子功能、蛋白质定位和降解等。
6. 蛋白质丰度和翻译后修饰的动态变化也可能导致癌细胞异质性。目前正在开发基于光学、光谱学和微阵列技术的新型蛋白质组学技术，用于分析单个细胞。

英文摘要：

Advances in the generation and interpretation of proteomics data have spurred a transition from focusing on protein identification to functional analysis. Here we review recent proteomics results that have elucidated new aspects of the roles and regulation of signal transduction pathways in cancer using the epidermal growth factor receptor (EGFR), ERK and breakpoint cluster region (BCR)–ABL1 networks as examples. The emerging theme is to understand cancer signalling as networks of multiprotein machines which process information in a highly dynamic environment that is shaped by changing protein interactions and post-translational modifications (PTMs). Cancerous genetic mutations derange these protein networks in complex ways that are tractable by proteomics.

摘要翻译： 

蛋白质组学数据生成与解读技术的进步，推动研究重心从蛋白质鉴定转向功能分析。本文综述了近期利用表皮生长因子受体（EGFR）、ERK 及 BCR-ABL1 网络为范例、揭示癌症信号转导通路作用与调控新机制的蛋白质组学成果。核心观点认为，癌症信号应被视为由多蛋白机器组成的网络，这些网络在蛋白相互作用和翻译后修饰（PTM）持续变化的高度动态环境中处理信息。致癌突变以复杂方式扰乱这些蛋白网络，而蛋白质组学可有效解析其变化。

原文链接：

Functional proteomics to dissect tyrosine kinase signalling pathways in cancer