Context-dependent regulation of receptor tyrosine kinases: Insights from systems biology approaches.

IF 7.9 Q1 Medicine Wiley Interdisciplinary Reviews-Systems Biology and Medicine Pub Date : 2019-03-01 Epub Date: 2018-09-26 DOI:10.1002/wsbm.1437
Inez Lam, Christina M Pickering, Feilim Mac Gabhann
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引用次数: 3

Abstract

Receptor tyrosine kinases (RTKs) are cell membrane proteins that provide cells with the ability to sense proteins in their environments. Many RTKs are essential to development and organ growth. Derangement of RTKs-by mutation or by overexpression-is central to several developmental and adult disorders including cancer, short stature, and vascular pathologies. The mechanism of action of RTKs is complex and is regulated by contextual components, including the existence of multiple competing ligands and receptors in many families, the intracellular location of the RTK, the dynamic and cell-specific coexpression of other RTKs, and the commonality of downstream signaling pathways. This means that both the state of the cell and the microenvironment outside the cell play a role, which makes sense given the pivotal location of RTKs as the nexus linking the extracellular milieu to intracellular signaling and modification of cell behavior. In this review, we describe these different contextual components through the lens of systems biology, in which both computational modeling and experimental "omics" approaches have been used to better understand RTK networks. The complexity of these networks is such that using these systems biology approaches is necessary to get a handle on the mechanisms of pathology and the design of therapeutics targeting RTKs. In particular, we describe in detail three concrete examples (involving ErbB3, VEGFR2, and AXL) that illustrate how systems approaches can reveal key mechanistic and therapeutic insights. This article is categorized under: Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models Translational, Genomic, and Systems Medicine > Therapeutic Methods.

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受体酪氨酸激酶的上下文依赖性调控:来自系统生物学方法的见解。
受体酪氨酸激酶(RTKs)是一种细胞膜蛋白,为细胞提供在其环境中感知蛋白质的能力。许多RTK对发育和器官生长至关重要。RTKs突变或过度表达导致的紊乱是多种发育和成人疾病的核心,包括癌症、身材矮小和血管病变。RTK的作用机制是复杂的,受上下文成分的调节,包括许多家族中存在多种竞争性配体和受体,RTK的细胞内位置,其他RTK的动态和细胞特异性共表达,以及下游信号通路的共同性。这意味着细胞的状态和细胞外的微环境都发挥着作用,考虑到RTK的关键位置,这是有意义的,因为RTK是连接细胞外环境与细胞内信号传导和细胞行为修饰的纽带。在这篇综述中,我们通过系统生物学的视角描述了这些不同的上下文组件,其中计算建模和实验“组学”方法都被用来更好地理解RTK网络。这些网络的复杂性使得使用这些系统生物学方法对于掌握病理机制和针对RTK的治疗方法的设计是必要的。特别是,我们详细描述了三个具体的例子(涉及ErbB3、VEGFR2和AXL),这些例子说明了系统方法如何揭示关键的机制和治疗见解。本文分类如下:生物学机制>系统特性和过程的细胞信号模型>机制模型转化、基因组和系统医学>治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
18.40
自引率
0.00%
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0
审稿时长
>12 weeks
期刊介绍: Journal Name:Wiley Interdisciplinary Reviews-Systems Biology and Medicine Focus: Strong interdisciplinary focus Serves as an encyclopedic reference for systems biology research Conceptual Framework: Systems biology asserts the study of organisms as hierarchical systems or networks Individual biological components interact in complex ways within these systems Article Coverage: Discusses biology, methods, and models Spans systems from a few molecules to whole species Topical Coverage: Developmental Biology Physiology Biological Mechanisms Models of Systems, Properties, and Processes Laboratory Methods and Technologies Translational, Genomic, and Systems Medicine
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