Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland.
Wiley Interdiscip Rev Syst Biol Med. 2019 Mar;11(2):e1437. doi: 10.1002/wsbm.1437. Epub 2018 Sep 26.
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.
受体酪氨酸激酶（RTKs）是细胞膜蛋白，使细胞能够感知其环境中的蛋白质。许多 RTKs 对发育和器官生长至关重要。RTKs 的失调——通过突变或过度表达——是几种发育和成人疾病（包括癌症、身材矮小和血管病理学）的核心。RTKs 的作用机制复杂，受上下文成分的调节，包括许多家族中存在多种竞争配体和受体、RTK 的细胞内位置、其他 RTKs 的动态和细胞特异性共表达以及下游信号通路的共性。这意味着细胞的状态和细胞外的微环境都起着作用，这是有意义的，因为 RTKs 作为连接细胞外环境与细胞内信号转导和细胞行为改变的枢纽，处于关键位置。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成分，其中计算建模和实验“组学”方法都被用于更好地理解 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理解病理学机制和设计针对 RTKs 的治疗方法是必要的。特别是，我们详细描述了三个具体的例子（涉及 ErbB3、VEGFR2 和 AXL），说明了系统方法如何揭示关键的机制和治疗见解。本文属于以下类别： 生物机制 > 细胞信号 系统特性和过程的模型 > 机制模型 转化、基因组和系统医学 > 治疗方法。
