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

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 K E Y W O R D S cell signaling, computational model, receptor tyrosine kinase, systems biology 1 | INTRODUCTION 1.1 | Receptor tyrosine kinases and their mechanisms of actionReceptor tyrosine kinases (RTKs) are key components linking the microenvironment outside of the cell to the signaling networks inside of the cell, and to consequent changes in cell decision-making and behavior (Figure 1). Just as integrins sense extracellular matrix proteins and mechanical strain, and just as cadherins make direct contact between adjacent cells, RTKs *These authors have contributed equally to this study.

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