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

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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
The twin roles of receptor tyrosine kinases (RTKs): sensing and signal initiation. Both roles are regulated; sensing by extracellular components; signal initiation by intracellular components; and both by expression of the RTK
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Specific examples of context‐dependent regulation of RTKs. In each case, systems biology approaches played a key role in identifying and quantifying the context for these RTK systems. These examples are described in detail in this review. (a) Insight into the complex interactions and signaling of the multiple ligands and receptors of the ErbB family enables the design of better therapies to target this system. (b) Immobilized VEGF ligand can activate VEGFR but prevents receptor trafficking, leading to differences in phosphorylation and signaling. (c) The AXL receptor responds differently to spatial uniformity and heterogeneity of the GAS6 ligand, which can alter the signaling of other RTKs such as ErbB
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RTK signaling and context‐dependent regulation. (a) Signal propagation and intracellular trafficking of RTKs. Each phosphorylated tyrosine on an RTK can serve as a different site for scaffolding of adaptors and signaling proteins. In cell culture, we can see patterns of multiple tyrosines activated, but currently it is unclear whether that is due to multiple phosphorylation on each receptor molecule or to a mixed population of single‐site‐activated receptors. (b) Summary of the major contextual components that regulate RTKs: ligands, receptors, trafficking, and signaling. Within each category, key considerations that influence the context‐ that is, that might alter the behavior of the RTK network, are listed. The RTKs themselves serve as the mediator between the microenvironment and cell state. (c) Glossary of the ligands, receptors, and signaling proteins mentioned in this review
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Translational, Genomic, and Systems Medicine > Therapeutic Methods
Models of Systems Properties and Processes > Mechanistic Models
Biological Mechanisms > Cell Signaling

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