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Context-dependent regulation of receptor tyrosine kinases: Insights from systems biology approaches
Inez Lam1,2, Christina M Pickering1,2, Feilim Mac Gabhann1,2,3,4
1Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
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.
Insights
Receptor tyrosine kinases (RTKs) are crucial for cell communication and development. Systems biology approaches help untangle complex RTK networks to understand diseases and design targeted therapies.
Area of Science:
- Cellular Biology
- Biochemistry
- Systems Biology
Background:
- Receptor tyrosine kinases (RTKs) are cell membrane proteins vital for sensing the cellular environment and regulating development and organ growth.
- Dysregulation of RTKs, through mutation or overexpression, is implicated in various disorders, including cancer, short stature, and vascular diseases.
- RTK function is intricate, influenced by competing ligands, receptor coexpression, intracellular localization, and shared downstream pathways.
Purpose of the Study:
- To review the contextual components regulating RTK activity through a systems biology lens.
- To elucidate how systems biology approaches, including computational modeling and omics, enhance understanding of RTK networks.
- To illustrate the application of systems approaches in revealing mechanistic and therapeutic insights using specific RTK examples.
Main Methods:
- Review of existing literature on RTK function and regulation.
- Application of systems biology principles to analyze RTK networks.
- Detailed examination of three case studies: ErbB3, VEGFR2, and AXL signaling pathways.
- Integration of computational modeling and experimental 'omics' data.
Main Results:
- RTK activity is modulated by a complex interplay of intra- and extracellular factors.
- Systems biology approaches provide a framework for dissecting RTK network complexity.
- Analysis of ErbB3, VEGFR2, and AXL pathways demonstrates the power of systems approaches in identifying therapeutic targets.
Conclusions:
- Understanding RTK networks requires a systems-level perspective due to their complexity.
- Systems biology is essential for deciphering disease mechanisms involving RTKs.
- Targeted therapeutic strategies for RTK-related disorders can be advanced through systems biology insights.
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