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Published on: September 28, 2018
Regulation of receptor tyrosine kinase ligand processing
Colin Adrain1, Matthew Freeman
1MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom.
Abstract:
A primary mode of regulating receptor tyrosine kinase (RTK) signaling is to control access of ligand to its receptor. Many RTK ligands are synthesized as transmembrane proteins. Frequently, the active ligand must be released from the membrane by proteolysis before signaling can occur. Here, we discuss RTK ligand shedding and describe the proteases that catalyze it in flies and mammals. We focus principally on the control of EGF receptor ligand shedding, but also refer to ligands of other RTKs. Two prominent themes emerge. First, control by regulated trafficking and cellular compartmentalization of the proteases and their ligand substrates plays a key role in shedding. Second, many external signals converge on the shedding proteases and their control machinery. Proteases therefore act as regulatory hubs that integrate information that the cell receives and translate it into precise outgoing signals. The activation of signaling by proteases is therefore an essential element of the cellular communication machinery.
Insights
Receptor tyrosine kinase (RTK) ligand shedding, a key step in cell signaling, is regulated by proteases. These proteases integrate external signals, controlling cellular communication.
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- Receptor tyrosine kinase (RTK) signaling is crucial for cellular functions.
- Many RTK ligands are initially membrane-bound and require release for activation.
- Proteolytic shedding is a critical mechanism for RTK ligand release.
Purpose of the Study:
- To discuss the process of RTK ligand shedding.
- To describe the proteases involved in ligand shedding in flies and mammals.
- To highlight the regulatory mechanisms controlling ligand shedding.
Main Methods:
- Review of existing literature on RTK ligand shedding.
- Analysis of proteases involved in shedding across different species.
- Focus on epidermal growth factor (EGF) receptor ligand shedding.
Main Results:
- Regulated trafficking and cellular compartmentalization of proteases and substrates are key to shedding.
- External signals converge on shedding proteases, integrating cellular information.
- Proteases act as regulatory hubs translating external signals into cellular responses.
Conclusions:
- Protease-mediated ligand shedding is an essential component of cellular communication.
- The regulation of shedding integrates diverse signaling pathways.
- Understanding shedding provides insights into RTK signaling control.
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