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Published on: March 1, 2017
Dissecting Discoidin Domain Receptor 2 Dynamics in Fibrosis with a Programmable Collagen-Mimetic Probe.
Yinghua Liu1, Xufei Wang1, Xiaotong Ma1
1Guangdong Provincial Engineering Research Center of Molecular Imaging, Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, the Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong 519000, China.
Researchers developed a fluorescent probe to track collagen receptor DDR2 activation in real-time, revealing how fibrillar collagen drives fibrotic disease progression. This tool enables precise mapping of active fibrotic niches and disease-driving cells.
Area of Science:
- Biochemistry and Molecular Biology
- Cell Biology
- Biomedical Engineering
Background:
- Collagen receptors are crucial for extracellular matrix signaling, but distinguishing activation from expression in real-time has been challenging.
- Understanding fibrotic progression is hindered by the lack of tools to monitor functional collagen receptor activation.
- Discoidin Domain Receptor 2 (DDR2) is the only receptor tyrosine kinase family that signals collagen, playing a role in fibrosis.
Purpose of the Study:
- To develop a tool for real-time monitoring of functional collagen receptor activation, specifically targeting Discoidin Domain Receptor 2 (DDR2).
- To investigate the activation kinetics of DDR2 and the role of collagen structure in this process.
- To establish a platform for imaging and potentially modulating fibrotic diseases.
Main Methods:
- Development of a fluorescent triple-helical collagen-mimetic peptide (CMP) probe ([GVMGFO]3) targeting the ligand-engaging conformation of DDR2.
- In vivo and ex vivo application of the probe to identify active fibrotic niches and disease-driving fibroblasts in pulmonary fibrosis models.
- Engineering of Zn2+-coordinated supramolecular assemblies of a modified CMP ([H-GVMGFO-H]3) to rapidly activate DDR2.
Main Results:
- The CMP probe successfully identified active fibrotic niches in vivo and mapped activated fibroblasts ex vivo without altering baseline signaling.
- Revealed that fibrillar collagen, unlike monomeric collagen, arrests DDR2 trafficking, promoting sustained receptor clustering and phosphorylation, thus explaining slow activation kinetics.
- Engineered supramolecular CMP assemblies triggered rapid DDR2 activation within minutes, mimicking the effect of fibrillar collagen.
Conclusions:
- The developed CMP probe is a valuable chemical tool for dissecting collagen-receptor dynamics in real-time.
- Fibrillar collagen's physical anchoring is essential for sustained DDR2 activation and plays a critical role in fibrotic progression.
- This work provides a novel platform for imaging and modulating fibrotic diseases by understanding collagen-receptor interplay.
