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Inflammation-Induced CCR7 Oligomers Form Scaffolds to Integrate Distinct Signaling Pathways for Efficient Cell
Mark A Hauser1, Karin Schaeuble1, Ilona Kindinger1
1Biotechnology Institute Thurgau (BITg) at the University of Konstanz, 8280 Kreuzlingen, Switzerland.
Immunity
|January 21, 2016
Summary
Chemokine receptor CCR7 oligomerization enhances immune cell migration by activating Src kinase signaling. This oligomerization creates signaling hubs for directed cell movement during host defense.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Host defense relies on precise cell migration.
- Chemokines guide cell movement via specific signaling pathways.
Purpose of the Study:
- Investigate the role of chemokine receptor CCR7 oligomerization in cell migration.
- Elucidate the signaling mechanisms underlying CCR7-mediated chemotaxis.
Main Methods:
- Mutagenesis screen to identify CCR7 oligomerization interfaces.
- Analysis of a CCR7 single nucleotide polymorphism (SNP) with super-oligomer characteristics.
- Investigated Src kinase and SHP2 phosphatase involvement in signaling.
Main Results:
- Inflammatory stimuli induce CCR7 oligomerization in dendritic cells and T cells.
- Oligomerization enables both G protein-dependent and Src kinase-dependent signaling.
- A hydrophobic interface near the NPXXY motif is crucial for oligomerization and migration.
- Src kinase phosphorylates oligomeric CCR7, creating docking sites for SH2-domain proteins.
- CCL21-biased signaling involving SHP2 controls efficient cell migration.
Conclusions:
- CCR7 oligomers act as molecular hubs integrating distinct signaling pathways.
- Oligomerization-dependent Src kinase signaling is essential for efficient CCR7-mediated chemotaxis.
- Understanding these pathways offers insights into immune cell trafficking and host defense.
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