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Immunity. 2016 Jan 19;44(1):59-72. doi: 10.1016/j.immuni.2015.12.010.

Inflammation-Induced CCR7 Oligomers Form Scaffolds to Integrate Distinct Signaling Pathways for Efficient Cell Migration.

Author information

1
Biotechnology Institute Thurgau (BITg) at the University of Konstanz, 8280 Kreuzlingen, Switzerland.
2
Department of Immunology, University Hospital Zurich, University of Zurich, 8044 Zurich, Switzerland.
3
Klinikum Konstanz, 78464 Konstanz, Germany.
4
Chair of Cell Biology, University of Konstanz, 78464 Konstanz, Germany.
5
Biotechnology Institute Thurgau (BITg) at the University of Konstanz, 8280 Kreuzlingen, Switzerland. Electronic address: daniel.legler@bitg.ch.

Abstract

Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and T cell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G protein-coupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways.

PMID:
26789922
DOI:
10.1016/j.immuni.2015.12.010
[Indexed for MEDLINE]
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