title: Inflammation-Induced CCR7 Oligomers Form Scaffolds to Integrate Distinct Signaling Pathways for Efficient Cell Migration.
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.
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, 8280 Kreuzlingen, Switzerland.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hauser
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, 8280 Kreuzlingen, Switzerland.
authors.forename: Karin
authors.initials: K
authors.lastname: Schaeuble
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, 8280 Kreuzlingen, Switzerland.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kindinger
authors.affiliation: Department of Immunology, University Hospital Zurich, University of Zurich, 8044 Zurich, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Impellizzieri
authors.affiliation: Klinikum Konstanz, 78464 Konstanz, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Krueger
authors.affiliation: Chair of Cell Biology, University of Konstanz, 78464 Konstanz, Germany.
authors.forename: Christof R
authors.initials: CR
authors.lastname: Hauck
authors.affiliation: Department of Immunology, University Hospital Zurich, University of Zurich, 8044 Zurich, Switzerland.
authors.forename: Onur
authors.initials: O
authors.lastname: Boyman
authors.affiliation: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, 8280 Kreuzlingen, Switzerland. Electronic address: daniel.legler@bitg.ch.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Legler
mesh_terms: D002633:Chemotaxis / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D060888:Real-Time Polymerase Chain Reaction; D054400:Receptors, CCR7 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: C515370:CCR7 protein, human; D054400:Receptors, CCR7