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Chemokine Receptor CCR7 Triggers an Endomembrane Signaling Complex for Spatial Rac Activation.

  • Laufer JM Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, 8280 Kreuzlingen, Switzerland; Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany.
  • Hauser MA Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, 8280 Kreuzlingen, Switzerland.
  • Kindinger I Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, 8280 Kreuzlingen, Switzerland.
  • Purvanov V Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, 8280 Kreuzlingen, Switzerland.
  • Pauli A Klinikum Konstanz, Mainaustrasse 35, 78464 Konstanz, Germany.
  • Legler DF Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, 8280 Kreuzlingen, Switzerland; Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, Universitätsstrasse 10, 78464 Konstanz, Germany. Electronic address: daniel.legler@bitg.ch.
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  • 2019-10-24
Published in:
  • Cell reports. - 2019
CCR7
Rac1
Src
Vav1
cell migration
chemokine
endomembrane signaling
β-arrestin
Animals
Cell Membrane
Cell Movement
Cells, Cultured
HEK293 Cells
Humans
Mice
Protein Binding
Proto-Oncogene Proteins c-vav
Receptors, CCR7
Signal Transduction
beta-Arrestins
rac1 GTP-Binding Protein
src-Family Kinases
English Chemokine-guided cell migration is pivotal for many immunological and developmental processes. How chemokine receptor signaling persists to guarantee sustained directional migration despite receptor desensitization and internalization remains poorly understood. Here, we uncover a function for an intracellular pool of the chemokine receptor CCR7 present in human dendritic cells and cellular model systems. We find that CCR7 signaling, initiated at the plasma membrane, is translocated by joint trafficking of β-arrestin and Src kinase to endomembrane-residing CCR7. There, Src tyrosine phosphorylates CCR7, required for the recruitment of Vav1 to form an endomembrane-residing multi-protein signaling complex comprising CCR7, the RhoGEF Vav1, and its effector, Rac1. Interfering with vesicular trafficking affects CCR7-driven cell migration, whereas CCR7:Vav1 interaction at endomembranes is essential for local Rac1 recruitment to CCR7. Photoactivation of Rac1 at endomembranes leads to lamellipodia formation at the cell's leading edge, supporting the role of sustained endomembrane signaling in guiding cell migration.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/61565
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