Abstract
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.
Highlights
Chemokines are pivotal orchestrators of cell migration
We find that CCR7 signaling, initiated at the plasma membrane, is translocated by joint trafficking of b-arrestin and Src kinase to endomembrane-residing CCR7
Leukocytes Possess Distinct Intracellular Pools of CCR7 Continuous CCR7 signaling over the timescale of hours is key for leukocyte motility in chemokine-rich lymph nodes (Forster et al, 2008), while chemokine-triggered CCR7 itself has been shown to be rapidly desensitized (Yoshida et al, 1998; Kohout et al, 2004), internalized (Bardi et al, 2001; Otero et al, 2006), and subsequently recycled back to the plasma membrane to re-participate in chemokine recognition and cell migration (Schaeuble et al, 2012)
Summary
Chemokines are pivotal orchestrators of cell migration. Locally produced chemokines provide essential guidance cues for organogenesis, regeneration, and immune surveillance and for the development of many diseases (Thelen and Stein, 2008). Leukocytes recognize chemokines through cognate chemokine receptors, which belong to the G-protein-coupled receptor (GPCR) superfamily and signal through heterotrimeric G proteins for cell migration (Legler and Thelen, 2018). Other receptors, including CCR7 and CCR5, enter the recycling pathway to be delivered back to the plasma membrane, where they replenish the cell surface with ‘‘fresh,’’ ligand-free receptors that re-participate in chemokine sensing (Mueller and Strange, 2004; Otero et al, 2006, 2008). Both pathways do not explain how chemokines control sustained directional cell migration
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