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

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. [Display omitted] •Human DCs possess endomembranal CCR7 and orient the TGN toward the cell front•The endomembrane CCR7 pool is formed by de novo synthesis and receptor trafficking•Chemokines initiate a signaling complex including CCR7, Vav1, and Rac1 at the TGN•β-arrestin and Src are required to drive the endomembranal CCR7 signaling complex Laufer et al. identify a role for an endomembrane pool of the chemokine receptor CCR7 in dendritic cells. They demonstrate that chemokine triggering at the cell surface initiates the formation of an endomembrane signaling complex comprising CCR7, Vav1, and Rac1. They found that endomembranal Rac1 activation results in lamellipodia formation.